Kohei Wakatsuki

Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo

Recent basic and clinical studies have shown that the programmed death ligand (PD‐L)/PD‐1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti‐angiogeneic treatment might augment the efficacy of PD‐1 blockade. To this end, we evaluated combining the blockade of PD‐1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon‐26 adenocarcinoma. Interestingly, simultaneous treatment with anti‐PD‐1 and anti‐VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD‐1 blockade had no impact on tumour angiogenesis. PD‐1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up‐regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD‐1 blockade. In conclusion, simultaneous blockade of PD‐1 and VEGFR2 induced a synergistic in‐vivo anti‐tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application.

Clinicopathological and prognostic significance of mucin phenotype in gastric cancer

Gastric and intestinal mucin phenotype cell markers are widely expressed in gastric carcinoma cells, irrespective of their tumor histological type. In the present study, we tried to reveal the clinicopathological significance of mucin phenotype in human gastric carcinomas. Moreover, we investigated the clinical significance of RUNX3 in association with mucin phenotype.

Prognostic importance of tumour-infiltrating memory T cells in oesophageal squamous cell carcinoma

Memory T cells survive for many months and years and are critically important for host defence in humans. In tumour immunity, they have been also suggested to play a significant role in tumour progression and metastasis. However, the role of memory T cells in actual human cancer remains largely unknown. In this study, the clinical importance of tumour‐infiltrating CD45RO+ memory T cells was investigated in human oesophageal squamous cell carcinoma (OSCC). CD45RO+ T cells were evaluated by immunohistochemistry in primary OSCC tumours from 105 patients. Patients were classified into two groups as CD45RO+hi or CD45RO+lo based on the number of cells stained positively for CD45RO. No significant difference was observed between CD45RO status and several clinicopathological prognostic factors. However, the postoperative overall and disease‐free survival for CD45RO+hi patients was significantly better than for CD45RO+lo patients. Furthermore, there were significant correlations of CD45RO status in the primary tumour with postoperative lymph node and pulmonary recurrence, suggesting that memory T cells may control postoperative metastatic recurrence. Most importantly, CD45RO+ memory T cell status has a significant prognostic value for OSCC independently of conventional tumour–node–metastasis (TNM) classification. Our study may provide a rationale for developing a novel immunotherapy in intentional induction of memory T cells for the treatment of oesophageal cancer.

Clinical impact of tumor-infiltrating CD45RO+ memory T cells on human gastric cancer

Memory T cells survive for months and even years and are critical for host defense in humans. They have been recently suggested to play a significant role in tumor immunity. In this study, we aimed to investigate the clinical impact of tumor-infiltrating memory T cells on human gastric cancer. We evaluated CD45RO(+)T cells infiltrating into primary gastric cancer tissues by immunohistochemistry in 101 patients with gastric cancer. Patients were classified into 2 groups (CD45RO(+Hi) and CD45RO(+Lo)) based on the number of positively stained T cells. There was no significant correlation observed between CD45RO status and post-operative prognosis in early gastric cancer. By contrast, in advanced cancer, the post-operative overall and disease-free survival of patients with CD45RO(+Hi) were significantly improved compared to those of patients with CD45RO(+Lo). In addition, CD45RO status in the primary tumors significantly correlated with the development of post-operative recurrence, particularly peritoneal recurrence. Furthermore, the local expression of interferon-γ (IFN-γ) in the CD45RO(+Hi) tumors was significantly higher than that in the CD45RO(+Lo) tumors, suggesting that CD45RO(+) T cells induced local immune activation. Multivariate analysis indicated that the CD45RO(+) status was an independent prognostic factor in advanced gastric cancer. In conclusion, tumor-infiltrating CD45RO(+) memory T cells are functional and have significant prognostic value in human gastric cancer. Our data suggest that adaptive immune response is clinically critical in gastric cancer.

Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma.

Background:The endothelin axis has been shown to have a pivotal role in several human malignancies. The aim of this study was to clarify the clinical importance of endothelin receptor type B (ETBR) in human oesophageal squamous cell carcinoma (OSCC).Methods:We evaluated ETBR expression in 107 patients with OSCC by immunohistochemistry. Microvessel density (MVD) and lymphatic vessel density were assessed by CD31 and D2-40 immunostaining, respectively. Furthermore, CD4, CD8, and CD45RO+ tumour-infiltrating lymphocytes (TILs) were immunohistochemically analysed.Results:Sixty-one (57%) cases showed high expression of ETBR. Endothelin receptor type B expression was correlated with several clinicopathological factors including tumour differentiation, tumour depth, and lymph node metastasis. The overall and disease-specific survival rates were significantly lower in patients with high ETBR expression than patients with low expression. Furthermore, multivariate analysis revealed that ETBR status was an independent prognostic factor for patient survival. Mechanistic analysis indicated that MVD was significantly higher in tumour tissues with high ETBR expression compared with those with low expression, suggesting that angiogenesis may be a key mechanism in tumour progression and metastasis of OSCC mediated by ETBR expression. By contrast, there were no significant correlations between TILs and ETBR expression.Conclusion:Endothelin receptor type B has a pivotal role in oesophageal cancer and may be therapeutic target for this intractable malignancy.

Significant involvement of herpesvirus entry mediator in human esophageal squamous cell carcinoma.

Herpesvirus entry mediator (HVEM) is known to regulate immune response and to be expressed in several human malignancies. However, to the authorss knowledge, the precise role of HVEM in human cancer biology remains unknown. The objective of the current study was to clarify the clinical significance of HVEM in human esophageal squamous cell carcinoma as well as its in vivo functions.

A defect of the abdominal wall with intestinal fistulas after the repair of incisional hernia using Composix Kugel Patch

INTRODUCTION In the present paper, we show a rare case of the large abdominal wall defect and enterocutaneous fistulas after the tension free repair using prostheses for incisional hernia. PRESENTATION OF CASE The patient, a 70-year-old man, had a history of a hemicolectomy for a perforating colon cancer, complicated by a large incisional hernia that was closed primarily but recurred. Three years later, the hernia was repaired at the time of a second colectomy using a Composix Kugel Patch. His course was complicated by a chronic postoperative wound infection with eventual development of enterocutaneous fistulas. The patient was successfully treated with extirpation of the prosthesis, resection of the fistulized bowel, and placement of a tensor fasciae latae myocutaneous flap. DISCUSSION Enterocutaneous fistulas are a known complication of incisional hernia repairs using prostheses. Additional clinical data are required to confirm the safety and efficacy of this procedure as it becomes more widely adopted. CONCLUSION Extirpation of the prosthesis should be performed without delay to prevent serious complications. Reconstruction with a tensor fasciae latae myocutaneous flap was useful for the large abdominal wall defect.

Intrathoracic hernia of a retrosternal colonic graft after esophagectomy: Report of a case

We report a case of intrathoracic herniation of the colonic interposition pulled up through the retrosternal space after subtotal esophagectomy for esophageal cancer. The patient, a 68-year-old man, presented with progressive dysphagia about 1 year after this operation. We performed left thoracotomy and laparotomy, which revealed the reconstructed colon herniating into the left thoracic cavity through a large defect in the left mediastinal pleura. The redundant colon was resected, and the colonic graft was shortened and straightened. We concluded that the defect in the mediastinal pleura and colonic redundancy had permitted the colonic graft to herniate into the left thoracic cavity.

An esophageal gastrointestinal stromal tumor with regional lymph node metastasis

We report a case of a 72-year-old woman with an esophageal gastrointestinal stromal tumor (GIST) with regional lymph node metastasis. Endoscopy and barium esophagography revealed a large submucosal tumor in the lower esophagus. Computed tomography showed a solid 8-cm tumor, suggesting an esophageal mesenchymal tumor. Endoscopic ultrasonography-guided fine-needle aspiration biopsy was positive for c-KIT and CD34, and negative for desmin and S-100. The patient underwent middle and lower esophagectomy via left thoracotomy, followed by gastric tube reconstruction. The tumor was completely resected, but a metastasis in the right paracardial lymph node was observed. Pathological examination confirmed the tumor to be high risk. We are carefully following up the patient.

A comparison of surgery and radiation therapy for cT1 esophageal squamous cell carcinoma

Surgery and radiation therapy have been used to treat esophageal squamous cell carcinoma. However, treatment outcomes have not yet been extensively investigated. The aim of this study was to compare surgery and radiation therapy for clinical T1 esophageal squamous cell carcinoma. A total of 67 clinical T1 esophageal squamous cell carcinoma patients were treated between January 1997 and December 2005; 29 had undergone radical esophagectomy (surgery group) and 38 were treated with definitive radiation therapy (radiation group). The mean patient age was lower in the surgery group than in the radiation group. In surgery group, respiratory complications, anastomotic leaks, recurrent nerve palsies, and anastomotic stenosis occurred in 7, 8, 6, and 5 patients, respectively. In radiation group, leucopenia, esophagitis, pericarditis were observed in 15, 3, and 3 patients, respectively. The 5-year overall survival rate for the surgery group was 68.9%, and 74.3% for the radiation group. There were no significant difference between groups (P= 0.3780). The 5-year relapse-free survival rate in the surgery group was 61.8% and 38.8% in the radiation group. The relapse-free survival rate was significantly higher in the surgery group than in the radiation group (P= 0.0051). The 5-year overall and relapse-free survival rates for tumors invaded into but not through the muscularis mucosa were 83.3% and 75.0%, respectively, in the surgery group and 78.8% and 33.3%, respectively, in the radiation group. There were no significant differences. The 5-year overall survival rates for patients with tumors that invaded the submucosal layer was 64.9% in the surgery group and 66.5% in the radiation group. This difference was not significant (P= 0.8712). The 5-year relapse-free survival rate in the surgery group (56.0%) was significantly higher than that in the radiation group (41.8%; P= 0.0219). In conclusion, surgery may become a standard treatment for cT1 esophageal cancer that can offer longer relapse-free survival, particularly for patients with tumors that invade the submucosa.