Takahiro Heishi

Vasohibin-1 Expression in Endothelium of Tumor Blood Vessels Regulates Angiogenesis

In this study, we characterized the significance of the vascular endothelial growth factor-inducible angiogenesis inhibitor vasohibin-1 to tumors. In pathological sections of non-small cell lung carcinoma, vasohibin-1 was present in the endothelial cells of blood vessels of the tumor stroma, but not in the lymphatics. In cancer cells, the presence of vasohibin-1 was associated with hypoxia-inducible factor 1alpha/vascular endothelial growth factor and fibroblast growth factor-2 expression. We then examined the function of vasohibin-1 in the mouse by subcutaneously inoculating with Lewis lung carcinoma cells. Resultant tumors in vasohibin-1(-/-) mice contained more immature blood vessels and fewer apoptotic tumor cells than tumors in wild-type mice. In wild-type mice that had been inoculated with Lewis lung carcinoma cells, tail vein injection of adenovirus containing the human vasohibin-1 gene inhibited tumor growth and tumor angiogenesis. Moreover, the remaining tumor vessels in adenoviral human vasohibin-1 gene-treated mice were small, round, and mature, surrounded by mural cells. The addition of adenoviral human vasohibin-1 gene to cisplatin treatment improved cisplatins antitumor activity in mice. These results suggest that endogenous vasohibin-1 is not only involved in tumor angiogenesis, but when sufficient exogenous vasohibin-1 is supplied, it blocks sprouting angiogenesis by tumors, matures the remaining vessels, and enhances the antitumor effect of conventional chemotherapy.

Endogenous Angiogenesis Inhibitor Vasohibin1 Exhibits Broad-Spectrum Antilymphangiogenic Activity and Suppresses Lymph Node Metastasis

During cancer progression, the angiogenesis that occurs is involved in tumor growth and hematogenous-distant metastasis, whereas lymphangiogenesis is involved in regional lymph node metastasis. Angiogenesis is counterregulated by various endogenous inhibitors; however, little is known about endogenous inhibitors of lymphangiogenesis. We recently isolated vasohibin1 as an angiogenesis inhibitor intrinsic to the endothelium and further demonstrated its anticancer activity through angiogenesis inhibition. Here, we examined the effect of vasohibin1 on lymphangiogenesis. Vasohibin1 exhibited broad-spectrum antilymphangiogenic activity in the mouse cornea induced by factors including VEGF-A, VEGF-C, FGF2, and PDGF-BB. We then inoculated highly lymph node-metastatic cancer cells into mice and examined the effect of vasohibin1 on lymph node metastasis. Tail-vein injection of adenovirus containing the human vasohibin1 gene inhibited tumor lymphangiogenesis and regional lymph node metastasis. Moreover, local injection of recombinant vasohibin1 inhibited lymph node metastasis. These results suggest vasohibin1 to be the first known intrinsic factor having broad-spectrum antilymphangiogenic activity and indicate that it suppresses lymph node metastasis.

Impairment of VEGF-A-stimulated lamellipodial extensions and motility of vascular endothelial cells by chondromodulin-I, a cartilage-derived angiogenesis inhibitor

Chondromodulin-I (ChM-I) is a cartilage-derived angiogenesis inhibitor that has been identified as inhibitory to the growth activity of vascular endothelial cells. In our present study, we demonstrate the anti-angiogenic activity of recombinant human ChM-I (rhChM-I) in mouse corneal angiogenesis and examine its action. We focus on the VEGF-A-induced migration of vascular endothelial cells, a critical regulatory step in angiogenesis. In a modified Boyden chamber assay, nanomolar concentrations of rhChM-I inhibited the chemotactic migration of human umbilical vein endothelial cells (HUVECs) induced by VEGF-A as well as by FGF-2 and IGF-I. The ChM-I action was found to be endothelial cell-specific and independent of cell adhesions. Time-lapse analysis further revealed that rhChM-I markedly reduces VEGF-A-stimulated motility of HUVECs and causes frequent alterations of the moving front due to the appearance of multiple transient protrusions. This action involved the inhibition of cell spreading and the disrupted reorganization of the actin cytoskeleton upon VEGF-A stimulation. Consistent with these observations, rhChM-I was found to significantly reduce the activity of Rac1/Cdc42 during cell spreading, and the VEGF-A-induced Rac1 activity but not its basal activity in quiescent cells. Taken together, our present data suggest that ChM-I impairs the VEGF-A-stimulated motility of endothelial cells by destabilizing lamellipodial extensions.

Combined thoracoscopic and endoscopic surgery for a large esophageal schwannoma

A 47-year-old woman presented to our hospital with complaints of dysphagia. Esophagogastroduodenoscopy identified a submucosal tumor in the left wall of the esophagus that was diagnosed as a benign schwannoma on biopsy. Computed tomography revealed a tumor of length 60 mm in the thoracic esophagus, with its cranial edge at the level of the aortic arch. On endoscopy, a submucosal tunnel was created 40 mm proximal to the cranial edge of the tumor, and its oral end was dissected from the mucosal and muscular layers. This was followed by the resection of the entire tumor by left-sided thoracoscopy. The esophageal defect was closed in layer by continuous suture from the thoracic side. Endoscopic closure was achieved by using clips. No postoperative complications were observed. Oral diet was resumed from postoperative day 7 and the patient was discharged on postoperative day 9. This combined approach has not been described for similar tumors. Our experience demonstrated that large esophageal tumors can be safely excised with minimally invasive surgery by using a combination of thoracoscopy and endoscopy.

Treatment of spontaneous esophageal rupture (Boerhaave syndrome) using thoracoscopic surgery and sivelestat sodium hydrate

Background The mortality rate of spontaneous esophageal rupture remains 20% to 40% due to severe respiratory failure. We have performed thoracoscopic surgery for esophageal disease at our department since 1994. Sivelestat sodium hydrate reportedly improves the pulmonary outcome in the patients with acute lung injury (ALI). Methods We retrospectively evaluated the usefulness of thoracoscopic surgery and perioperative administration of sivelestat sodium hydrate for spontaneous esophageal rupture in 12 patients who underwent thoracoscopy at our department between 2002 and 2014. Results The patient cohort included 11 males and one female (median age, 61 years). The lower left esophageal wall was perforated in all patients. Surgical procedures consisted of thoracoscopic suture and thoracic drainage in six patients, transhiatal suture and thoracoscopic thoracic drainage in five, and thoracoscopic esophagectomy and thoracic drainage in one. The median time from onset to surgery was 8 hours with a surgical duration of 210 minutes, blood loss 260 mL, postoperative ventilator management 1 day, intensive care unit (ICU) stay 5 days, and interval to restoration of oral ingestion 13 days. Postoperative complications included respiratory failure in four patients, pyothorax in three, and leakage in one. There was no instance of perioperative mortality. Regarding perioperative administration of sivelestat sodium hydrate, the postoperative arterial oxygen partial pressure-to-fractional inspired oxygen ratio (P/F) and C-reactive protein (CRP) levels in the administration group were significantly better than those in the non-administration group on postoperative days 4 (P=0.035) and 5 (P=0.037), respectively. In contrast, there was no significant difference between the groups in median time of ventilator management, ICU stay, oral ingestion following surgery, or hospital stay. Conclusions Thoracoscopic surgery obtained acceptable results in all patients, including two with a significant time elapse from onset to treatment. Furthermore, sivelestat sodium hydrate was suggested to help improve postoperative respiration and inflammatory response.

Different strategy of salvage esophagectomy between residual and recurrent esophageal cancer after definitive chemoradiotherapy

Background Clinical outcomes appear to differ between patients with residual or recurrent esophageal cancer after definitive chemoradiotherapy. We aimed to identify the patients most likely to benefit from this high-risk surgery, divided by the patients whose cancer was residual and recurrent groups, respectively. Methods We retrospectively examined 100 cases of patients who failed to respond to definitive chemoradiotherapy for thoracic esophageal squamous cell carcinoma and subsequently underwent salvage transthoracic esophagectomy. Results In-hospital morbidity was similar in both groups. T status prior to administration of chemoradiotherapy correlated with survival in the group with residual cancer (P=0.010), but this relationship was not significant in the group with recurrent cancer (P=0.635). On the other hand, pathological T status showed a significant correlation with survival in both the residual (P<0.001) and recurrent groups (P=0.001). Patients with T3 disease in the recurrent group showed better survival, similar to T0-2 patients, while worse survival was demonstrated in the residual group. In the recurrent group, N status before chemoradiotherapy did not correlate with survival (P=0.895). Conclusions Patients with residual cancer would have good prognosis by salvage esophagectomy in cases in which the cancer had not invaded to the adventitia at the time of chemoradiotherapy and surgery. Conversely, patients whose cancer was recurrent might benefit from salvage surgery if the cancer appears to be resectable. T and N status before chemoradiotherapy are not important factors in consideration of salvage esophagectomy in cases of recurrent cancer.

Curative resection of advanced esophageal cancer with metachronous stage IV breast cancer: A case report

Highlights • Our literature search revealed no curative surgery cases for esophageal cancer in patients with multiple primary cancers with distant metastasis.• We report a case of esophageal cancer with metachronous breast cancer involving liver and mediastinal lymph node metastasis and cancerous peritonitis.• Curative resection of esophageal cancer can be considered when the prognosis of the additional cancer is not poor.

Bilateral approach for thoracoscopic esophagectomy with lymph node dissection in the dorsal area of the thoracic aorta in patients with esophageal cancer: A report of two cases

Highlights • We presented two esophageal cancer patients performed thoracoscopic esophagectomy.• These two cases have lymph node metastasis of dorsal area of thoracic aorta (DTA).• We performed successfully underwent the dissection of lymph node of DTA.• The bilateral thoracoscopic approach performedsafely in the prone position.• The long-term outcome of lymphadenectomy in the DTA among esophageal cancer patients remain controversial.