Clinical significance of vascular endothelial growth factor and Delta-like ligand 4 in small pulmonary adenocarcinoma

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The notch ligand Delta-like ligand 4 (DLL4) is induced by VEGF and acts as a negative regulator of tumor angiogenesis by reducing the numbers of non-productive sprouting vessels. Several reports have shown the prognostic role of VEGF expression in non-small cell lung cancer. However, the correlation between VEGF and DLL4 expression and their clinical significance in non-small cell lung cancer remains unclear. The aim of this study was to analyze the correlation between the expression of VEGF/DLL4 and the clinicopathological background. Fifty-eight patients with lung adenocarcinomas measuring less than 3 cm in diameter who underwent surgical resection at Kawasaki Medical School Hospital from 2008 to 2010 were enrolled in this study. The expressions of VEGF, DLL4, CD31, and Ki-67 were analyzed using immunohistochemical staining. The tumor cells were VEGF-positive in 44 patients (75.9%) and DLL4-positive in 41 patients (70.7%). No statistically significant association was observed between the patients\u27 characteristics and VEGF/DLL4 expression. A high VEGF expression level tended to be associated with a high DLL4 expression level (P = 0.050, r = 0.258). The mean Ki-67 index was significantly lower in the patients with high VEGF expression (9.5 vs. 18.2, P = 0.011), but no significant difference was observed when patients were compared according to their DLL4 expression levels (11.8 vs. 11.0, P = 0.804). The mean Ki-67 index was higher in the VEGF_ DLL4_ patients than in the VEGFhigh DLL4high patients by a marginally significant difference (20.1 vs. 10.9 P = 0.056). The 3-year recurrence-free survival rates of the VEGF_/DLL4_ and the VEGF_/DLL4_ patients were 83.3% and 35.7%, respectively. The prognosis of the VEGF_/DLL4_ patients was significantly better than that of the VEGF_/DLL4_ patients (P = 0.032). To investigate the significance of the difference in tumor proliferation and prognosis between the VEGF_/DLL4_ and the VEGF_/DLL4_ patients, we evaluated the morphologic effect of VEGF/DLL4 expression on the intratumoral capillaries by counting the number of capillaries and calculating the luminal area (μm^2). No significant differences were seen between either the VEGF or DLL4 expression levels and the mean number of intratumoral capillaries or the luminal area (μm^2). In conclusion, VEGF_/DLL4_ patients with small pulmonary adenocarcinoma had a significantly poorer prognosis, although no significant difference in a morphological evaluation of the capillaries was seen between VEGF_/DLL4_ and VEGF_/DLL4_ patients

A novel ex vivo lung cancer model based on bioengineered rat lungs

Introduction: Two-dimensional cell cultures have contributed substantially to lung cancer research, but 3D cultures are gaining attention as a new, more efficient, and effective research model. A model reproducing the 3D characteristics and tumor microenvironment of the lungs in vivo, including the co-existence of healthy alveolar cells with lung cancer cells, is ideal. Here, we describe the creation of a successful ex vivo lung cancer model based on bioengineered lungs formed by decellularization and recellularization.Methods: Human cancer cells were directly implanted into a bioengineered rat lung, which was created with a decellularized rat lung scaffold reseeded with epithelial cells, endothelial cells and adipose-derived stem cells. Four human lung cancer cell lines (A549, PC-9, H1299, and PC-6) were applied to demonstrate forming cancer nodules on recellularized lungs and histopathological assessment were made among these models. MUC-1 expression analysis, RNA-seq analysis and drug response test were performed to demonstrate the superiority of this cancer model.Results: The morphology and MUC-1 expression of the model were like those of lung cancer in vivo. RNA sequencing revealed an elevated expression of genes related to epithelial-mesenchymal transition, hypoxia, and TNF-α signaling via NF-κB; but suppression of cell cycle-related genes including E2F. Drug response assays showed that gefitinib suppressed PC-9 cell proliferation equally well in the 3D lung cancer model as in 2D culture dishes, albeit over a smaller volume of cells, suggesting that fluctuations in gefitinib resistance genes such as JUN may affect drug sensitivity.Conclusions: A novel ex vivo lung cancer model was closely reproduced the 3D structure and microenvironment of the actual lungs, highlighting its possible use as a platform for lung cancer research and pathophysiological studies

A Case of Cholesterol Crystal Embolization with Hemorrhagic Intestinal Ulcer

Cholesterol crystal embolization (CCE) is a rare systemic embolism caused　by formation of cholesterol crystals from atherosclerotic plaques. CCE usually occurs during　vascular manipulation such as vascular surgery or endovascular catheter manipulation, or　due to anticoagulation or thrombolytic therapy. We report a rare case of localized intestinal　ulcer with active hemorrhage caused by spontaneous CCE. An 83-year-old man with a history　of hypertension and diabetes was treated with a percutaneous coronary intervention (PCI)　for myocardial infarction. Melena occurred eight days after PCI. An abdominal computed　tomography revealed small intestinal ulcer, extravasation of the gastrointestinal tract and　bleeding in the abdominal cavity. The patient was diagnosed as bleeding from the small　intestinal ulcer, so an emergency laparotomy was performed. Partial resection of the small　intestine was performed. A histopathological examination indicated that small intestine　obstruction was caused by CCE. A histopathological examination indicated that small intestinal　obstruction was caused by CCE. Therefore, in cases of intestinal obstruction after vascular　manipulation, CCE should also be considered

Evaluation of intra-ductal cancer spread using contrast superb micro-vascular imaging (SMI) : a case report

Currently, breast conserving surgery has been adopted to treat more than half of all breast cancer patients in Japan. When performing breast-conserving surgery, an appropriate margin needs to be determined for radical cure. The resection volume influences the esthetic outcome, but a cancer-positive resection stump is also important risk factor of local recurrence. Additionally, the degree of cancer progression influences the surgical method, so understanding the appropriate resection margin is necessary for the surgeons. We report here on a 50- year old patient whose intra-ductal cancer progression was shown, as predicted, by contrast SMI (superb micro-vascular imaging). A one-cm size tumor mass was palpable with a clear boundary. B-mode ultrasound confirmed the presence of a breast duct towards the nipple from the tumor mass. Using contrast SMI, an accelerated blood flow was detected around the duct, which suggested intra-ductal progression. The pathological results also showed intra-ductal progression to the nipple from the tumor. Around the progression area, a meandering vessel was found and the vessel was able to be visualized by contrast SMI

Degos 病の関与が疑われた腸管気腫症の一例

症例は70歳代男性．既往に脳梗塞，パーキンソン病があり抗凝固薬を内服していた．デイサービス利用中に倦怠感および血圧低下を認め近医を受診し入院加療となった．入院２日目に40℃の熱発があり，腹部造影CT を施行したところfree air を認め外科的治療目的に当院へ救急搬送された．造影CT では肝彎曲部から脾彎曲部にかけての横行結腸に腸間膜気腫および腸管壁内ガスを認めた．明らかな腸間膜虚血および壊死を示唆する所見はなかった．消化管穿孔または腸管気腫症が考えられ緊急手術が検討されたが，腹部症状に乏しく液体成分など腸管内容の流出を示唆する所見がないことから一旦保存的加療を行った．また，体幹部を中心に小豆大までの皮膚潰瘍が多発していた．皮膚病理所見，既往および今回の病態からDegos 病と診断された．入院６日目に注腸造影および腹部CT を施行したところ，free air はほぼ消失しており，造影剤の腸管外漏出は認めず８日目に退院となった．Degos 病は皮膚の萎縮性丘疹を呈し，消化管の多発性潰瘍や穿孔，中枢神経系の出血や梗塞を特徴とし，病態としては末梢の血栓性血管炎が主体と考えられている．今回我々は，Degos病の関連が疑われた腸管気腫症の一例を経験したので文献的考察を加えて報告する．The patient was a 70 year-old-male. His past medical history was significant for cerebral infarction and Parkinson’s disease. He presented with malaise and hypotension and had been admitted to a local hospital three days ago. After admission，he had a fever of 40℃ and a computed tomography (CT) showed free air in the upper abdomen，he was referred to our hospital for an operation. A contrast-enhanced computed tomography also showed free air and pneumatosis intestinalis in transverse colon, with no evidence of mesenteric ischemia such as superior mesenteric artery occlusion (SMA) or non-occulusive mesenteric ischemia. Due to no abdominal pain and intraperitoneal fluid, we assessed that pneumatosis cystoides intestinalis was more probable than intestinal perforation. It was observed that the patient had many skin ulcers the size of red beans which were located around the chest and abdomen. A skin biopsy was performed，indicating Degos’ disease by a pathological exam. On day 6 of admission，we performed a barium enema exam and plain abdomen computed tomography (CT), it was seen that the free air almost disappeared and there was no leakage of the contrast medium. He was discharged on day 8. Patients with Degos’ disease present atrophic papula with perforation of intestinal or cerebral vascular accidents such as hemorrhage or infarction. This is considered a cause for bythrombotic angiitis of the peripheral vessels. We present a report with reference to the relevant literature

A surgical case of pulmonary adenocarcinoma in the right upper lobe associated with a systemic artery‐to‐pulmonary artery fistula

Abstract A 52‐year‐old female never‐smoker with an abnormal shadow in the right lung detected on radiography was referred to our institution. Contrast‐enhanced computed tomography revealed an irregular nodule in the upper lobe of the right lung, suggestive of a pulmonary vascular abnormality. Angiography revealed a direct communication between the right internal mammary artery (IMA) and the right upper lobe pulmonary artery branches, with dilated and tortuous vascular proliferation. As multiple branch arteries were seen flowing into the upper lobe from the IMA, transcatheter selective embolization of these vessels and right upper lobectomy by video‐assisted thoracoscopic surgery were performed. Contrary to the clinical diagnosis, the pathological finding was a pulmonary adenocarcinoma of the right upper lobe. Additional lymph node dissection was performed later. We report an extremely rare and unprecedented case of pulmonary adenocarcinoma fed by the right IMA, with a literature review