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Background and Aims: Mutations of the NT5E gene encoding the cluster of differentiation 73 (CD73) protein have been found in patients with characteristic calcification of joints and arteries (CALJA). CD73 plays a protective role against aortic valve calcification and its deletion results in aortic valve calcification. However, there have been no reports of a patient with CALJA with aortic stenosis. Methods: We describe two extremely rare cases of two sisters with identical NT5E gene mutation patterns, both of whom presented severe aortic stenosis and limb ischemia. Genetic examination for definitive diagnosis was also performed in both patients. Results: Both patients underwent aortic valve replacement and bilateral distal arterial bypass surgeries successfully. They were genetically diagnosed with CALJA based on the NT5E mutation. Conclusions: NT5E mutation should be considered in patients requiring aortic valve replacement for a calcified aortic valve and bypass surgery for specific calcified and occluded arteries.

Reactive oxygen species (ROS) such as superoxide, hydroxyl radical, and hydrogen peroxide play an important role in the maintenance of life. However, production of excessive ROS and/or deficiency of the antioxidant system lead to oxidative stress and cause a variety of diseases. In the present study, we used electron spin resonance (ESR) to detect ROS in vivo to clarify its roles in redox dynamics and organ damage. However, the limited permeability of microwaves and low anatomic resolution of ESR equipment made it difficult to apply clinically. Nitroxide is widely used as a sensitive redox sensor for in vivo ESR analysis. The unpaired electrons of nitroxide are known to cause the T1 relaxation time-shortening effect of water protons, creating magnetic resonance imaging (MRI) effects. The remarkable development of MRI has facilitated the spatiotemporal analysis of nitroxide, which was previously impossible. In a rat model, we have been able to image and analyze the process of nitroxide reduction using MRI. MRI using nitroxide as a contrast medium is considered to be clinically applicable for evaluation of organ redox, imaging of ROS (which cause organ damage), and evaluation of therapeutic effects. In this review, we describe current advances in the analysis of in vivo redox capacity in animals using ESR and MRI equipment. We consider that redox evaluation using MRI can contribute to advances in clinical medicine.

Background Approximately 25% of coronary arteriovenous fistulas present aneurysmal dilatation; however, spontaneous rupture of the aneurysm is rare. Most coronary arteries branching the feeding arteries demonstrate aneurysmal formation, possibly because of shunt flow. Case report A 48-year-old woman was referred to our institution for surgical management of ruptured aneurysm of coronary arteriovenous fistula. The aneurysm was located on the left-anterior aspect of the pulmonary artery trunk, communicating with both left and right coronary arteries through two small feeding arteries draining into the pulmonary artery trunk. Both left and right coronary arteries showed normal diameter. The feeding arteries were ligated externally, and fistulous openings were closed within the aneurysm. Postoperative course was uneventful. Conclusion Aneurysm of coronary arteriovenous fistula can occur in patients without aneurysmal coronary artery. Although the association of ruptured aneurysm with coronary fistulas is relatively rare, it should be considered a potential cause of acute cardiac tamponade.

Background NT5Egenetic mutations are known to result in calcification of joints and arteries (CALJA), and worldwide, 14 patients from 7 families have been reported.Methods and Results:A total of 5 patients from 2 independent families with CALJA were found in Japan. Of them, 3 complained of intermittent claudication (IC), and 1 suffered from bilateral chronic limb-threatening ischemia (CLTI). Whole-exome sequencing analysis revealed an identical mutation pattern (c.G3C on the exon 1 start codon) that was unique compared withNT5Emutations reported in other countries. Conclusions Vascular specialists need to recognize CALJA as a rare cause of ischemic IC and CLTI.

This retrospective study investigated the effect of perioperative oral care intervention on postoperative outcomes in patients undergoing lung cancer resection, in terms of the length of postoperative hospital stay and the incidence of postoperative respiratory infections. In total, 585 patients underwent lung resection for lung cancer, 397 received perioperative oral care intervention, whereas the remaining 188 did not. This study retrospectively investigated the demographic and clinical characteristics (including postoperative complications and postoperative hospital stay) of each group. To determine whether perioperative oral care intervention was independently associated with either postoperative hospital stay or postoperative respiratory infections, multivariate analysis, multiple regression analysis, and multivariate logistic regression analysis were conducted. Parameters significantly associated with a prolonged postoperative hospital stay in lung cancer surgery patients were older age, postoperative complications, increased intraoperative bleeding, more invasive operative approach (e.g., open surgery), and lack of perioperative oral care intervention (standard partial regression coefficient (s) = 0.083, p = 0.027). Furthermore, older age and longer operative time were significant independent risk factors for the occurrence of postoperative respiratory infections. Lack of perioperative oral care intervention was a potential risk factor for the occurrence of postoperative respiratory infections, although not statistically significant (odds ratio = 2.448, 95% confidence interval = 0.966–6.204, p = 0.059). These results highlight the importance of perioperative oral care intervention prior to lung cancer surgery, in order to shorten postoperative hospital stay and reduce the risk of postoperative respiratory infections.

Background Saphenous vein graft aneurysm (SVGA) is a rare complication after coronary artery bypass grafting; however, it may lead to fatal conditions. A redo sternotomy poses a high risk of injury to the patent graft. Case report A 59-year-old man with chest pain was diagnosed with a giant SVGA (67 mm) anastomosed to the right coronary artery (RCA) and compressing the right atrium. Considering the high risk of injury to a patent graft through the sternum, a surgical procedure was planned without redo sternotomy. Through an upper midline abdominal incision, redo bypass grafting was performed to the distal RCA using the right gastroepiploic artery, followed by resection of the aneurysm using the right anterior lateral thoracotomy approach. The postoperative course was uneventful. Conclusion In patients with an SVGA anastomosed to the right coronary system, our surgical strategy may be a useful alternative to redo sternotomy to avoid injury to the patent graft.

The prognostic nutrition index is an immunonutritional indicator and postoperative predictor of oncological surgery. However, its prognostic value in cardiovascular disease is unknown. This study assessed the value of the prognostic nutrition index in cardiovascular surgery. This retrospective study included 453 patients who underwent cardiovascular surgery. The patients were divided according to cutoff values of the prognostic nutrition index

Total arch replacement using the frozen elephant trunk procedure is performed for true lumen expansion of the descending aorta in patients with type A acute aortic dissection. However, the remodelling effect of the frozen elephant trunk on the dissected descending aorta is unclear. We aimed to evaluate the effect of the frozen elephant trunk on postoperative descending aortic remodelling after surgery. Between December 2012 and January 2020, we retrospectively investigated 24 patients who underwent total arch replacement using the frozen elephant trunk for type A acute aortic dissection. Remodelling of the descending aorta was evaluated using computed tomography. The aortic remodelling effect, based on aortic true lumen ratio, was determined for (i) DeBakey type (type I versus type III retrograde); (ii) thoracic endovascular aneurysm repair reintervention status (reintervention versus no reintervention); and (iii) stent length of the frozen elephant trunk (60 vs 90 mm). Postoperative true lumen ratio significantly increased in the type I dissection group. The true lumen ratio in the no-reintervention group, which had many patients with the type I dissection, significantly increased after the frozen elephant trunk. Aortic remodelling due to the frozen elephant trunk can be expected after type I acute aortic dissections.

A 75-year-old woman who underwent total aortic arch replacement complained of dyspnea for a few days. Computed tomography revealed a thoracic aortic aneurysm causing compression of the trachea. She was referred to our hospital for surgical treatment. The tracheal stenosis was severe, with a risk of an inability to ventilate during the general anesthesia. Therefore, under respiratory support for venovenous extracorporeal membrane oxygenation (VV-ECMO), we performed decompression of the thoracic aortic aneurysm by thoracic endovascular aneurysm repair, followed by tracheal stent placement. The postoperative course was uneventful, and she was discharged without any symptoms. VV-ECMO is useful for treatment of tracheal stenosis.

Background The right gastroepiploic artery (RGEA) is a useful in-situ graft, and skeletonization is effective to prevent spasm and achieve good patency. To harvest the skeletonized RGEA easily, ultrasonic scalpel has been widely used, but the tip shape of conventional ultrasonic device was not optimal for this procedure. Recently, a novel hybrid ultrasonic/bipolar energy device (THUNDERBEAT Open Fine Jaw [TOFJ]) has been developed and is widely used in general surgery. Surgical technique The operator holds forceps in left hand and TOFJ in right hand, incises the anterior layer of the omentum, and extends the incision distally along the RGEA. The side branches and satellite veins were sealed and cut. Because the tip of the TOFJ is well-designed to easily grasp and peel off the tissue, there is no need to change instruments throughout the procedure. After the dissection was advanced distally, the proximal side was subsequently dissected. Conclusions This novel device is useful for harvesting skeletonized RGEA.

Spinal cord injury (SCI) following endovascular aortic repair (EVAR) for an abdominal aortic aneurysm (AAA) is a rare but serious complication. Case 1 presented with ruptured AAA and shock and underwent emergency EVAR. The patient developed incomplete paraplegia 2 days following EVAR. Case 2, diagnosed with impending rupture of AAA with extremely shaggy aorta, was treated with emergency EVAR. The patient was diagnosed with complete paraplegia soon after EVAR. Case 3 underwent elective EVAR and developed delayed paraplegia 2 weeks later. In EVAR, the etiology of SCI leading to paraplegia is often multifactorial. Surgeons must consider the possibility of SCI-induced paraplegia.

Endograft infection after abdominal endovascular aortic repair is a rare but catastrophic complication associated with high perioperative mortality and postoperative recurrent infection. The optimal surgical treatment is still controversial, particularly regarding in situ or extra-anatomical revascularization. Herein, we describe a successful surgically treated case of a patient with an endograft infection complicated with abscess formation in the retroperitoneal space around the right common iliac artery. We performed an aortobifemoral bypass grafting using the reversed L-shaped technique by rerouting the right leg of the new prosthesis to avoid the infected area. The patient is doing well 1 year after surgery without recurrent infection. This technique was considered to be advantageous because revascularization could be performed remotely from the infected area.

An extensive infection of the native aortic or prosthetic valve beyond the aortic annulus could be complicated with various types and degrees of tissue destruction. The left ventricular–aortic discontinuity resulting from extensive infective endocarditis often necessitates pericardial reconstruction of the left ventricular outflow tract and subsequent aortic root replacement. Furthermore, if the membranous ventricular septum is involved with infective tissue destruction, communication between the left ventricle and right atrium, known as a Gerbode defect, and complete atrioventricular block could occur. Surgical reconstruction of these complex pathologies is challenging, with high mortality and morbidity. Herein, we present a rare case of prosthetic valve endocarditis complicated with both left ventricular–aortic discontinuity and an acquired Gerbode defect. At the time of surgery, left ventricular outflow tract reconstruction and the technically more demanding aortic root replacement were considered inevitable because of extensive tissue destruction. However, we performed circumferential left ventricular outflow tract reconstruction with a xenopericardial patch and supra-annular aortic valve replacement using the Solo Smart bovine pericardial stentless valve as a technically less demanding alternative to aortic root replacement. The postoperative course was uneventful, and the patient is well 1 year postoperatively, without valvular dysfunction and recurrent infection.

Here we report a rare case of atypical Kawasaki disease (KD) in a patient presenting with systemic arteritis affecting the coronary arteries, brain, and internal mammary arteries (IMAs). A 25-year-old man was referred to our institute with angina pectoris. Coronary angiography revealed coronary artery aneurysms and triple-vessel disease. Three-dimensional brain computed tomography showed multiple small saccular aneurysms on the vertebral and posterior inferior cerebellar arteries. Off-pump coronary artery bypass (OPCAB) grafting ​​​​​​was performed; however, the bilateral IMAs were tightly adhered and not patent. OPCAB was completed using the bilateral radial and gastroepiploic arteries. This is the first report of KD involving the IMA.

The purpose of this study was to evaluate the short- and mid-term outcomes of open aortic arch surgery and debranching thoracic endovascular aortic repair( TEVAR) in octogenarians.Between 2011 and 2019, 26 patients with atherosclerotic aortic arch aneurysms underwent surgery at our institution [open aortic arch surgery( group O):10 patients, debranching TEVAR(group D):16 patients].There was no operative death in either group. The mean length of hospitalization and intensive care unit stay were 49 and 13 days in group O and 12 and 2 days in group O, respectively. Kaplan-Meier analyses of overall survival (1/6/12/24/36/48 months) showed mortality rates of 100/100/88/88/70/70% in group O and 100/100/87/61/43/26% in group D, respectively.The acceptable outcomes was demonstrated in octogenarians underwent both open aortic arch surgery and debranching TEVAR. Because of early postoperative recovery, debranching TEVER is considered to be a feasible alternative to conventional open aortic arch surgery in octogenarians.

Transfemoral endovascular repair has been widely accepted as an effective treatment for type B aortic dissection. However, if the dissection extends to the femoral artery, the transfemoral approach increases the risk of access complications. We describe a case of acute complicated type B aortic dissection involving the dissected bilateral femoral arteries. Successful endovascular repair without access complications was performed through an appropriate access route created by a femoral arterial conduit. We believe that this approach results in reliable cannulation of the true lumen and the reduction of the risk for intimal injury in aortic dissection with the dissected femoral artery.

Previous studies have reported the feasibility and efficacy of thoracoscopic anatomical sublobar resection under three-dimensional computed tomography (3DCT) simulation; however, its long-term outcomes have not been clearly established in primary lung cancer. This study aimed to evaluate the long-term outcomes of this technique. We retrospectively reviewed data from 112 consecutive patients with selected clinical stage IA non-small cell lung cancer (NSCLC) who underwent thoracoscopic anatomical sublobar resection from 2004 to 2014. This procedure was planned using preoperative 3DCT simulation to ensure sufficient surgical margins and enabled tailor-made surgery for each patient. Patients who had predominantly ground glass opacity lung cancers underwent anatomical sublobar resection as a curative-intent resection. Other patients who were high-risk candidates for lobectomy underwent anatomical sublobar resection as a compromised limited resection. Of the 112 cases, 82 had a curative-intent resection, while 30 had a compromised limited resection. Recurrence occurred in only 2 cases (1.8%), both of which were in the compromised limited group. A second primary lung cancer was observed in 5 cases (4.5%). Of the 5 patients, 4 underwent surgery for a second cancer and had no recurrence. The 5-year overall survival, lung cancer-specific overall survival, and recurrence-free survival rates were 92.5%, 100%, and 98.2%, respectively, for all cases; 97.6%, 100%, and 100%, respectively, in the curative-intent group; and 75.8%, 100% and 92.6%, respectively, in the compromised limited group. Thoracoscopic anatomical sublobar resection under 3DCT simulation may be an acceptable alternative treatment in selected patients with NSCLC. Clinical registration number: IRB No. 2020-98 (Dated: 2020.6.30).

Background A double left brachiocephalic vein is an extremely rare venous anomaly. Case presentation Herein, we present the case of a 79-year-old woman with a double left brachiocephalic vein who underwent cardiac surgical procedures. The normal left brachiocephalic vein was patent, and the accessory left brachiocephalic vein passed across the heart and aorta in front of the pericardium and drained into the superior vena cava. She underwent surgical ligation of the accessory left brachiocephalic vein, followed by an aortic valve replacement and coronary artery bypass grafting. Her postoperative recovery was uneventful, without any venous complications from the ligation of the accessory vein. The patient is doing well one year after the surgery. Conclusions The presence of double left brachiocephalic veins should be recognized before cardiac surgery in order for us to avoid intraoperative technical issues concerning this venous anomaly and unpredictable intraoperative bleeding due to injury of the accessory left brachiocephalic vein.

In the currently evolving field of endovascular surgery, most brachiocephalic aneurysms are treated with stent grafts. Connective tissue disorders are considered a relative contraindication for endovascular repair because of the risk of adverse events at the landing zone in the aorta and its branches, although the surgical grafts from previous repairs could provide stable landing zones. We attempted a new hybrid operative technique for a brachiocephalic aneurysm in a patient with Loeys-Dietz syndrome, who was unsuitable for open surgery because of multiple previous surgeries and possible lung malignancy. The operation was performed by creating an appropriate landing zone using a prosthetic graft followed by endovascular stent grafting, which yielded good results. This hybrid operation is expected to expand the potential for endovascular treatment in patients with connective tissue diseases who are deemed unsuitable for open surgery.

NT5Egenetic mutations are known to result in calcification of joints and arteries (CALJA), and worldwide, 14 patients from 7 families have been reported.Methods and Results:A total of 5 patients from 2 independent families with CALJA were found in Japan. Of them, 3 complained of intermittent claudication (IC), and 1 suffered from bilateral chronic limb-threatening ischemia (CLTI). Whole-exome sequencing analysis revealed an identical mutation pattern (c.G3C on the exon 1 start codon) that was unique compared withNT5Emutations reported in other countries.Vascular specialists need to recognize CALJA as a rare cause of ischemic IC and CLTI.

We present a case of palliative pleuro-peritoneal shunt for refractory hydrothorax complicated with unresectable cardiac tumor. The patient was a 77-year-old woman, who was admitted to our hospital for evaluation of intractable pleural effusion. It was attributed to severe diastolic dysfunction associated with cardiac tumor. The cardiac tumor occupied a large area of the anterior surface of the right atrium, and curative surgical resection was difficult. Therefore, we planned multidisciplinary staged treatment with chemotherapy followed by tumor excision. Persistent intractable bilateral pleural effusion necessitated repeat chest drainage. To maintain the patient's quality of daily life, bilateral pleuro-peritoneal shunts were inserted. Then, the problem of pleural effusion was resolved and her symptoms were improved. However, she expired 3 months later, due to deterioration of general condition. Pleuro-peritoneal shunting is a useful palliative approach to improve quality of life in patients with refractory hydrothorax.

We report a case of patch closure of posterior type ventricular septal perforation (VSP) with posterior left ventricular aneurysm (PLVAN) through right ventricular incision. A 70-year-old man was transferred to our hospital because of persistent epigastric pain. He was diagnosed with inferior acute myocardial infarction, and percutaneous coronary intervention was performed to the right coronary artery[ atrio-ventricular(AV)]. After 2 weeks, he developed congestive heart failure and was treated with inotropic support and intra-aortic balloon pumping. Echocardiography and computed tomography (CT)showed posterior type VSP between PLVAN and the right ventricle. The operation was performed via standard median sternotomy and under cardiopulmonary bypass. After right ventricle incision parallel to the left anterior descending artery, there was VSP (20×20 mm) behind the trabecular septmarginalis (TSM). We closed VSP with a 2-layer patch (40×40 mm) consisted of Dacron and bovine pericardial patches. Postoperative echocardiography showed no residual shunt, and postoperative CT showed no enlargement of PLVAN. He was discharged home on foot without right heart failure and has been well without major complications.

Objectives: According to the International Registry of Acute Aortic Dissection, >70% of patients with type-B aortic dissection (AD) have delayed aortic growth. The objective of this study was to investigate the morphologic characteristics of aortic enlargement in type-B AD. Methods: A total of 120 patients with uncomplicated acute type-B aortic dissection (uATBAD) were divided into 4 groups according to the presence of a patent or thrombosed false lumen (FL) with or without aortic enlargement. In all groups, the area of the true lumen (TL) and the FL were measured on axial computed tomography images. Results: A total of 120 uATBAD patients were evaluated: patent FL with (PE, N = 28, 23%) or without aortic enlargement (PU, N = 17, 14%) and thrombosed FL with (TE, N = 34, 28%) or without enlargement (TU, N = 41, 34%). The initial aortic diameter was not significantly different among the 4 groups (PE vs. PU = 39 ± 8 vs. 37 ± 10 (p = 0.354); TE vs. TU = 38 ± 6 vs. 37 ± 6 (p = 0.391)). The area of the FL tended to be larger in the PE group. In contrast, the area of the TL was significantly larger in the TE group. Late outcomes of uATBAD treated with optimal medical treatment were acceptable. Conclusions: In patients with uATBAD and a thrombosed FL, the patients with aortic enlargement tended to be increased TL size. In contrast, in patients with a patent FL, the patients with aortic enlargement tended to be increased FL size.

Introduction: The number of cases for which the Batista procedure is indicated is small, but some patients with appropriate indication can achieve good therapeutic results. Objective: To avoid incorrect left ventricular incision and obtain good surgical results in patients with dilated cardiomyopathy suitable for partial left ventriculectomy, we employed intraoperative direct echocardiography to determine the exact extent and position of the myocardial incision, even for surgeons who are not very experienced with the Batista procedure. Methods: A 72-year-old man with dilated cardiomyopathy underwent the Batista procedure with the aid of epicardial echocardiography to confirm the location of both the papillary muscles and the diseased myocardium. Results: We were able to accurately perform left ventricular incision and remove the diseased lateral ventricular wall. Two years later, the patient had no symptoms of heart failure, and his brain natriuretic peptide (BNP) level decreased from 1155 to 49.3 pg/mL. Conclusions: We believe that the use of intraoperative echocardiography may have the potential to make the Batista procedure less technically demanding and more reproducible for surgeons with little experience in the procedure.

Background and aims The optimal valve and prosthesis in patients with aortic valve infective endocarditis with annular abscess is controversial. If extensive annular defects occur after debridement, standard techniques are difficult; more complex aortic root replacement (ARR) or aortic valve translocation technique are inevitable. The Solo Smart stentless bioprosthesis is specially designed for supra-annular implantation without annular stitches. Methods Nineteen patients with active aortic valve infective endocarditis underwent aortic valve replacement in the past 3 years. Of these, we performed aortic valve replacement using the Solo Smart valve in four patients with extensive annular destruction and complex aortic root pathologies requiring reconstruction. Results Although more than two-thirds of the annular structure was missing after radical debridement of infected tissues, supra-annular aortic valve replacement with the Solo Smart valve could be performed successfully in all four patients. All patients are doing well without prosthetic valve dysfunction and/or recurrent infection. Conclusion The supra-annular aortic valve replacement using the Solo Smart valve is considered to be a useful alternative to standard aortic valve replacement in patients complicated with extensive annular defect. It is a simple and technically less demanding alternative to ARR or aortic valve translocation technique.

Objectives: Uncomplicated type B aortic dissection is generally treated with medical management including antihypertensive therapy. The purpose of this study is to investigate risk factors associated with the aortic enlargement in medically treated patients. Methods: Between July 2004 and April 2016, 127 consecutive patients with acute type B aortic dissection were treated in our institution. Of these, 104 patients diagnosed with uncomplicated type B dissection were managed medically as an initial treatment. According to the diameter of the dissected aorta, these patients were retrospectively placed into 2 groups: 1) enlargement group (group E: n=36); and 2) unchanged group (group U: n=68). Results: There was statistically significant difference regarding the initial diameter of the dissected aorta (group E: 42±7 mm, group U: 36±7 mm) (p

Background: Visualization of intersegmental planes in the lung is desirable for precise anatomical lung segmentectomy. We developed the slip-knot method for creating inflation-deflation lines. This study aimed to assess relevant data for thoracoscopic segmentectomy performed using this method. Methods: In the slip-knot method, the objective segmental bronchus is looped with a monofilament thread. One end of the thread is then pulled during temporary bilateral ventilation, causing the knot to slip toward the bronchus. Thereafter, bronchial ligation is tightened to block the outflow of segmental air, ensuring that the segment remains expanded while the other reserved segments collapse on resumption of unilateral ventilation. Data from 221 patients who underwent thoracoscopic pulmonary segmentectomy between 2010 and 2016 were analyzed. Results: A total of 147 patients (67%) were indicated for the slip-knot method, and 74 cases (33%) were non-adaptive cases. Ninety six percent of 147 cases were well adapted to the slip-knot method, which allowed us to obtain good inflation-deflation line images to determine the intersegmental plane. The mean operative time was 171±51 min (range, 71–367 min). The mean duration of chest tube insertion was 1.5±1.2 days (range, 1–7 days). Three cases (2.0%) had prolonged air-leakage and one (0.7%) case had readmission for late air-leakage. Conclusions: Our method enables determination of anatomical intersegmental planes using only one monofilament thread, thus facilitating thoracoscopic pulmonary anatomical segmentectomy.

A 64-year-old woman, with a history of hepatocellular carcinoma, developed recurrent metastatic lung nodules after lung metastasectomy 10 years ago. Computed tomography (CT) revealed tumors in the right middle, and left lower lobes. We planned a right middle lobectomy. Before operating, a contrast-enhanced CT in the pulmonary venous phase revealed a tumor in the pulmonary vein resembling a thrombus, indicating that the CT failed to facilitate accurate diagnosis. Following venous clamping and incision, the intravenous polypoid mass was surgically removed. As contrast-enhanced CT focuses on pulmonary arterial phases and might not detect venous lesions, we highlight the usefulness of venous phase contrast-enhanced CT for detecting pulmonary venous tumor thrombosis. Large lung metastatic carcinomas with venous extension may embolize to distant organs. Therefore, venous phase contrast-enhancement is essential for preoperative assessments of large or persisting metastatic lung tumors.