Risk and Prognosis of Upper Extremity Deep Vein Thrombosis.

Objectives: We aimed to investigate the clinical features of upper extremity deep vein thrombosis (UEDVT). Methods: We retrospectively reviewed the background, thrombus site, treatment, and outcome of 76 UEDVT patients. Results: Of the 76 UEDVT patients, 44 (57.9%) were men, and 51 (67.1%) were complicated by malignancy, 44 (57.9%) had an indwelling central vein (CV) catheter, 8 (10.5%) had concomitant pulmonary embolization (PE), and 33 (43.3%) were symptomatic. Regarding the thrombus site, the right internal jugular vein was the most common, with 30 cases (35.3%). As regards the treatment method, 53 patients (69.7%) received oral anticoagulants. In 2015, when direct oral anticoagulants (DOACs) was covered by insurance, there were 44 UEDVT cases, of which 34 (77.3%) received DOACs. Outcomes at a mean observation period of 37.5±41.5 months included 40 deaths (52.6%) with a mean survival of 16.3±21.3 months. The most common cause of death was malignancy, with 33 cases (82.5%). Conclusion: In the background of UEDVT, the combination of indwelling CV catheter placement and malignancy was frequently observed. While the risk of recurrence or PE complications is low, the prognosis of UEDVT complicated by malignancy is extremely poor.

Real-Time Assessment of Tissue Oxygen Saturation Using a Novel Oximeter During Revascularization for Acute Limb Ischemia: A Case Report.

Emergency surgery was performed to treat acute lower limb ischemia caused by heart thromboembolism and concomitant popliteal artery aneurysm. Using a near-infrared spectroscopy oximeter, regional tissue oxygen saturation (rSO2) was monitored to assess the tissue perfusion pre-, intra-, and postoperatively. rSO2 values did not increase sufficiently following thromboembolectomy of the superficial femoral artery, but they dramatically recovered after additional popliteal-anterior tibial bypass surgery. The affected limb was successfully salvaged. rSO2 monitoring was easily measured intraoperatively, which might be beneficial in evaluating tissue perfusion in patients with acute limb ischemia.

The Usefulness of a Three-Microneedle Device for Indocyanine Green Fluorescence Lymphography.

Background: Indocyanine green (ICG) fluorescence lymphography is widely used to diagnose lymphedema. There is little consensus on the appropriate injection method for ICG fluorescence lymphangiography. We used a three-microneedle device (TMD) for skin injection of ICG solution and investigated its usefulness. Methods and Results: Thirty healthy volunteers were injected with ICG solution using a 27-gauge (27G) needle in one foot and a TMD in the other foot. Injection-related pain was evaluated using the Numerical Rating Scale (NRS) and Face Rating Scale (FRS). The skin depth of the injected ICG solution was evaluated by injecting the solution into the skin of amputated lower limbs using a 27G needle or TMD using ICG fluorescence microscopy. The median and interquartile range of the NRS scores was 3 (3-4) and 2 (2-4) in the 27G needle and TMD groups, respectively; that of the FRS scores was 2 (2-3) and 2 (1-2) in the 27G needle and TMD groups, respectively. Injection-related pain was significantly lower with the TMD than with the 27G needle. The lymphatic vessels were similarly visible using both needles. The depth of the ICG solution varied for each injection with a 27G needle (400-1200 µm) and was consistent at ∼300-700 µm below the skin surface using the TMD. Injection depth was significantly different between the 27G needle and the TMD. Conclusions: Injection-related pain decreased using the TMD, and ICG solution depth was consistent on fluorescence lymphography. A TMD may be useful for ICG fluorescence lymphography. Clinical Trials Registry (UMIN-CTR; ID: UMIN000033425).

Characteristics and Prognostic Factors of Venous Thromboembolism in Cancer Patients.

Background: Improving the prognosis of patients with malignant tumors is increasing the number of patients who develop venous thromboembolism. We examined the characteristics and prognostic factors of VTE patients with cancer. Methods: We diagnosed 725 VTE patients from April 2005 to March 2018. There were 322 cancer associated patients (CAT) and 403 non-cancer associated patients (nonCAT). We examined characteristics and prognostic factors of VTE in CAT patients. Results: There were 156 women and 166 men in CAT, and 132 women and 271 men in nonCAT. There was no significant difference in the location of proximal portion of thrombus. When locations were divided into left leg, right leg, and bilateral legs, bilateral cases were more common in CAT group. Comparing the overall survival after VTE diagnosis in the CAT group, the prognosis was poor in patients with high D-dimer level (≧6 µg/mL) along with cancer metastasis and recurrence. Conclusions: Various VTE factors predict prognosis in CAT patients, and CAT is important in the treatment of cancer patients. (This is secondary publication from Jpn J Phlebol 2020; 31(3): 153-159.).

The Patency of Tibial/Peroneal Arteries Affects the Increment of Regional Tissue Saturation of Oxygen in Each Angiosome after Superficial Femoral Artery Revascularization.

Objective: The angiosome model is a controversial concept in the revascularization of patients with chronic limb-threatening ischemia (CLTI). The aim of this study was to demonstrate the importance of patency of the tibial/peroneal arteries for regional tissue oxygenation in each angiosome during endovascular therapy (EVT) of the superficial femoral artery (SFA). Materials and Methods: We devised a novel near-infrared spectroscopy oximeter, "TOE-20," for real-time monitoring of regional tissue oxygen saturation (rSO2). Using TOE-20, we prospectively assessed rSO2 at each angiosome in 23 CLTI patients who underwent successful revascularization of the SFA. During EVT, three sensor probes were placed at the dorsal foot, plantar foot, and outer ankle for rSO2 monitoring. Results: At the end of EVT, rSO2 at all angiosomes was significantly elevated by SFA revascularization. The change in rSO2 in each angiosome was larger in patients with patent relevant arteries than in those with occluded relevant arteries (i.e., anterior tibial artery patency, posterior tibial artery patency, and peroneal artery patency). Conclusion: The patency of the tibial/peroneal arteries is important for regional tissue oxygenation in EVT. Using TOE-20 and rSO2-based revascularization, it may possible to anticipate whether an ischemic ulcer will heal or not.

Role of Subcutaneous Adipose Tissues in the Pathophysiology of Secondary Lymphedema.

Background: Secondary lymphedema (LE) occurs due to the disruption of lymphatic circulation. Lymphatic fluid accumulation in subcutaneous tissues induces adipocyte proliferation. Obesity is an important risk factor for the occurrence and deterioration of LE. Although the relationship between LE and subcutaneous adipose tissue increase has been reported clinically, their pathophysiological relationship remains unknown. Thus, we aimed to verify whether subcutaneous adipose tissue increase is involved in the pathophysiology of secondary LE. Methods and Results: The hindlimb model of secondary LE was created using male Sprague-Dawley rats (control and LE groups; n = 5 each). Skin samples were obtained on postoperative day 168. Histological examination and quantitative real-time polymerase chain reaction analysis of inflammatory adipokines, tumor necrosis factor-alpha (Tnf-α), C-C chemokine ligand 2 (Ccl2), and interleukin-6 (Il-6) were performed. Limb volume and subcutaneous adipose tissues significantly increased in the LE group compared with those in the control. Macrophages aggregated in the augmented adipose tissues, around the adipocytes, and formed crown-like structures (CLSs). The number of CLSs significantly increased in the LE group. These macrophages expressed transforming growth factor-beta 1 (TGF-ß1). Inflammatory adipokine secretion was not observed. Although Il-6 expression increased in the LE group, IL-6 was expressed in subcutaneous myofibroblasts but not in subcutaneous adipocytes. Conclusion: As TGF-ß1 derived from subcutaneous myofibroblasts is involved in skin fibrosis during LE, TGF-ß1 derived from adipose tissues may also play a similar role. Drug treatment for subcutaneous adipose tissue reduction may improve the skin condition in secondary LE and may be a new therapeutic strategy.

Differences in Vasa Vasorum Distribution in Human Aortic Aneurysms and Atheromas.

The pathophysiological difference between aortic atheromas and aneurysms is unknown. We focused on the vasa vasorum (VV), which play a critical role in maintaining aortic homeostasis and are also involved in vascular diseases. We investigated the differences in VV between the atheromas and aneurysms. Human abdominal aortic samples were obtained from patients with abdominal aortic aneurysm during surgery or autopsy cases. Autopsy cases were divided into 2 groups according to atheromas. The VV were evaluated using immunohistochemical staining for von Willebrand factor. Intimal VV increased in both the atheroma and aneurysm groups, medial VV increased, and adventitial VV decreased only in the aneurysm group. We also observed that the medial VV were connected to the adventitial VV in the atheroma group and to intimal VV in the aneurysm group. We suggest the outside-in VV or inside-out VV theories. Atheroma induces hypoxia of aortic walls, and angiogenic factors might induce an increase of intimal VV derived from adventitial VV (outside-in VV). However, adventitial VV decrease induces hypoxia of aortic walls, and angiogenic factors might induce an increase of intimal VV derived from aortic lumen (inside-out VV). These differences of VV may contribute in elucidating the pathophysiology of aortic diseases.

A Pilot Study Investigating the Use of Regional Oxygen Saturation as a Predictor of Ischemic Wound Healing Outcome after Endovascular Treatment in Patients with Chronic Limb-Threatening Ischemia.

Objective: To determine the prognostic value of regional tissue oxygenation saturation (rSO2) for ulcer healing after endovascular treatment (EVT) of peripheral arterial disease (PAD). Materials and Methods: Among PAD patients, 34 patients with chronic limb-threatening ischemia underwent EVT for limb salvage. We retrospectively analyzed the cutoff rSO2 values on postoperative day 1 to predict ulcer healing and patient prognosis. Skin perfusion pressure (SPP) and transcutaneous oxygen pressure (TcPO2) were also used to assess wound healing. Results: A finger-mounted tissue oximeter can easily measure rSO2 on the dorsal foot. Among the 34 patients, the ulcer healed in 25, and no changes were observed in 2 patients at 1 month after EVT. However, 7 patients needed major amputation at the same time. Wound healing was achieved in all patients with rSO2≥50%. With this cutoff, the sensitivity and specificity of the new device for wound healing were 100% and 64%, respectively. In all the wound healing cases, SPP was ≥45 mmHg, and TcPO2 was ≥40 mmHg. Conclusion: To assess limb ischemia, rSO2 can be measured quickly and easily using this device. We suggest that an rSO2>50% shows good prognosis for ulcer healing.

Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery.

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.

Target region oxygenation-based endovascular treatment in a chronic limb-threatening ischemia patient with multifocal arterial diseases.

Patients with chronic limb-threatening ischemia often have multiple segmental diseases requiring revascularization. However, there is no defined milestone to indicate sufficient endovascular treatment (EVT). Using multiple near-infrared spectroscopic oximeters, we intraoperatively monitored regional tissue oxygen saturation (rSO2) to perform target region oxygenation-based EVT for a patient with chronic limb-threatening ischemia. Stent placement at the superficial femoral artery and angioplasty of the tibioperoneal trunk enabled rSO2 in the target ischemic regions (dorsal foot and heel) to be >50% for ulcer healing. We herein describe target region oxygenation-based EVT with rSO2 monitoring as an effective strategy for performing the minimum requisite procedures.

K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models. METHODS: A hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model were also used to examine the ability of K-134 to prevent rupture. RESULTS: K-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol (P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE-/- mouse model, K-134 inhibited rupture and significantly improved survival (P < .01). CONCLUSIONS: K-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS-Vascular Science 2020;1:219-32.). CLINICAL RELEVANCE: This study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA.

Development of a Noninvasive Skin Evaluation Method for Lower Limb Lymphedema.

Background: The skin's condition is altered in lymphedema patients, and evaluating this change is important. Some noninvasive methods for evaluating skin condition have been reported, especially in upper limb lymphedema. However, evaluating the skin in lower limb lymphedema remains challenging and is often limited to palpation. We aimed to develop a noninvasive skin evaluation method for lower limb lymphedema patients. Methods and Results: Twenty-five lower limb lymphedema patients were included. Skin induration and elasticity were measured using Indentometer® IDM 400 and Cutometer® MPA580. The relationship between the properties of skin from the healthy forearm and thigh, those of the affected thigh, and age was analyzed. Predicted skin induration age (IA) and elasticity age (EA) were calculated from the forearm, whereas actual values were calculated from the thigh, and the differences (ΔIA and ΔEA) were assessed. Patients were classified according to the International Society of Lymphology clinical staging system, and the differences in ΔIA and ΔEA were analyzed among the three groups (healthy, stage I/IIa, and stage IIb/III). Skin biopsy was performed in five unilateral lower limb lymphedema patients, and the dermal elastic fiber area was determined using microscopy with Elastica van Gieson staining. ΔEA significantly increased with disease progression, but ΔIA did not change significantly. Microscopy revealed elastic fiber filamentous changes, with decreased elastic fiber areas in lymphedema-affected skin. Conclusion: To our knowledge, this is the first report to evaluate lower limb skin elasticity in lymphedema quantitatively and noninvasively. ΔEA is useful for evaluating skin condition progression in lymphedema patients.

Utility of a Finger-Mounted Tissue Oximeter with Near-Infrared Spectroscopy to Evaluate Limb Ischemia in Patients with Peripheral Arterial Disease.

Objective: To investigate whether a finger-mounted tissue oximeter is useful in evaluating limb blood flow in patients with peripheral arterial disease (PAD). Materials and Methods: Seventy-two patients with PAD were included, and the ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO2), and skin perfusion pressure (SPP) were measured. The regional tissue oxygenation saturation (rSO2) was measured using a finger-mounted tissue oximeter at the ankle, dorsal foot, and each dorsal and plantar toe. Correlations between rSO2 and ABI and between TcPO2 and SPP were analyzed. The patients were divided into three groups: Fontaine IIa (F-IIa), IIb (F-IIb), and III and IV (F-III/IV) groups. The difference in rSO2 between each group was analyzed. Results: Significant correlations were observed between rSO2 and TcPO2 and between rSO2 and SPP. TcPO2 and SPP in the F-III/IV group were significantly lower than those in the F-IIa group. rSO2 in the F-IIb and F-III/IV groups was significantly lower than that in the F-IIa group. Conclusion: The measurement of rSO2 using finger-mounted tissue oximetry is quick, simple, and painless. It can be used on any skin area and is useful to evaluate limb circulation in patients with PAD.

Characteristics of Symptomatic Pulmonary Thromboembolism among Postoperative and Hospitalized Patients.

Backgrounds: Pulmonary thromboembolism (PTE) is severe complication which may arise during all medical service. The purpose of this study is to evaluate inpatient symptomatic PTE. Materials and Methods: From 2005 to 2016, we experienced 75 symptomatic PTE patients among 600 venous thromboembolism patients. According to the place of occurrence, patients were divided to inpatient group and outpatient group. We further divided inpatient group to surgical group and non-surgical group. Results: Inpatients group, 38 had PTE (surgical: 23, non-surgical: 15). Outpatients group, 37 had PTE (with medical practice: 22, without medical practice: 15). Severity of PTE were follows; cardiac arrest 2, massive 13, sub-massive 18, non-massive 42. In surgical group, anticoagulation had been used in 3/23 (13.6%), intermittent pneumatic compression had been used in 16/23 (72.9%), compression stockings had been used in 20/23 (90.9%). In non-surgical group, no anticoagulation had not been used, intermittent pneumatic compression had been used in 2/15 (13.3%), compression stockings had been used in 2/15 (13.3%). Conclusion: As PTE prophylaxis, anticoagulation had been scarcely used in surgical group. Delayed anticoagulation may decrease symptomatic PTE in surgical patients. Despite adequate prophylaxis, PTE cannot be prevented completely. Medical staff and patients should recognize the risk of PTE together. (This is a translation of Jpn J Phlebol 2018; 29(1): 33-40.).

Axillo-Axillary Artery Bypass With Coil Embolization of the Innominate Artery for a Traumatic Innominate Artery Aneurysm: A Case Report.

BACKGROUND: Innominate artery aneurysm (IAA) is a rare cervical artery aneurysm. Although atherosclerosis is its most common cause, IAAs due to cervical injury are often reported. Operative indications for IAAs include rupture or symptomatic aneurysm, saccular aneurysm, aneurysm with a diameter of 3 cm or greater, and aneurysmal change of the origin of the innominate artery. Although the ligature of the innominate artery or open surgical repair is well described, the usefulness of endovascular repair has also recently been reported. Herein, we report a case of traumatic IAA with infection in the cervical region after tracheostomy. CASE PRESENTATION: A 40-year-old man with cholecystolithiasis planned to undergo laparoscopic cholecystectomy at another hospital. Urgent tracheostomy was performed because of laryngeal edema at the induction of general anesthesia. Enhanced computed tomography angiography 1 week after the tracheostomy revealed a saccular IAA. The patient was deemed to be at high risk for aneurysm rupture and was referred to our hospital. Preoperative Matas test, Allcock test, and innominate arterial stump pressure measurement were performed to assess the cerebral blood flow and ischemic tolerance of the brain. These examinations showed the patency of the circle of Willis. An axillo-axillary artery bypass with coil embolization of the innominate artery was performed to avoid postoperative vascular graft infection. No postoperative complications such as infection or cerebral infarction occurred. Magnetic resonance imaging angiography performed 6 months after surgical treatment showed that the aneurysm had disappeared, and patency of the bypass graft was present. There were no postoperative complications, such as neurological deficits or graft infection, at more than 5 years after surgery. CONCLUSIONS: We report a successfully treated case of IAA after tracheostomy. Axillo-axillary artery bypass with coil embolization of the innominate artery is an effective treatment of IAA with cervical infection.