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Background: To report the incidence and risk factors associated with ocular neovascularization (NV) in patients with central retinal artery occlusion (CRAO)., Methods: This retrospective study included patients diagnosed with acute CRAO in a single tertiary center. Medical charts were reviewed for ocular NV occurrences. We analyzed systemic and ocular conditions on first visit and demographic data., Results: Eighty-seven eyes were eligible for this study. Among these, 13 eyes had ocular NV after CRAO, with an incidence of 15%. The prevalences of hypertension, diabetes mellitus, history of stroke, chronic kidney disease (CKD), and age at first visit were higher among patients with ocular NV than among patients without ocular NV after CRAO. Moreover, most patients with CKD in the ocular NV group had undergone dialysis. A multivariate regression analysis revealed that CKD (hazard ratio [HR]: 9.27, 95% CI, 1.87-46.05, p = 0.006) and glaucoma history (HR: 7.52, 95% CI, 1.14-49.46, p = 0.036) were significant risk factors for developing ocular NV among patients with CRAO., Conclusion: CKD and glaucoma history were significant risk factors for developing ocular NV after CRAO, particularly among patients that underwent dialysis., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Aims: To determine the prevalence of neovascularity in the supraspinatus tendon of patients presenting with clinically painful unilateral rotator cuff tendinopathy (RCT) using conventional colour Doppler ultrasound (CDU), power Doppler ultrasound (PDU), and superb microvascular imaging (SMI). The association between Doppler findings and clinical scores was also assessed., Methods: The bilateral supraspinatus of consecutive patients presented with unilateral RCT clinically were evaluated with grey-scale ultrasound (tendon thickening, heterogeneous echotexture, and hypoechogenicity), CDU, PDU, and SMI. The prevalence of neovascularity and grey-scale changes on duplex imaging techniques were analysed. The relationship between neovascularity on CDU, PDU, SMI, and pain/disability as determined using a visual analogue scale (VAS) and the Oxford Shoulder Score (OSS) were assessed., Results: Fifty-nine patients (mean age 53 years, 39 women) were recruited. Of the symptomatic supraspinatus tendons, 42.4% (25/59) demonstrated neovascularity on SMI, compared to 6.8% (4/59) on PDU and 5.1% (3/59) on CDU. Of the asymptomatic supraspinatus tendons, 5.1% (3/59) depicted neovascularity on SMI but not on conventional Doppler techniques. SMI showed a significant correlation with the VAS (r 2  = 0.560, p<0.001) and OSS (r 2  = 0.62, p<0.001). PDU weakly correlated with the VAS and OSS (r 2  = 0.312, p=0.016; r 2  = 0.260, p=0.047, respectively) while CDU did not show a significant relationship., Conclusion: SMI is superior in demonstrating neovascularity and shows better correlation with pain and functional deficit compared to conventional Doppler in patients with painful RCT. SMI also showed vascularity to a lesser degree in the asymptomatic tendon. Further large-scale studies are needed to prove the diagnostic value of SMI in the assessment of RCT., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background Evidence of the association between serum lipid profiles and intraplaque neovascularization (IPN) is still limited. We aimed to study the value of a novel Doppler method, superb microvascular imaging, in correlating serum lipid profiles and evidence of IPN in a population with a high risk of stroke. Methods and Results A community-based cross-sectional study was conducted in Beijing, China. Residents (aged ≥40 years) underwent questionnaire interviews, physical examinations, and laboratory testing in 2018 and 2019. Subjects with a high risk of stroke were then selected. Standard carotid ultrasound and carotid plaque superb microvascular imaging examinations were then performed on the high-stroke-risk participants. Logistic regression was used to evaluate the relationship between serum lipid profiles and carotid plaque IPN. Overall, a total of 250 individuals (mean age, 67.20±8.12 years; 66.4% men) met the study inclusion criteria. Superb microvascular imaging revealed carotid plaque IPN in 96 subjects (38.4%). Subjects with IPN were more likely to be current smokers (34.0% versus 46.9%, P =0.046), and their identified carotid plaques were much thicker (2.35±0.63 mm versus 2.75±0.80 mm, P =0.001). Serum lipids, including total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were positively associated with the presence of IPN (4.33±1.00 mmol/L versus 4.79±1.12 mmol/L, P =0.001; 2.96±0.92 mmol/L versus 3.40±1.01 mmol/L, P =0.001; 2.18±0.76 mmol/L versus 2.46±0.80 mmol/L, P =0.005, respectively), and after adjustment for other confounders, the positive relationship remained significant. Furthermore, non-high-density lipoprotein cholesterol (odds ratio, 2.62 [95% CI, 1.35-5.06]) was significantly associated with the presence of carotid plaque IPN even after adjusting for low-density lipoprotein cholesterol. Conclusions Total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were positively associated with the presence of carotid IPN in a Chinese high-stroke-risk population. Further prospective studies should be conducted to better understand how much finding IPN adds to current stroke prediction tools.

Purpose: To evaluate the incidence and risk factors of neovascularization in unaffected fellow eyes of patients diagnosed with type 3 neovascularization in Korea., Methods: This retrospective study included 93 unaffected fellow eyes of 93 patients diagnosed with type 3 neovascularization. For initial type 3 neovascularization diagnosis, optical coherence tomography and angiography were conducted. These baseline data were compared between patients with and without neovascularization in their fellow eyes during the follow-up period., Results: The mean follow-up period was 66.1±31.1 months. Neovascularization developed in 49 (52.8%) fellow eyes after a mean period of 29.5±19.6 months. In the fellow eye neovascularization group, the incidence of soft drusen and reticular pseudodrusen was significantly higher than that in the non-neovascularization group (83.7% vs. 36.5%, p<0.001; 67.3% vs. 40.9%, p = 0.017, respectively), but the choroidal vascularity index (CVI) showed a significantly lower value (60.7±2.0% vs. 61.7±2.5%; p = 0.047). The presence of reticular pseudodrusen was related with the duration from baseline to development of fellow eye neovascularization (p = 0.038)., Conclusion: Neovascularization developed in 52.8% of unaffected fellow eyes. The presence of soft drusen, reticular pseudodrusen, and lower CVI values can be considered risk factors of neovascularization in unaffected fellow eyes of patients with type 3 neovascularization. The lower CVI values suggest that choroidal ischemic change may affect the development of choroidal neovascularization in these patients., Competing Interests: The authors have declared that no competing interests exist.

Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.

Purpose: To report predictive factors for therapeutic response to anti-VEGF in patients with neovascular age-related macular degeneration (nAMD) in daily clinical practice in our patient population., Methods: Retrospective cohort study including 56 patients (69 eyes) with nAMD treated with anti-VEGF, followed for at least two years between February 2012 and April 2018. Patients received three intravitreal anti-VEGF (bevacizumab) injections (loading dose) and were monitored and treated according to a PRN regimen. We analysed whether a gain in visual acuity of 15 or more ETDRS letters at the final visit was associated with demographic characteristics, presence of systemic comorbidities, fundus lesions or measurable improvement on Cirrus optical coherence tomography (OCT) between the first and last visit., Results: After a mean follow-up of 15.5 months (4.7-27.8 interquartile range), central retinal thickness (CRT) (RR: 1.004; IC 95%: 1.001-1.007; P=0.011) and macular hemorrhage (RR: 0.30; IC 95%: 0.10-0.90, P=0.032) at baseline were found to be useful predictive factors for visual acuity improvement (≥15 letters) in patients treated for nAMD by anti-VEGF in a real world clinical setting., Conclusion: In the present series of patients with nAMD receiving a loading dose of bevacizumab and followed according to a PRN regimen for 24 months, the only predictable factors for a ≥15 letter gain in visual acuity were anatomical response as measured by OCT and macular hemorrhage at baseline., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Age-related macular degeneration (AMD) constitutes a prevalent, chronic, and progressive retinal degenerative disease of the macula that affects elderly people and cause central vision impairment. Despite therapeutic advances in the management of neovascular AMD, none of the currently used treatments cures the disease or reverses its course. Medical treatment of neovascular AMD experienced a significant advance due to the introduction of vascular endothelial growth factor inhibitors (anti-VEGF), which dramatically changed the prognosis of the disease. However, although anti-VEGF therapy has become the standard treatment for neovascular AMD, many patients do not respond adequately to this therapy or experience a slow loss of efficacy of anti-VEGF agents after repeated administration. Additionally, current treatment with intravitreal anti-VEGF agents is associated with a significant treatment burden for patients, caregivers, and physicians. New approaches have been proposed for treating neovascular AMD. Among them, designed ankyrin repeat proteins (DARPins) seem to be as effective as monthly ranibizumab, but with greater durability, which may enhance patient compliance with needed injections.

Background and Aims: External counter-pulsation (ECP) generates sheer stress thereby improving endothelial function and anginal symptoms in coronary artery disease. Endothelial dysfunction is also involved in the pathogenesis of T2DM. The aim of this pilot study was to investigate the use of ECP at different doses in improving endothelial function and glycaemic markers in T2DM., Methods: This prospective study involved 46 subjects with T2DM randomly assigned to receive 35 sessions of ECP at different regimens (0.5 h versus 1 h) and duration (7 versus 12 weeks). Endothelial function was evaluated by reactive hyperaemia index (RHI) via peripheral arterial tonometry at the start, midpoint and end of study. Other secondary outcomes included fasting glucose, HOMA-IR, HbA1c, blood pressure, lipid profile, weight and vibration sense., Results: There was no change in RHI across all 3 regimens of ECP individually or collectively at the end of the study (ΔRHI +0.01%, p = 0.458). Glycaemic markers also remained unchanged at endpoint. Subgroup analysis showed an improvement in RHI (ΔRHI +20.6%, p = 0.0178) in subjects with more severe endothelial dysfunction at baseline., Conclusion: ECP did not show a beneficial effect on endothelial function or glycemic control in this South-East Asian population with T2DM at any of the three regimens. This may partly be explained by less severe endothelial dysfunction and less insulin resistance in our population at baseline., Competing Interests: Declaration of competing interest This is a Principal Investigator-initiated study, with research support from Renew Group Private Limited. The terms of this arrangement have been reviewed and approved by the National University Hospital Singapore in accordance with its policy on objectivity in research and with the funding source. The author has no conflict of interest., (Copyright © 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Introduction: To describe the one-year functional outcomes of treatment-naïve neovascular age-related macular degeneration (nAMD) treated with anti-VEGF agents at the Dijon University Hospital Ophthalmology Department., Methods: Real-life interventional study including all treatment-naïve nAMD patients from January 2016 to December 2018 in the Ophthalmology Department of Dijon University Hospital. Data were retrospectively collected from the Fight Retinal Blindness! (FRB!) registry. At baseline, medical history, visual acuity (VA), type of lesion and activity on angiography and optical coherence tomography (OCT), and treatment were recorded. On follow-up, VA, lesion activity and treatment were recorded., Results: Three-hundred twenty eyes of 259 patients were included, of which 65.6% were female and with a mean age of 80.1±11.1 years. Mean VA (standard deviation, SD) at baseline was 53.2 ETDRS letters (25.3). All patients received anti-VEGF injections, of which 164 eyes (51.2%), 152 eyes (47.5%) and 4 eyes (1.2%) were treated with aflibercept, ranibizumab and bevacizumab, respectively. A total of 198 eyes of 169 patients completed the 12-month follow-up, with a median (first quartile, third quartile) of 12 visits (10, 13). At one year (n=198), the overall mean VA gain [95% CI] was +3.3 ETDRS letters [0.7, 5.9] and 173 (87.4%) of the treated eyes did not lose 15 or more letters. We found no statistically significant difference in mean VA gain between aflibercept and ranibizumab., Conclusion: This real-world study confirmed the efficacy of anti-VEGF agents in nAMD and the feasibility of analyzing data in an international registry., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Vasculogenic mimicry (VM) refers to a new tubular network of the blood supply system with abundant extracellular matrix. VM is similar to capillaries but does not involve endothelial cells. As a traditional herbal medicine commonly used in China, baicalein possesses anti-inflammatory and lipoxygenase activities. However, the effects of baicalein on the process of VM formation in non-small cell lung cancer (NSCLC) and the underlying mechanisms have remained poorly understood. In this study, baicalein was found to inhibit the viability and motility of A549 cells and induced the breakage of the cytoskeletal actin filament network. In addition, baicalein significantly decreased the formation of VM and downregulated the expressions of VM-associated factors, such as VE-cadherin, EphA2, MMP14, MMP2, MMP9, PI3K and LAMC2, similar to the effects of ROCK inhibitors. Indeed, baicalein inhibited RhoA/ROCK expression in vitro and in vivo, suggesting the underlying mechanisms of reduced VM formation. Collectively, baicalein suppressed the formation of VM in NSCLC by targeting the RhoA/ROCK signaling pathway, indicating that baicalein might serve as an emerging drug for NSCLC., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Our primary aim was to report the incidence of enhanced myometrial vascularity (EMV) in consecutive women attending our early pregnancy assessment unit, following first-trimester miscarriage. We aimed further to evaluate the clinical presentation and complications associated with expectant and surgical management of EMV in these women., Methods: This was a prospective cohort study conducted in a London teaching hospital between June 2015 and June 2018, including consecutive patients with an observation of EMV on transvaginal ultrasonography following first-trimester miscarriage. The diagnosis was made following the subjective identification of EMV using color Doppler ultrasonography and a peak systolic velocity (PSV) ≥ 20 cm/s within the collection of vessels. Women were followed up with repeat scans every 14 days. Management was expectant unless intervention was indicated because of excessive or prolonged bleeding, persistent presence of retained tissue in the endometrial cavity or patient choice. The final clinical outcome was recorded. Time to resolution of EMV was defined as the interval from detection of EMV until resolution., Results: During the study period, there were 2627 first-trimester fetal losses in the department and, of these, 40 patients were diagnosed with EMV, hence the incidence of EMV following miscarriage was 1.52%. All cases were associated with ultrasound evidence of retained products of conception (RPOC) at presentation (mean dimensions, 22 × 20 × 20 mm). Thirty-one patients opted initially for expectant management, of which 18 had successful resolution without intervention, five were lost to follow-up and eight subsequently had surgical evacuation due to patient choice. No expectantly managed case required emergency intervention. Nine patients chose surgical evacuation as primary treatment. No significant correlation was seen between PSV within the EMV at presentation and blood loss at surgery. Median PSV was 47 (range, 20-148) cm/s. The estimated blood loss in all cases managed surgically ranged from 20-300 mL. Presence of RPOC was confirmed in all specimens that were sent for analysis following surgery. For cases successfully managed expectantly, the mean time to resolution was 48 (range, 21-84) days. In the nine cases managed surgically from the beginning, the mean time to resolution of EMV was 10.6 (range, 3-29) days., Conclusions: This study suggests that EMV is an uncommon finding following miscarriage and is associated with the presence of RPOC. Expectant management was a safe option in our cohort, with minimal bleeding, although it was associated with protracted time to resolution. In patients who opted for surgery, the maximum blood loss was 300 mL and no patient required blood transfusion or embolization. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

To investigate changes in the size of the population of patients who are receiving long-term, active treatment for neovascular age-related macular degeneration (AMD). This retrospective, observational study included 18,165 patients who received anti-vascular endothelial growth factor injections (3,974 eyes). The injections performed were divided into the following three groups: group 1, injections performed right after the initial diagnosis; group 2, injections performed <24 months; and group 3, injection performed ≥24 months. Time-dependent changes in the proportion of injections in each group were analyzed. The total number of injections markedly increased from 431 in the 1st quarter of 2014 to 1,323 in the 4th quarter of 2018. There were significant changes in the proportion of injections in each group over time (P < 0.001). The proportions of group 1, group 2, and group 3 in the 1st quarter of 2014 were 17.4%, 65.4%, and 17.2%, respectively. The proportions changed to 10.6%, 50.2%, and 39.5% in the 4th quarter of 2018, respectively. The marked increase in the proportions of group 3 may suggest an increase in the patient population that underwent long-term active treatment. The socioeconomic influence of this trend should be considered when establishing future strategies for neovascular AMD.

We investigate the clinical and pathological features related to variations in colorectal tumour apoptosis, proliferation and angiogenesis and the influence of the latter in short-term mortality (2 years); 551 tumour samples from a prospective cohort of patients with colorectal cancer were examined and tumour biology markers were determined as follows: percentage of apoptotic cells, by the terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling technique; Ki-67 antigen, as a cell proliferation marker and density of microvessels (as a marker of angiogenesis). An increase in the percentage of cellular apoptosis is significantly related to the presence of poorly differentiated tumours, with vascular invasion (p < 0.001). The CD105 angiogenesis marker is not related to any clinical-pathological parameter except that of higher frequency in older patients (p = 0.03). Ki-67 is more frequently expressed in tumours with less nervous invasion (p = 0.05). Neither apoptosis nor angiogenesis present any significant association with short-term survival. The only marker clearly related to 2-year survival is Ki-67, which is shown to be a good prognostic factor in the multivariate analysis (hazard ratio = 0.49; 95% confidence interval = 0.27-0.90). Therefore, in a prospective cohort of colorectal cancer patients, only Ki-67 is a marker of good prognosis in short-term follow-up.

In recent years, wound repair, especially chronic and refractory wounds, is still a growing worldwide health problem that concerns the physical and mental health of patients and the productivity of society as a whole. In many developed countries and developing countries, such as China, rapid economic growth, negative lifestyle changes (such as increased dietary fat intake and reduced physical activity), and increasingly serious aging problems have led to more and more refractory wounds caused by chronic diseases, such as diabetes and microvascular diseases. There is a clear and orderly stage in the process of wound healing, and the malfunction of any step will lead to poor healing effect. There are many causes of refractory wounds, among which the poor vascular network is closely related. This review focuses on the role and improvement of the microvasculature in wound repair. In addition, the future developmental trend of wound regenerative therapy (active factors, [stem] cells, tissue-induced biomaterials, gene therapy, etc) is also considered.

Carotid artery atherosclerosis is one of the major risk factors for ischemic stroke. Intraplaque neovascularization (IPN) is one of the steps toward the development of vulnerable plaque. Superb microvascular imaging (SMI) is a new ultrasonographic technique for visualizing low-velocity and microvascular flow by clutter suppression to extract flow signals from large to small vessels and enables visualization of intraplaque microvascular flow (IMVF) without echo contrast media. We aimed to investigate the association between IMVF signal in SMI and MRI plaque imaging among patients with atherosclerotic carotid stenosis. We prospectively enrolled patients (>18 years old) with mild to severe carotid stenosis (more than 50% in cross-sectional area) diagnosed by carotid ultrasonography between August 2017 and April 2018, irrespective of sex and history of stroke. A total of 40 patients (31 men, 9 women; mean age, 75.1 ± 10.0 years) were enrolled. SMI revealed IPN findings in 21 patients. SMI clearly visualized the direction of pulsatile flow movement in microvessels and IPN was easily classified into the two types of Type V (n=2) and Type E (n=19). Multivariate logistic regression analysis presented that microvascular flow signal in carotid plaque on SMI was identified as a significant predictor of intraplaque hemorrhage as evaluated by MRI (OR, 8.46; 95%CI, 1.44-49.9; p=0.018). This study demonstrated a significant association between the presence of IMVF signal in SMI and intraplaque hemorrhage characterized by high-intensity lesions on MRI T1-FFE images., (Copyright © 2018. Published by Elsevier Inc.)

The objective of the present study was to investigate the expression of B7 homologue 3 (B7‑H3) in muscle‑invasive bladder cancer (MIBC) tissues, evaluate its correlation with patient clinicopathological characteristics, and to explore the effect of B7‑H3 on MIBC cells. B7‑H3 expression levels in tumor tissues from 115 patients undergoing radical cystectomy for MIBC were detected by immunohistochemical staining, followed by analysis of the association with clinicopathological characteristics and survival. A B7‑H3‑silenced cell line was established by RNA interference (RNAi). Alterations in cell proliferation, cell cycle, migration and invasion were analyzed in vitro. The proteins associated with cancer cell behavior were detected by western blot analysis. In addition, we utilized a xenograft tumor assay in nude mice to test the inhibitory effect of B7‑H3 shRNA on MIBC in vivo. The results revealed that, among the 115 patients, the B7‑H3 expression level was significantly associated with an increased incidence of distant metastasis (P=0.014) and vascular invasion (P=0.031), whereas it was not statistically associated with sex, age, pathologic grade, tumor stage, recurrence and lymphatic metastasis. Overall survival (OS) and progression‑free survival (PFS) were significantly worse for patients with high B7‑H3 expression (P<0.001 and P<0.001, respectively) among the 115 MIBC patients. Suppression of B7‑H3 significantly inhibited the proliferation, caused G2 phase arrest, as well as declined migration and invasion abilities in vitro. The protein expression of Ki67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP2) and MMP9 were decreased in the T24/B7‑H3 shRNA group compared with the control (P<0.05, respectively). Finally, we were able to inhibit tumor development by decreasing B7‑H3 expression in vivo. In conclusion, a high expression level of B7‑H3 in MIBC tissues is associated with a poor clinicopathological status and poor prognosis, and promotes the development of MIBC in vitro and in vivo. Thus, B7‑H3 may be a potential novel biomarker for the poor prognosis of MIBC patients.

Angiogenesis plays a crucial role in malignant tumor progression and development. The present study aimed to identify lead plants with selective anti-angiogenic properties. A total of 26 methanolic extracts obtained from 18 plants growing in Saudi Arabia and Jordan that belong to the Lamiaceae family were screened for their cytotoxic and anti-angiogenic activities using MTT and rat aortic ring assays, respectively. Four novel extracts of Thymbra capitata (L.) Cav., Phlomis viscosa Poir, Salvia samuelssonii Rech.f., and Premna resinosa (Hochst.) Schauer were identified for their selective anti-angiogenic effects. These extracts did not exhibit cytotoxic effects on human endothelial cells (EA.hy926) indicating the involvement of indirect anti-angiogenic mechanisms. The active extracts are potential candidates for further phytochemical and mechanistic studies.

Purpose: To test the hypotheses that pathological biomarkers including CD34 positive endothelial cell and microvessel density (MVD) of the primary breast tumor can be used to predict the probability of occurrence for bone metastases and provide information for appropriate therapeutic strategies at an early stage., Methods: Three groups of CD34 immunohistochemical stained slices (n=60) were acquired from surgical specimens of sixty patients including non-metastasis (group 1), only lymph node metastasis (group 2), and bone metastasis (group 3). MVD was measured by TissueGnostics system., Results: The MVD measurement results were 57.14±23.00 in group 1, 86.44±21.13 in group 2, and 126.85±47.89 in group 3. There were statistical differences between group 1 and group 2 (P=0.0002), between group 2 and group 3 (P=0.0014) and between group 1 and group 3 (P<0.0001). The strong correlations were found between CD34 positive cell measurement and its percentage (group 1, r=0.74, P=0.0002; group 2, r=0.62, P=0.0034; group 3, r=0.84, P<0.0001), and between CD34 positive endothelial cell measurement and MVD (r=0.61, P<0.0001)., Conclusions: Quantitative CD34 positive endothelial cell and MVD measurements of the primary breast tumor have a strong correlation with the occurrence rate of bone metastases, which predicts the probability of occurrence for bone metastases at an early stage., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Bone metastases are common complications of many cancers. Among the mechanisms that set the scene for the development of bone metastases, several are shared by all forms of metastatic dissemination (pre-metastatic niche formation and chemotactic attraction of malignant cells, which invade the host tissue) and others are specific of bone tissue (homing of malignant cells to bone marrow niches and acquisition of an osteomimetic cell phenotype). After a latency period that can last several years, the malignant cells can proliferate into tumors that alter the normal bone remodeling process by inducing dysregulation of osteoblast and osteoclast function. These metastases may be lytic, characterized by major bone destruction; sclerotic, with excess bone formation; or mixed. Osteolysis occurs when the tumor cells stimulate osteoclast activity and inhibit osteoblast activity, whereas the opposite effects lead to bone sclerosis. Moreover, the mineralized bone matrix plays a major role in the formation of bone metastases, as its degradation releases growth factors and calcium that exert mitogenic effects on tumor cells. Thus, bone metastases are the site of a vicious circle in which mechanisms involved in bone resorption/formation promote tumor growth and vice versa., (Copyright © 2017. Published by Elsevier SAS.)

The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.

With the widespread use of gadoxetic acid-enhanced magnetic resonance imaging, liver nodules appearing as hypovascular in the arterial phase and hypointense in the hepatobiliary phase, defined as hypovascular hypointense nodules, are increasingly detected in patients with cirrhosis and are considered precursor nodules. We sought to evaluate the interval to vascularization development in hepatitis C virus/hepatitis B virus co-infected-associated precursor nodules (BC-HHN group) compared with that in hepatitis C virus mono-infected-associated precursor nodules (C-HHN group) in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance imaging. The interval to vascularization development was estimated by the Kaplan-Meier method and compared using the Cox proportional hazards model. The mean intervals to vascularization development in the BC-HHN and C-HHN groups were 272.9±31.1 and 603.8±47.6 days, respectively (p<0.001). The cumulative vascularization development incidence at 6, 12, and 18 months was 44.9%, 73.5%, and 91.8%, respectively, in the BC-HHN group and 16.9%, 39.0%, and 55.8%, respectively, in the C-HHN group (p<0.001). The multivariate analysis showed that the presence of hepatitis B virus co-infection (hazard ratio: 1.819; 95% confidence interval: 1.222-2.707; p = 0.003) and male sex (hazard ratio: 1.753; 95% confidence interval: 1.029-2.985; p = 0.039) were predictors of vascularization development. More than half of the hypovascular hypointense nodules showed high-signal changes on T2-weighted imaging, and almost half of them showed restricted diffusion on diffusion-weighted images, but these did not predict vascularization development. In a hepatitis C virus- and hepatitis B virus-endemic area, such as Taiwan, precursor nodules in the BC-HHN group tended to have shorter intervals to vascularization development, especially in male patients.

Following the approval of bevacizumab, an antibody targeting VEGF-A, for advanced non-squamous non-small cell lung cancer (NSCLC) in 2006, intensive efforts were put into the clinical development of antiangiogenic agents for NSCLC. Currently, the other antiangiogenic agents approved for NSCLC are ramucirumab, a VEGF receptor-2 (VEGFR-2)-targeting antibody indicated for both squamous and non-squamous NSCLC in the United States, and nintedanib, an anti-VEGFR-1/2/3, platelet-derived growth factor receptor-α/β, fibroblast growth factor receptor-1/2/3 angiokinase inhibitor indicated for adenocarcinoma of the lung in the European Union. Many other antiangiogenic agents are being evaluated in phase III trials for NSCLC, including aflibercept, sunitinib, sorafenib, cediranib, and vandetanib. Although many of the same signaling pathways are targeted by these novel agents, mixed efficacy results have been observed in these trials. Moreover, safety issues have raised concerns about using antiangiogenic agents in this patient population, and fatal bleeding events have been reported. Importantly, although no biomarker has yet been validated for antiangiogenic agents in NSCLC, biomarkers that show potential include circulating levels of short VEGF-A isoforms, expression of neuropilin-1 and VEGFR-1 in tumors and plasma, genetic variants in VEGF-A and VEGFR, and tumor protein p53 mutations (with the latter having been shown to correlate with increased levels of VEGF-A transcripts). This review provides an overview of the clinical benefit and risk associated with the use of antiangiogenic agents for NSCLC, and summarizes the research to date on the identification of predictive biomarkers for antiangiogenic therapies. Clin Cancer Res; 23(5); 1137-48. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Purpose:: To analyze the effects of injections of intravitreal triamcinolone acetonide (IVTA) and intravitreal bevacizumab (IVB) on the incidence rates of anterior segment neovascularization (ASN) and neovascular glaucoma (NVG) in patients with macular edema secondary to central retinal vein occlusion (CRVO)., Methods:: In this prospective, randomized, double-masked, sham-controlled study, 35 patients with macular edema following CRVO were randomized to intravitreal bevacizumab, intravitreal triamcinolone acetonide, or sham injections during the first 6 months of the study. The primary outcome was the incidence rate of ASN at month 6. The secondary outcomes were the mean changes from baseline in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography over time to month 12., Results:: ASN developed in 8 (22.86%) eyes, including 5 (62.50%) eyes in the sham group and 3 (37.50%) eyes in the IVTA group, during 12 months of fol low-up (p=0.009). BCVA differed significantly (p<0.05) among the groups only at month 1. CFT did not differ significantly (p<0.05) among the groups over 12 months. NVG required surgery and developed in one eye despite laser treatment., Conclusion:: Early treatment with intravitreal antivascular endothelial growth factor therapy decreases the rates of ASN and NVG after CRVO.

Aim: To investigate the ability of arterial spin labelling (ASL) perfusion parameters to distinguish high-grade from low-grade gliomas., Materials and Methods: The PubMed and EMBASE databases were systematically searched for relevant articles published up to September 2015. Studies that evaluated both high- and low-grade gliomas using ASL were included. The random effect model was used to calculate the standardised mean difference (SMD) of maximum mean absolute tumour blood flow values (aTBF max , aTBF mean ) and maximum mean relative tumour blood flow (rTBF max , rTBF mean ) between high- and low-grade gliomas., Results: Nine studies encompassing 305 patients with high- and low-grade gliomas, met all inclusion and exclusion criteria and were included in the study. Compared with low-grade gliomas, high-grade gliomas had a significant increase in all ASL perfusion values: aTBF max (SMD=0.70, 95% confidence interval [CI]: 0.22-1.19, p=0.0046); aTBF mean (SMD=0.86, 95% CI: 0.2-1.52, p=0.01); rTBF max (SMD=1.08, 95% CI: 0.54-1.63, p=0.0001) and rTBF mean (SMD=0.88, 95% CI: 0.35-1.4, p=0.0011)., Conclusions: The current study results indicate that tumour blood flow from ASL differs significantly with respect to the glioma grade. Despite some limitations, there is evidence that ASL may be useful to distinguish high- and low-grade gliomas. Further larger-scale studies are necessary to examine the utility of ASL to distinguish tumour grade., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study investigated the controversy of whether hypervascularity on color Doppler sonography correlates with thyroid malignancy by reviewing the literature and sonographic-pathologic correlation., Methods: Over a 20-year period, 698 thyroid nodules had color Doppler and histopathologic data. Intranodular vascularity was graded 0 to 3+, and histopathologic findings were recorded., Results: The data were collected from 698 patients (557 women and 141 men) with a mean age of 48 years (range, 16-87 years). Of the 698 neoplasms, 425 were malignant (mean size, 1.7 cm; range, 0.4-9 cm; 150 ≤1 cm), and 273 were benign. The carcinomas included 391 papillary, 12 Hürthle cell, 9 medullary, 6 follicular, 5 poorly differentiated, and 2 anaplastic. The grading of intranodular vascularity was 0 in 63.3%, 1+ in 12.9%, 2+ in 6.6%, and 3+ in 17.4%. Among thyroid carcinomas, follicular carcinoma and the encapsulated subtype of the follicular variant of papillary carcinoma had significantly higher intranodular vascularity than the rest (P < .0001). Benign neoplasms included 226 follicular adenoma/adenomatoid nodules (mean size, 3.2 cm; range, 1.2-8.0 cm), 42 Hürthle cell adenoma/adenomatoid nodules (mean size, 2.6 cm; range, 0.8-5.5 cm), and 5 hyalinizing trabecular adenomas (mean size, 2.4 cm; range, 0.6-6.0 cm; 4 ≤1 cm). The grading of intranodular vascularity was 0 in 6.9%, 1+ in 12.1%, 2+ in 2.6%, and 3+ in 78.4%. Intranodular hypervascularity was associated with adenoma/adenomatoid thyroid nodules, whereas a lack of vascularity was related to thyroid carcinomas (P < .0001)., Conclusions: Most sonographically detected thyroid cancers lack intranodular vascularity, and most hypervascular thyroid nodules are adenoma/adenomatoid nodules, the encapsulated subtype of the follicular variant of papillary carcinoma, or follicular carcinomas., (© 2016 by the American Institute of Ultrasound in Medicine.)

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel-Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA's approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.

In order to investigate the influence of season and month of birth on the risk of neovascular age-related macular degeneration (n-AMD) in Italy, we evaluated the month birth and sex of all patients, recorded in the anti-vascular endothelial growth factor (VEGF) monitoring registry of the Italian Medicines Agency, born between 1925-1944, who received intravitreal anti-VEGF injections for n-AMD between January 1, 2013 and July 29, 2015. The numbers of all births in Italy in the same years, extracted from the Italian National Institute of Statistics, were used to calculate the expected number of n-AMD cases. Overall, 45,845 patients (19,207 men, 26,638 women) received intravitreal anti-VEGF for n-AMD; in the same years, 20,140,426 people (10,334,262 male, 9,806,164 female) were born in Italy. Comparing the observed number of n-AMD cases with the expected number of n- AMD cases in each season, we found that the season-specific risk for n-AMD was 2.5% higher for those born in summer (OR=1.03, Bonferroni-corrected P =0.008) and 3% lower for those born in winter (OR=0.96, Bonferroni-corrected P =0.0004). When considering the month of birth, the risk of n-AMD was 5.9% lower for people born in January (OR=0.93, Bonferroni-corrected P =0.0012). The factors causing such differences should be determined.

Purpose: To investigate the incidence of neovascularization of the iris (NVI) and clinical features of patients with NVI following acute central retinal artery occlusion (CRAO)., Methods: A retrospective review of 214 consecutive CRAO patients who visited one tertiary hospital between January 2009 and January 2015 was conducted. In total, 110 patients were eligible for this study after excluding patients with arteritic CRAO, a lack of follow-up, iatrogenic CRAO secondary to cosmetic filler injection, or NVI detected before CRAO attack. Fluorescein angiography (FA) was applied until retinal arterial reperfusion was achieved, typically within 1 to 3 months., Results: The incidence of NVI was 10.9% (12 out of 110 patients). Neovascular glaucoma was found in seven patients (6.4%). The mean time to NVI diagnosis after CRAO events was 3.0 months (range, 1 week to 15 months). The cumulative incidence was 5.5% at 3 months, 7.3% at 6 months, and 10.9% at 15 months. Severely narrowed ipsilateral carotid arteries were observed in only three patients (27.3%). The other nine patients (75.0%) showed no predisposing conditions for NVI, such as proliferative diabetic retinopathy or central retinal vein occlusion. Reperfusion rate and prevalence of diabetes were significantly different between patients with NVI and patients without NVI (reperfusion: 0% [NVI] vs. 94.7% [no NVI], p < 0.001; diabetes: 50.0% [NVI] vs. 17.3% [no NVI], p = 0.017)., Conclusions: CRAO may lead to NVI and neovascular glaucoma caused by chronic retinal ischemia from reperfusion failure. Our results indicate that follow-up fluorescein angiography is important to evaluate retinal artery reperfusion after acute CRAO events, and that prophylactic treatment such as panretinal photocoagulation should be considered if retinal arterial perfusion is not recovered., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: It is not clear if progression-free survival (PFS) is a good surrogate end-point for overall survival (OS) for metastatic colorectal cancer if antiangiogenic therapies are used., Materials and Methods: We investigated randomized controlled trials testing antiangiogenic agents against chemotherapy. Log hazard ratios (HR) for PFS and OS were used to construct linear regression models. The surrogate threshold effect (STE) was calculated., Results: Thirteen studies and 24 comparison arms were available, including 7,179 patients. This model returned a significant correlation between PFS and OS (R(2)=0.68, p<0.001) with an STE of 0.83. Analysis restricted to first-line gave similar results (R(2)=0.68, p<0.001, STE=0.75)., Conclusion: There is a significant correlation between the effect of treatment on PFS and OS. PFS remains a good surrogate end-point for OS even if anti-angiogenic agents are used., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Tea leaf (Camellia sinensis) is rich in catechins, which endow tea with various health benefits. There are more than ten catechin compounds in tea, among which epigallocatechingallate (EGCG) is the most abundant. Epidemiological studies on the association between tea consumption and the risk of breast cancer were summarized, and the inhibitory effects of tea catechins on breast cancer, with EGCG as a representative compound, were reviewed in the present paper. The controversial results regarding the role of tea in breast cancer and areas for further study were discussed.

Women with hypertensive disorders of pregnancy (HDP) have higher levels of antiangiogenic growth factors during pregnancy than women with normotensive pregnancies. Since angiogenesis is necessary for solid cancer growth and spread, we hypothesized that women with a history of HDP might have a reduced risk of solid cancers (cancers other than lymphomas, hematologic cancers and nonmelanoma skin cancers) later in life. In a register-based cohort study of 1.08 million women giving birth at least once between 1978 and 2011, we used Cox regression to estimate hazard ratios (HRs) comparing solid cancer rates for women with and without a history of HDP. In this cohort, 68,236 women (6.3%) had ≥1 pregnancy complicated by HDP and 42,236 women (3.9%) developed solid tumors during follow-up. A history of HDP was not associated with a clinically meaningful reduction in the overall rate of solid cancer (HR 0.96, 95% confidence interval 0.92-1.00), regardless of HDP severity or time since HDP, nor was there a general tendency toward reduced solid cancer rates across organ sites. A history of HDP was only significantly associated with decreased rates of breast and lung cancers and with increased rates of endometrial and urinary tract cancers. Overall, our results do not support the hypothesis that women with a history of HDP have a reduced overall risk of solid cancer due to a persistent post-HDP antiangiogenic state or an innate tendency toward antiangiogenesis. Observed associations with specific cancers may instead be due to other pregnancy-related mechanisms or to residual/unmeasured confounding., (© 2016 UICC.)

The syndrome of recurrent vitreous hemorrhages in young men was described for the first time by Henry Eales in 1880. The association with a clinical manifestation of ocular inflammation was reported 5years later. Eales disease affects young adults who present with ischemic retinal vasculitis, with the peripheral retina most commonly affected. Most cases have been reported in South Asia. Although the etiology of this abnormality is unknown, it may be related to an immune sensitivity to Mycobacterium tuberculosis antigens. Its pathogenesis is related to extensive ischemia that affects the retina, secondary to an obliterative retinal vasculopathy with release of angiogenic factors of the VEGF type. Involvement of the retina is the hallmark of the disease, which manifests as follows: periphlebitis, retinal capillary ischemia most often affecting the periphery with secondary proliferative retinopathy and retinal and/or papillary neovascularization, recurrent vitreous hemorrhages and tractional retinal detachment. These complications are potentially blinding. The natural history of Eales disease varies, with temporary or permanent remission in some cases and continuous progression in others. Progression is often bilateral, which necessitates regular follow-up. The treatment of Eales disease depends on the stage of the disease and is not well defined. Observation only, pars plana vitrectomy surgery and/or intravitreal injections of anti-VEGF are recommended in cases of vitreous hemorrhage, associated with corticosteroids when retinal vasculitis is present. Laser pan-retinal photocoagulation is necessary when neovascularization is present., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Thyroid nodules are very common and less than 10% of them are malignant. They pose a serious diagnostic and therapeutic problem with respect to their benign or malignant nature. The study of some clinical and paraclinical factors for presumed malignancy makes it possible to codify appropriate therapeutic strategy. The aim of this study was to investigate predictors of malignancy in nodular goiters and to compare our results with those reported in the literature. This retrospective study consisted of 500 cases of nodular goiter operated in the Department of Otorhinolaryngology (ear, nose and throat or ENT) and Head and Neck Surgery at Avicenne military hospital in Marrakech between 2006 and 2012. The percentage of cancers was 6,8%. The average age of our patients was 46 years, with a sex-ratio of 5 (F/H). The hard nature of the nodule was present in 94,4% of the cases of cancer by palpation; irregular boundaries were present in 64.70% of the cases of cancer. Three nodules were fixed and malignant. Cervical lymphadenopathy were observed in 8 patients, 7 of which had cancer. Ultrasound examination showed hypoechoic appearance in 61,8% of the malignant nodules, with smooth-edges in 88,24% of the cases. Intranodular vascularization was found in 35,3% of the cases of cancers, with microcalcifications in 55,9% of the cases. Perinodular hypoechoic halo was incomplete in 73,5% of the cases of cancer. Our patients were euthyroid in 84,6% of the cases. Predictors of malignancy in nodular goiters were present in our first clinical study: patients over the age of 60 years, hard consistency of nodule, fixity, irregular and poorly defined character by palpation, as well as presence of cervical adenopathy on examination; and echographic features: hypoechoic character, smooth-edges, presence of microcalcifications and visualization of intranodular vascularization with or without peri-nodular vascularization. Although some of these factors are highly predictive of malignancy, only final histology provides certainty of diagnosis. Clinicians should base their clinical practice and patient management on a body of clinical arguments.

Achilles (AT) and patellar tendons (PT) are commonly affected by tendinopathy in adult athletes but prevalence of symptoms and morphological changes in adolescents is unclear. The study aimed to determine prevalence of tendinopathy and intratendinous changes in ATs and PTs of adolescent athletes. A total of 760 adolescent athletes (13.0 ± 1.9 years; 160 ± 13 cm; 50 ± 14 kg) were examined. History, local clinical examination, and longitudinal Doppler ultrasound analysis for both ATs and PTs were performed including identification of intratendinous echoic changes and vascularization. Diagnosis of tendinopathy was complied clinically in case of positive history of tendon pain and tendon pain on palpation. Achilles tendinopathy was diagnosed in 1.8% and patellar tendinopathy in 5.8%. Vascularizations were visible in 3.0% of ATs and 11.4% of PTs, hypoechogenicities in 0.7% and 3.2% as well as hyperechogenicities in 0% and 0.3%, respectively. Vascularizations and hypoechogenicities were statistically significantly more often in males than in females (P ≤ 0.02). Subjects with patellar tendinopathy had higher prevalence of structural intratendinous changes than those without PT symptoms (P ≤ 0.001). In adolescent athletes, patellar tendinopathy is three times more frequent compared with Achilles tendinopathy. Longitudinal studies are necessary to investigate physiological or pathological origin of vascularizations and its predictive value in development of tendinopathy., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: We aimed to elucidate the relationship between mild-to-moderate renal impairment and the development of coronary collateral vessels (CCV) in patients with acute coronary syndrome (ACS)., Methods: We enrolled 461 patients with ACS who underwent coronary angiography for the first time. The development of CCV was assessed with the Rentrop score. Kidney function was classified according to the estimated glomerular filtration rate (eGFR). The Gensini score was used to show the extent of atherosclerosis., Results: The mean eGFR value was 89.9 ± 24.3 U/l for patients with no development of collaterals and 82.7 ± 20.5 for patients who had CCV. The mean age was 59 ± 11 years and 349 patients (75.7 %) were male. Rentrop classifications 1-2-3 (presence of CCV) were determined in 222 (48.1 %) patients. The presence of CCV was significantly associated with low levels of eGFR (p = 0.001), increased serum creatinine levels (p = 0.034), high levels of serum albumin (0.036), and the Gensini score (p < 0.001). Multivariate analysis showed that the Gensini score was an independent predictor of the presence of CCV (OR = 1.090, 95 % CI: 1.032-1.151, p = 0.002)., Conclusion: We suggest that the association between mild-to-moderate renal impairment and the presence of CCV may be explained by increased myocardial ischemia and severe CAD.

Objective: Atherosclerosis is the main underlying cause of the majority of cardiovascular events. Although cardiovascular diseases (CVD) are a major challenge in both males and females, gender specific differences in the prevalence of CVD have been observed. This may indicate that there are differences in the development of atherosclerosis between males and females. The presence of intraplaque neovessels (IPN) is an imaging marker for plaque vulnerability. The aim of this study was to investigate the impact of gender on IPN., Methods: A total of 159 patients with ≥1 cardiovascular risk factor were included in this prospective study (mean age 56.9±8.7 years, 47% females). Patients had no symptoms of carotid atherosclerotic disease. All patients underwent a standard carotid ultrasound examination in conjunction with contrast-enhanced ultrasound (CEUS). The presence of atherosclerotic plaques was assessed according to the Mannheim consensus. IPN was assessed using a visual grading scale and semi-automated quantification software., Results: Subclinical atherosclerosis was detected using standard carotid ultrasound and CEUS in 64 females (86%) and in 79 males (93%) (p=0.177). The mean atherosclerotic plaque sizes were not significantly different (p=0.068). Semi-automated quantification of IPN demonstrated that females had significant more IPN compared to males (p<0.05). After adjustment for clinical variables this association remained significant (p<0.05)., Conclusion: In this population at increased risk for CVD, females had significantly more IPN compared to males. This suggests that the females had a more vulnerable atherosclerotic plaque type., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The Children's Oncology Group (COG) renal tumor study (AREN03B2) requires real-time central review of radiology, pathology, and the surgical procedure to determine appropriate risk-based therapy. The purpose of this study was to determine the inter-rater reliability of the surgical reviews., Methods: Of the first 3200 enrolled AREN03B2 patients, a sample of 100 enriched for blood vessel involvement, spill, rupture, and lymph node involvement was selected for analysis. The surgical assessment was then performed independently by two blinded surgical reviewers and compared to the original assessment, which had been completed by another of the committee surgeons. Variables assessed included surgeon-determined local tumor stage, overall disease stage, type of renal procedure performed, presence of tumor rupture, occurrence of intraoperative tumor spill, blood vessel involvement, presence of peritoneal implants, and interpretation of residual disease. Inter-rater reliability was measured using the Fleiss' Kappa statistic two-sided hypothesis tests (Kappa, p-value)., Results: Local tumor stage correlated in all 3 reviews except in one case (Kappa=0.9775, p<0.001). Similarly, overall disease stage had excellent correlation (0.9422, p<0.001). There was strong correlation for type of renal procedure (0.8357, p<0.001), presence of tumor rupture (0.6858, p<0.001), intraoperative tumor spill (0.6493, p<0.001), and blood vessel involvement (0.6470, p<0.001). Variables that had lower correlation were determination of the presence of peritoneal implants (0.2753, p<0.001) and interpretation of residual disease status (0.5310, p<0.001)., Conclusion: The inter-rater reliability of the surgical review is high based on the great consistency in the 3 independent review results. This analysis provides validation and establishes precedent for real-time central surgical review to determine treatment assignment in a risk-based stratagem for multimodal cancer therapy., (© 2014.)

Nasopharyngeal carcinoma (NPC) is one of the most prevalent malignant tumors with poor prognosis in Southern China and Southeast Asia. Angiogenesis-related molecules can be promising therapeutic targets in NPC. To investigate the relationships of cancer-associated fibroblasts (CAFs) and chemokine-related molecules with neoangiogenesis, we compared immunohistochemical analyses of alpha-smooth-muscle actin (α-SMA), stroma-derived factor-1 (SDF-1), and its receptor CXCR4 in primary NPC specimens and chronic nasopharyngitis tissues. In addition, we examined the expression of vascular endothelial growth factor (VEGF-A), and CD133- and VEGF- receptor-2 (VEGFR-2) double positive cells, as endothelial progenitor cells (EPCs). We also assessed CD34-positive microvessels. Significantly higher expression of α -SMA was observed in fibroblasts in NPC stroma. The immunoreactive intensities of SDF-1 and CXCR4 were significantly higher in NPC cells. CXCR4-positive cells and CD133/VEGFR-2- double positive cells were observed in the stroma surrounding cancer nests, and VEGF was detected in both cancer and stromal cells. Microvessel density was significantly higher in the stroma of NPC tissues compared to chronic nasopharyngitis tissues. Our data suggest that CAFs and NPC tumor cells may enhance neoangiogenesis in a VEGF- and SDF-1-dependent manner by recruiting EPCs from the bone marrow into tumor stroma.

Objective: A high prevalence of neovascularity in lower extremity tendinopathies has been reported. Neovascularity in those with rotator cuff tendinopathy exclusively has not been examined. The objective was to determine the prevalence of neovascularization in patients with rotator cuff tendinopathy compared with asymptomatic controls., Design: Single-blind cross-sectional study., Setting: Research laboratory., Participants: Participants (n = 40; age = 44.9 years, 23-62 years; 20 females) with rotator cuff tendinopathy (n = 20) but without full-thickness rotator cuff tears, and asymptomatic controls that were age, gender, and hand dominance matched (n = 20) to the patients., Interventions: The participants laying in supine had their shoulder positioned in internal rotation and extension. Ultrasound images were collected of the supraspinatus tendon and subacromial bursae in the transverse and longitudinal planes using a linear transducer in color Doppler mode., Main Outcome Measures: Images were assessed for neovascularization by 2 trained raters who were blinded to group (rotator cuff tendinopathy or asymptomatic group)., Results: No statistically significant difference in neovascularization was identified between participants with and without rotator cuff tendinopathy (χ = 0.13, df = 1, P = 0.72). Neovascularization was identified in 6 of 20 patients with rotator cuff tendinopathy (30%) and 5 of 20 asymptomatic control participants (25%)., Conclusions: The authors found no differences in neovascularization rate in patients with rotator cuff tendinopathy (30%) and asymptomatic controls (25%). The study indicates that neovascularization is not related to presence of symptomatic tendinopathy in those with rotator cuff tendinopathy. Neovascularization may not be a relevant sonographic finding to aid the clinical assessment of those with rotator cuff tendinopathy.

Objective: Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries., Methods: The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software., Results: Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface (p < 0.05)., Conclusion: Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown., Methods: A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS)., Results: Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study., Conclusions: No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer., Impact: Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn't find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p = 0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p = 0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p = 0.837, OS; 61.0 vs. 62.4 months; p = 0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123-2.532; p = 0.012; OS: HR, 1.965; 95 % CI, 1.108-3.486; p = 0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p > 0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.

The existing literature on preoperative spine tumor embolization is limited in size of patient cohorts and diversity of tumor histologies. This report presents our experience with preoperative embolization of hypervascular thoracic, lumbar, and sacral spinal column tumors in the largest series to date. We conducted a retrospective review of 228 angiograms and 188 pre-operative embolizations for tumors involving thoracic, lumbar and sacral spinal column. Tumor vascularity was evaluated with conventional spinal angiography and was graded from 0 (same as normal adjacent vertebral body) to 3 (severe tumor blush with arteriovenous shunting). Embolic materials included poly vinyl alcohol (PVA) particles and detachable platinum coils and rarely, liquid embolics. The degree of embolization was graded as complete, near-complete, or partial. Anesthesia records were reviewed to document blood loss during surgery. Renal cell carcinoma (44.2%), thyroid carcinoma (9.2%), and leiomyosarcoma (6.6%) were the most common tumors out of a total of 40 tumor histologies. Hemangiopericytoma had the highest mean vascularity (2.6) of all tumor types with at least five representative cases followed by renal cell carcinoma (2.0) and thyroid carcinoma (2.0). PVA particles were used in 100% of cases. Detachable platinum coils were used in 51.6% of cases. Complete, near-complete, and partial embolizations were achieved in 86.1%, 12.7%, and 1.2% of all cases, respectively. There were no new post-procedure neurologic deficits or other complications with long-term morbidity. The mean intra-operative blood loss for the hypervascular tumors treated with pre-operative embolization was 1745 cc. Preoperative embolization of hypervascular thoracic, lumbar, and sacral spine tumors can be performed with high success rates and a high degree of safety at high volume centers.