Risk factors for ocular neovascularization after central retinal artery occlusion.

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.

Relationship Between Serum Lipid Profiles and Carotid Intraplaque Neovascularization in a High-Stroke-Risk Population: A Cross-Sectional Study in China.

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.

Unaffected fellow eye neovascularization in patients with type 3 neovascularization: Incidence and risk factors.

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.

Effects of external counter-pulsation on endothelial function assessed by peripheral artery tonometry, levels of glycaemia and metabolic markers in individuals with type 2 diabetes mellitus.

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.

Neovascular Age-Related Macular Degeneration: Therapeutic Management and New-Upcoming Approaches.

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.

Predictors of good visual outcomes in patients with neovascular age-related macular degeneration in daily practice.

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.

Baicalein suppresses vasculogenic mimicry through inhibiting RhoA/ROCK expression in lung cancer A549 cell line.

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.

Twelve-month outcomes of intra-vitreal anti-VEGF agents for treatment-naïve neovascular age-related macular degeneration eyes: French data from the fight for retinal blindness!

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.

Natural history of pregnancy-related enhanced myometrial vascularity following miscarriage.

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.

Increase in the Population of Patients with Neovascular Age-Related Macular Degeneration Who Underwent Long-Term Active Treatment.

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.

Clinical-pathological characteristics and short-term follow-up associated with proliferation, apoptosis and angiogenesis in a prospective cohort of patients with colorectal tumours.

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.

The Focus and Target: Angiogenesis in Refractory Wound Healing.

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.

Intraplaque Microvascular Flow Signal in Superb Microvascular Imaging and Magnetic Resonance Imaging Carotid Plaque Imaging in Patients with Atheromatous Carotid Artery Stenosis.

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.

B7­H3 promotes malignant progression of muscle­invasive bladder cancer.

The objective of the present study was to investigate the expression of B7 homologue 3 (B7­H3) in muscle­invasive bladder cancer (MIBC) tissues, evaluate its correlation with patient clinicopathological characteristics, and to explore the effect of B7­H3 on MIBC cells. B7­H3 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 B7­H3­silenced 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 B7­H3 shRNA on MIBC in vivo. The results revealed that, among the 115 patients, the B7­H3 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 progression­free survival (PFS) were significantly worse for patients with high B7­H3 expression (P<0.001 and P<0.001, respectively) among the 115 MIBC patients. Suppression of B7­H3 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/B7­H3 shRNA group compared with the control (P<0.05, respectively). Finally, we were able to inhibit tumor development by decreasing B7­H3 expression in vivo. In conclusion, a high expression level of B7­H3 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, B7­H3 may be a potential novel biomarker for the poor prognosis of MIBC patients.

Anti-angiogenic activity of Middle East medicinal plants of the Lamiaceae family.

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.

Tumor angiogenesis and bone metastasis - Correlation in invasive breast carcinoma.

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.

Interval to vascularization development in cirrhotic precursor nodules in patients with hepatitis B and C virus co-infections.

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.

Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma.

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.

Incidence of anterior segment neovascularization during intravitreal treatment for macular edema secondary to central retinal vein occlusion.

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.

Pathophysiology of bone metastases from solid malignancies.

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.