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Background Macrotrabecular-massive (MTM) subtype and vessels encapsulating tumor clusters (VETC) pattern of hepatocellular carcinoma (HCC) are associated with unfavorable prognosis. Purpose To estimate the potential of preoperative CT in the prediction of MTM subtype and VETC pattern. Materials and Methods Patients who underwent surgical resection or liver transplant and preoperative CT for HCC between January 2015 and June 2018 were retrospectively included in the primary cohort. CT imaging features were evaluated by two radiologists. Predictors associated with the MTM subtype or VETC pattern were determined by using logistic regression analyses and the performance was tested in a validation cohort. Prognostic factors associated with early recurrence after surgical resection were identified by using Cox regression analyses. Results The primary cohort included 170 patients (median age, 55 years; interquartile range, 48-63 years; 152 men). Serum α-fetoprotein level higher than 100 ng/mL (odds ratio [OR], 4.3; 95% CI: 2.1, 9.2; P < .001), intratumor necrosis (OR, 5.2; 95% CI: 2.5, 11.0; P < .001), and intratumor hemorrhage (OR, 5.4; 95% CI: 1.3, 23.3; P = .02) were independent predictors for MTM subtype, whereas tumor size greater than 5 cm (OR, 3.8; 95% CI: 1.7, 8.1; P = .001) and intratumor necrosis (OR, 2.1; 95% CI: 1.0, 4.4; P = .045) were independent predictors for VETC pattern. These features were used for the construction of ANH and SN scores (where A is α-fetoprotein level, N is necrosis, H is hemorrhage, and S is size), respectively, which showed comparable prediction performance in the primary and validation cohorts. Preoperative high ANH and high SN phenotype (hazard ratio, 1.9; 95% CI: 1.2, 3.0; P = .01) was independently associated with early recurrence after surgical resection. Conclusion Preoperative CT features could be used for the characterization of macrotrabecular-massive subtype and vessels that encapsulate tumor clusters pattern and were of prognostic significance for early recurrence in patients with hepatocellular carcinoma. Online supplemental material is available for this article. See also the editorial by Yoon and Kim in this issue. Published under a CC BY 4.0 license.

Purpose: Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients., Experimental Design: Patients with non-small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10-14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers., Results: Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, -0.71; P = 0.05) and tumor perfusion (K trans ; Spearman correlation, -0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, -0.73; P = 0.01) and GM-CSF (Spearman correlation, -1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, -0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations., Conclusions: Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted., (©2020 American Association for Cancer Research.)

Objective: Meningioma is an extra-axial tumor that forms adhesions toward the brain surface in the course of its growth. Predicting adhesions between the tumor and the brain surface leads to better predictions of surgical results. There are few studies on brain-tumor adhesions or postoperative hemorrhage. This study aimed to assess tumor vascularity of the dura and cerebral surface, and predict surgical outcomes using four-dimensional computed tomography angiography (4D CTA)., Patients and Methods: Using a dynamic contrast CT, we conducted a retrospective study of 27 patients with convexity (n = 15), falx (n = 6), and parasagittal (n = 6) meningiomas treated in our hospital from January 2016 to September 2018. We set the region of interest on the dural layer and cerebral surface side of meningiomas and calculated the mean CT value in each region. Distribution of blood flow in the tumor was classified into two groups: A, which has a higher CT value of the dural side than that of the brain surface side at every timing, and B, which meets the criteria other than those in group A. Demographic data, preoperative characteristic images, and postoperative complications were compared between the groups., Results: Twelve and 15 patients were classified into groups A and B, respectively. The extent of adhesions against the cerebral cortex in group A was significantly less severe compared with that in group B (p = 0.038). The rate of postoperative hemorrhage occurrence in group B (53%) was significantly higher than that in group A (8%) (p = 0.04). There were no significant differences in the other preoperative characteristic images or perioperative parameters between groups A and B., Conclusion: A 320-row dynamic contrast CT scanner can detect meningiomas with a high probability of severe adhesion toward the brain surface and postoperative intraparenchymal hematoma.

Background: To explore the correlation of flash dual source computed tomography perfusion imaging (CTPI) and regional lymph node metastasis of non-small cell lung cancer (NSCLC), and to evaluate the value of CT perfusion parameters in predicting regional lymph node metastasis of NSCLC., Methods: 120 consecutive patients with NSCLC confirmed by postoperative histopathology were underwent flash dual source CT perfusion imaging in pre-operation. The CT perfusion parameters of NSCLC, such as blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability (PMB) were obtained by the image post-processing. Then microvessel density (MVD), luminal vascular number (LVN), luminal vascular area (LVA) and luminal vascular perimeter (LVP) of NSCLC were counted by immunohistochemistry. These cases were divided into group A (patients with lymph node metastasis, 58 cases) and group B (patients without lymph node metastasis, 62 cases) according to their pathological results. The CT perfusion parameters and the microvessel parameters were contrastively analysed between the two groups. Receiver operating characteristic (ROC) curve was used to assess the diagnostic efficiency of CT perfusion parameters in predicting regional lymph node metastasis of NSCLC in pre-operation., Results: Group A presented significantly lower LVA, BF and higher MTT, PMB than Group B (P < 0.05), while BV, LVN, LVP and MVD were no significant difference (P > 0.05). Correlation analysis showed that BF was correlated with LVA and LVP (P < 0.05), while BV, MTT and PMB were not correlated with LVN, LVA and LVP (P > 0.05). All the perfusion parameters were not correlated with MVD. According to the ROC curve analysis, when BF < 85.16 ml/100 ml/min as a cutoff point to predict regional lymph node metastasis of NSCLC, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 60.8, 81.7, 71.5, 75.6 and 69.5% respectively., Conclusion: Flash dual source CT perfusion imaging can non-invasively indicate the luminal vascular structure of tumor and BF can be used as one of the important indexes in predicting regional lymph node metastasis of NSCLC in pre-operation.

Background: Colorectal cancer (CRC) is an important current problem concerning public health due to its high incidence and mortality. Advances in molecular and cellular knowledge and the detection of new disease biomarkers are very important to improve prognosis, prediction, and early diagnosis. In this study, we aimed to analyze the gene and protein expression levels of two angiogenic markers, VEGF and soluble Endoglin, during different tumor stages as well as at different stages of cancer treatment, to predict the diagnosis and evolution of colon and rectal cancer., Material and Methods: This study includes 133 CRC patients (93 with colon cancer and 40 with rectal cancer) on which the gene and protein expression of Endoglin (membrane and soluble form) and VEGF were analyzed by molecular and immunohistochemical techniques on different tumor stage samples and plasma obtained preoperatively as well as 3, 6, and 9 months after resection of the tumor., Results: VEGF and Endoglin gene expressions were higher in tumor tissue than in surrounding non-tumoral tissue for both types of cancer. The VEGF levels in plasma were found to decrease in less aggressive tumors, whereas soluble Endoglin was increased in preoperative samples of patients with metastasis. Membrane Endoglin expression was higher on the vascular endothelium of more aggressive tumors. In contrast, Endoglin expression was mainly in the colon epithelium in less aggressive stage tumors., Conclusion: Endoglin and VEGF are proteins with a major role in the tumor angiogenesis process. This study performed with a wide cohort of human samples shows that both proteins seem to be valuable biomarkers in the diagnosis and prognosis of CRC.

Background Tetralogy of Fallot with major aortopulmonary collateral arteries is a heterogeneous form of pulmonary artery (PA) stenosis that requires multiple forms of intervention. We present a patient-specific in vitro platform capable of sustained flow that can be used to train proceduralists and surgical teams in current interventions, as well as in developing novel therapeutic approaches to treat various vascular anomalies. Our objective is to develop an in vitro model of PA stenosis based on patient data that can be used as an in vitro phantom to model cardiovascular disease and explore potential interventions. Methods and Results From patient-specific scans obtained via computer tomography or 3-dimensional (3D) rotational angiography, we generated digital 3D models of the arteries. Subsequently, in vitro models of tetralogy of Fallot with major aortopulmonary collateral arteries were first 3D printed using biocompatible resins and next bioprinted using gelatin methacrylate hydrogel to simulate neonatal vasculature or second-order branches of an older patient with tetralogy of Fallot with major aortopulmonary collateral arteries. Printed models were used to study creation of extraluminal connection between an atretic PA and a major aortopulmonary collateral artery using a catheter-based interventional method. Following the recanalization, engineered PA constructs were perfused and flow was visualized using contrast agents and x-ray angiography. Further, computational fluid dynamics modeling was used to analyze flow in the recanalized model. Conclusions New 3D-printed and computational fluid dynamics models for vascular atresia were successfully created. We demonstrated the unique capability of a printed model to develop a novel technique for establishing blood flow in atretic vessels using clinical imaging, together with 3D bioprinting-based tissue engineering techniques. Additive biomanufacturing technologies can enable fabrication of functional vascular phantoms to model PA stenosis conditions that can help develop novel clinical applications.

Background: Numerous studies have shown that hepatocellular carcinoma (HCC) without microvascular invasion (MVI) may have better outcomes. This study established a preoperative MVI risk nomogram mainly incorporating three related risk factors of MVI in BCLC 0/A HCC after surgery., Methods: Independent predictors for the risk of MVI were investigated, and an MVI risk nomogram was established based on 60 patients in the training group who underwent curative hepatectomy for BCLC 0/A HCC and validated using a dataset in the validation group., Results: Univariate analysis in the training group showed that hepatitis viral B (HBV) DNA (P=0.034), tumor size (P<0.001), CT value in the venous phase (P=0.039), CT value in the delayed phase (P=0.017), peritumoral enhancement (P=0.013), visible small blood vessels in the arterial phase (P=0.002), and distance from the tumor to the inferior vena cava (IVC) (DTI, P=0.004) were risk factors significantly associated with the presence of MVI. According to multivariate analysis, the independent predictive factors of MVI, including tumor size (P=0.002), CT value in the delayed phase (P=0.018), and peritumoral enhancement (P=0.057), were incorporated in the corresponding nomogram. The nomogram displayed an unadjusted C-index of 0.851 and a bootstrap-corrected C-index of 0.832. Calibration curves also showed good agreement on the presence of MVI. ROC curve analyses showed that the nomogram had a large AUC (0.851)., Conclusions: The proposed nomogram consisting of tumor size, CT value in the delayed phase, and peritumoral enhancement was associated with MVI risk in BCLC 0/A HCC following curative hepatectomy., Competing Interests: The authors declare that they have no conflicts of interest.

Blood vessels are the important components of the circulatory systems that transport blood throughout the human body and maintain the homeostasis of physiological tissues. Pathologically, blood vessels are often affected by diseases, leading to the formation of unstable, irregular, and hyperpermeable blood vessels. In the tumor microenvironment, abnormal leakage of tumor blood vessels is related to the histological grade and malignant potential of tumors and may also facilitate metastasis of cancer. Visual diagnosis of blood vessels is very important for us to understand the occurrence and development of diseases. Multiphoton microscopy (MPM) is a potential label-free diagnostic tool based on second harmonic generation (SHG) and two-photon excited fluorescence (TPEF). MPM can effectively observe the morphological changes of biological tissues at the molecular and cellular levels. In this work, we demonstrate that label-free MPM can be used to visualize the microstructure of blood vessels in human normal breast and breast tumor tissue. Moreover, MPM can monitor the changes of blood vessels in tumor microenvironment. These results show that the MPM will become a promising technique for clinicians to study the properties of the microstructure of the blood vessels.

Purpose: To investigate the potential of colchicine to improve bleb function after trabeculectomy., Methods: To find the maximum usable colchicine concentration, an ocular irritation study was performed with the Draize test at concentrations of 0.001%, 0.01% and 0.1%. Additionally, the synergistic effect of topical colchicine instillation and MMC application to surgical site was evaluated in a rabbit model by measuring changes after trabeculectomy in intraocular pressure (IOP) and bleb morphology score at 3, 7, 14, 21, 28, 35, 42, and 49 days., Results: Experiments with a rabbit model of trabeculectomy showed that 0.04% MMC plus 0.01% colchicine was more effective than saline and 0.04% MMC alone in maintaining IOP reduction at days 7-49 (P < 0.01 at all time points) and day 49 (P < 0.05), respectively, while 0.04% MMC alone was more effective than saline only at days 7-35 (P < 0.05 at all time points). 0.04% MMC plus 0.01% colchicine and 0.04% MMC alone were more effective than saline at preserving bleb score at days 7-21 and 35-49 (P < 0.05 at all time points) and at days 7-35 (P < 0.05 at all time points), respectively., Conclusion: Colchicine may be a promising adjuvant for strengthening the effect of MMC and improving the survival of the filtering bleb in trabeculectomy., Competing Interests: Funding support for this research was provided by Santen, Co, Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Perihilar cholangiocarcinoma (PHCCA) is the most common type of cholangiocarcinoma with low resection rate and high morbidity. The study of PHCCA biomarkers made progresses slowly compared with intrahepatic cholangiocarcinoma because of surgical complexity and low possibility of radical surgery, which resulted in the difficulty of specimen obtainment. To screen and identify new biomarkers in PHCCA, we constructed a retrospective cohort with 121 PHCCA patients and a prospective cohort consisting of 64 PHCCA patients, and screened the candidate biomarkers by immunohistochemistry and quantified PCR. In our study, expression of high mobility group box 1 (HMGB1) was demonstrated to be significantly associated with microvascular density (MVD) and unfavorable prognosis of PHCCA in both retrospective and prospective study. Moreover, HMGB1 concentrations in bile and serum of PHCCA patients and healthy controls were detected and compared. Postoperative serum HMGB1 and reflux cholangitis indicated recurrence and unfavorable prognosis of PHCCA. With experiments in vitro and in vivo, we demonstrated that intracellular HMGB1 could be released from PHCCA cells and induce invasion and angiogenesis with LPS stimulation. VEGFR2 expression in vessel endothelial cells was upregulated by the released HMGB1 from PHCCA, resulting in the ectopic angiogenesis. In conclusion, intracellular HMGB1 could be released from PHCCA cells and promote angiogenesis via elevating VEGFR2 in vessel endothelial cells. High expression of HMGB1 was associated with MVD and poor prognosis in clinical analyzation. Postoperative serum HMGB1 and cholangitis could predict high recurrence and unfavorable prognosis.

Background: Vascular invasion, rather than tumor size, was applied into the 7th edition of the AJCC TNM staging system to predict survival of solitary hepatocellular carcinoma (HCC) patients. However, does this mean tumor size is of little value in prognostic prediction? The current study was designed to explore the prognostic ability of tumor sizes in solitary HCC., Methods: A total of 18 591 patients with solitary HCC categorized as T1 and T2 were retrieved from the Surveillance Epidemiology and End Results (SEER) database. The Cox proportional hazards regression model was adopted to evaluate the impact of tumor sizes on overall survival (OS) and disease-specific survival (DSS) in general and in subgroups stratified by vascular invasion and surgery type., Results: Large tumor sizes (>39 mm) were associated with unfavorable clinicopathologic characteristics. Compared with tumors ≤30 mm, tumors between 31-50 mm and tumors >50 mm showed significantly worse OS and DSS in general using multivariate analysis (all P < 0.001). In subgroup analyses, for patients without vascular invasion, tumor size was a notable prognostic indicator for OS in the radiofrequency ablation group (P < 0.001), rather than in the liver resection or transplantation group. Nevertheless, for patients with vascular invasion, tumor sizes exhibited a notable impact on OS in the liver resection and transplantation group., Conclusions: The AJCC TNM staging system for solitary HCC would be more comprehensive if tumor sizes were integrated into the T2 classification. Additionally, for T1 patients, tumor sizes play no role in the choice between resection and transplantation., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Contrast enhanced ultrasound (CEUS) has been suggested as an imaging tool for detection of asymptomatic carotid atherosclerotic disease (ACAD) at high risk of cerebral embolisation. The objective of this study was to evaluate CEUS and immunohistochemical (IHC) patterns in ACAD (i.e., without any neurologic symptoms in the last 6 months) and their correlations with histology., Methods: CEUS analysis was classified on a semiquantitative basis using a three-point classification scale. Plaque morphology was assessed using the American Heart Association (AHA) classification of atherosclerotic plaques, then accordingly assigned as non-vulnerable (AHA Type IV/V) or vulnerable (AHA Type VI). IHC analysis for intra-plaque neo-angiogenesis (IPN) was identified by CD34/VEGF immunostaining and classified on a semiquantitative basis using a four-point classification scale. Both CEUS and IHC analyses were performed and scored by single observers., Results: Fifty-eight consecutive asymptomatic patients (mean age 73 years, 33 males) undergoing carotid endarterectomy were included in the final analysis. Nineteen had AHA Class IV/V plaques, and the remaining 39 had AHA Class VI plaques. There were two main findings of the study: (a) histologically proven vulnerable plaques compared with histologically proven non-vulnerable plaques had denser IPN (p = .004), but did not show more pronounced contrast enhancement; (b) the correlation between IHC analysis and CEUS analysis was significant for both vulnerable and non-vulnerable plaques (p = .04 and p = .01, respectively), but it was direct for AHA Type IV/V plaques and inverse for AHA Type VI plaques., Conclusions: The main findings of the study were that histologically proven vulnerable plaques (i.e., AHA Class VI) as compared with histologically proven non-vulnerable plaques (i.e., AHA Class IV/V) had denser neo-vascularisation, but not more pronounced contrast enhancement., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line treatment for advanced lung adenocarcinoma (LUAD) cancer patients with activating EGFR mutations. However, most patients show acquired resistance to EGFR-TKIs, thereby resulting in a modest overall survival benefit. Here, we found that expression level of APE1 was closely associated with TKI resistance in LUAD. Our clinical data show that level of APE1 was inversely correlated with progression-free survival rate and median time to progression in EGFR-mutated LUAD patients. Additionally, we observed increased expression of APE1 in TKI-resistant LUAD cell lines compared to their parental cell lines. Overexpression of APE1-protected TKI-sensitive LUAD cells from TKI-induced cell growth inhibition and cell death. In contrast, inhibition of APE1-enhanced TKI-induced apoptosis, cell growth inhibition and tumor growth inhibition in TKI-resistant LUAD. In addition, we identified that APE1 positively regulates Akt activation and APE1 overexpression-induced TKI resistance was attenuated by inhibition of Akt activity. Finally, we demonstrated that inhibition of the redox function of APE1 enhances the sensitivity of TKI-resistant LUAD cells to TKI treatment and inhibits Akt phosphorylation in TKI-resistant LUAD cells, but not by inhibition of the APE1 DNA repair function. Taken together, our data show that increased expression of APE1 significantly contributes to TKI resistance development in LUAD, and targeting APE1 may reverse acquired resistance of LUAD cells to TKI treatment. Additionally, our data show that APE1 regulates TKI resistance in LUAD cells by activating Akt signaling through a redox-dependent mechanism.

Mounting evidence demonstrates that expression of ERO1α, an endoplasmic reticulum (ER)-resident oxidase, is a poor prognosis factor in a variety of human cancers. However, the clinical relevance of ERO1α and its molecular mechanisms underlying tumor progression have not been determined for hepatocellular carcinoma (HCC). ERO1α expression levels in HCC tissues and cells were detected by quantitative real-time PCR and western blotting. ERO1α shRNAs and overexpression vector were transfected into HCC cells to downregulate or upregulate ERO1α expression. In vitro and in vivo assays were performed to investigate the function of ERO1α in invasion, metastasis, and angiogenesis of HCC. We found high ERO1α expression in HCC tissues and cells that was significantly associated with metastasis and poor clinicopathologic features of vascular invasion, advanced Edmondson Grade, and TNM stage. Loss-of-function and gain-of-function studies showed that ERO1α prompted migration, invasion, epithelial-mesenchymal transition (EMT), and angiogenesis of HCC cells both in vitro and in vivo. Further studies verified a positive correlation between ERO1α and S1PR1, upregulated in metastatic HCC tissues compared with HCC tissues without metastasis. S1PR1 knockdown markedly diminished the effects of ERO1α on HCC cell migration, invasion and vascular endothelial growth factor (VEGF) expression. Most importantly, ERO1α knockdown significantly repressed the death of HCC xenograft mouse models by reducing tumor distant metastasis, and host angiogenesis by suppressing the expression of S1PR1, p-STAT3, and VEGF-A in HCC cells. Our findings suggest that ERO1α is significantly correlated with reduced survival and poor prognosis, and promotes HCC metastasis and angiogenesis by triggering the S1PR1/STAT3/VEGF-A signaling pathway. ERO1α might be a novel candidate in HCC prognosis and therapy.

Purpose: DNA hypermethylation in gene promoter regions (CpG islands) is emerging as an important pathway in colorectal cancer tumourigenesis. Whilst genetic mutations have been associated with extramural vascular invasion (EMVI) in rectal cancer, no such association has yet been made with epigenetic factors., Methods: 100 consecutive neoadjuvant-naïve patients undergoing curative surgery for rectal were classified according to the presence or absence of EMVI on histopathological examination. DNA was extracted from tumours and subjected to bisulfite conversion and methylation-specific PCR to determine CIMP status (high, intermediate, or low; according to a validated panel of 8 genes). CIMP status was correlated with EMVI status, histopathological, clinical, and demographic variables, in addition to overall (OS) and disease free (DFS) survival., Results: 51 patients were characterised as CIMP-low, 48 CIMP-intermediate, and one patient CIMP-high. EMVI-positivity was associated with CIMP-intermediate epigenotype (p < 0.001). Patients with EMVI-positive tumours were found to have significantly more advanced disease by pT, pN, and pAJCC categorisation (p = 0.002, p < 0.001, and = p < 0.001, respectively). EMVI-positivity was significantly associated with the requirement for adjuvant chemotherapy (p < 0.001), and worse DFS but not OS (p = 0.012 and p = 0.052)., Conclusions: Given the association between CIMP-intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients' cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer.

Objective: To investigate the imaging features observed in preoperative Gd-EOB-DTPA-dynamic enhanced MRI and correlated with the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients., Methods: 66 HCCs in 60 patients with preoperative Gd-EOB-DTPA-dynamic enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, peritumor enhancement during mid-arterial phase, peritumor hypointensity during hepatobiliary phase, signal intensity ratio on DWI and apparent diffusion coefficients (ADC), T1 relaxation times, and the reduction rate between pre- and postcontrast enhancement images were assessed. Correlation between these features and histopathological presence of MVI was analyzed to establish a prediction model., Results: Histopathology confirmed that MVI were observed in 17 of 66 HCCs. Univariate analysis showed tumor size ( p = 0.003), margin ( p = 0.013), peritumor enhancement ( p = 0.001), and hypointensity during hepatobiliary phase ( p = 0.004) were associated with MVI. A multiple logistic regression model was established, which showed tumor size, margin, and peritumor enhancement were combined predictors for the presence of MVI ( α = 0.1). R 2 of this prediction model was 0.353, and the sensitivity and specificity were 52.9% and 93.0%, respectively., Conclusion: Large tumor size, irregular tumor margin, and peritumor enhancement in preoperative Gd-EOB-DTPA-dynamic enhanced MRI can predict the presence of MVI in HCC.

Microvascular invasion (MVI) is rarely diagnosed preoperatively in hepatocellular carcinoma (HCC). The aim of this meta-analysis is to assess the diagnostic power of a non-smooth tumor margin on preoperative imaging for MVI. We performed a literature search using the PubMed, Embase and Cochrane Library databases, and 11 studies were included involving 618 MVI-positive cases and 1030 MVI-negative cases. Considerable heterogeneity was found, and was indicated to be attributable to the mean patient ages in the included studies. In subgroups of studies with a mean patient age older than 60 years and studies with computed tomography (CT) as the imaging method (as opposed to magnetic resonance imaging (MRI)), heterogeneity was low, and the diagnostic odds ratio (DOR) of the single two-dimensional imaging feature for MVI was 21.30 (95% CI [12.52, 36.23]) and 28.78 (95% CI [13.92, 59.36]), respectively; this power was equivalent to or greater than that of certain multivariable-based scoring systems. In conclusion, a non-smooth tumor margin on preoperative imaging is of great value for MVI assessment and should be considered for inclusion in future scoring systems.

Surgical margin status in cancer surgery represents an important oncologic parameter affecting overall prognosis. The risk of disease recurrence is minimized and survival often prolonged if margin-negative resection can be accomplished during cancer surgery. Unfortunately, negative margins are not always surgically achievable due to tumor invasion into adjacent tissues or involvement of critical vasculature. Herein, we present a novel intra-operative device created to facilitate a uniform and mild heating profile to cause hyperthermic destruction of vessel-encasing tumors while safeguarding the encased vessel. We use pancreatic ductal adenocarcinoma as an in vitro and an in vivo cancer model for these studies as it is a representative model of a tumor that commonly involves major mesenteric vessels. In vitro data suggests that mild hyperthermia (41-46 °C for ten minutes) is an optimal thermal dose to induce high levels of cancer cell death, alter cancer cell's proteomic profiles and eliminate cancer stem cells while preserving non-malignant cells. In vivo and in silico data supports the well-known phenomena of a vascular heat sink effect that causes high temperature differentials through tissues undergoing hyperthermia, however temperatures can be predicted and used as a tool for the surgeon to adjust thermal doses delivered for various tumor margins.

BACKGROUND The arteriovenous (AV) loop model enables axial vascularization to gain a functional microcirculatory system in tissue engineering constructs in vivo. These constructs might replace surgical flaps for the treatment of complex wounds in the future. Today, free flaps are often exposed to high-dose radiation after defect coverage, according to guideline-oriented treatment plans. Vascular response of AV loop-based constructs has not been evaluated after radiation, although it is of particular importance. It is further unclear whether the interposed venous AV loop graft is crucial for the induction of angiogenesis. MATERIAL AND METHODS We exposed the grafted vein to a single radiation dose of 2 Gy prior to loop construction to alter intrinsic and angio-inductive properties specifically within the graft. Vessel loops were embedded in a fibrin-filled chamber for 15 days and radiation-induced effects on flow-mediated vascularization were assessed by micro-CT and two-dimensional histological analysis. RESULTS Vessel amount was significantly impaired when an irradiated vein graft was used for AV loop construction. However, vessel growth and differentiation were still present. In contrast to vessel density, which was homogeneously diminished in constructs containing irradiated veins, vessel diameter was primarily decreased in the more peripheral regions. CONCLUSIONS Vascular luminal sprouts were significantly diminished in irradiated venous grafts, suggesting that the interposing vein constitutes a vital part of the AV loop model and is essential to initiate flow-mediate angiogenesis. These results add to the current understanding of AV loop-based neovascularization and suggest clinical implications for patients requiring combined AV loop-based tissue transfer and adjuvant radiotherapy.

Background: A case of exudative macroaneurysms in unilateral Eales' disease is reported. 'Eales disease' is an idiopathic bilateral occlusive periphlebitis with neovascularisation and mostly presents with vitreous hemorrhage., Case: A 30 year old male presented with diminution of vision in left eye (6/36) for 1 month. Slit Lamp examination of both eyes revealed normal anterior segment. Fundus examination of left eye with + 90 D lens revealed reddish lesions at the macula with surrounding circinate exudation. On peripheral examination hemorrhages were seen along with vasculitis in the superotemporal quadrant.The right eye fundus was normal.All laboratory investigations were found within normal limits., Conclusion: Eales' disease is mostly a bilateral condition but this case is rare as there is uniocular involvement with exudative macroaneurysms.Laser therapy was instituted which was effective in management of this condition with restoration of normal visual acuity.There was no relapse on follow up for 2 years., (© NEPjOPH.)

Objective: The purpose of this study is to explore the effects of microRNA-29b (miR-29b) regulating MAPK/ERK and PI3K/Akt signaling pathways on angiogenesis in endometrial carcinoma (EC) by targeting VEGFA., Methods: Between February 2013 and April 2015, 126 EC patients admitted to the Second Affiliated Hospital of Nanchang University were randomly selected, with 126 EC tissues and the corresponding adjacent normal tissues collected after surgery. The human EC cell lines RL-95-2 and HEC-1-B and human endometrial cells were assigned to the normal group (human endometrial cells), the blank group (untransfected RL-95-2 or HEC-1-B cells), the pMIR-control group (RL-95-2 or HEC-1-B cells transfected with an empty vector), the pMIR-miR-29b group (RL-95-2 or HEC-1-B cells transfected with the miR-29b plasmid), LNA-control group (RL-95-2 or HEC-1-B cells transfected with an oligonucleotide inhibitors control), the LNA-miR-29b inhibitors group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors), the LNA-miR-29b inhibitors + PD98059 group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors and PD98059, an inhibitor of the MAPK/ERK signaling pathway) and the LNA-miR-29b inhibitors + wortmannin group (RL-95-2 or HEC-1-B cells transfected with miRCURY LNATM miR-29b inhibitors and wortmannin, an inhibitor of the PI3K/Akt signaling pathway). qRT-PCR and Western blotting were conducted to detect the miR-29b expression and the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2. Immunohistochemistry (IHC) was performed to determine the microvessel density (MVD) expression in the EC tissues, adjacent normal tissues and nude-mice., Results: Compared with the adjacent normal tissues, miR-29b expression was down-regulated, the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated, and MVD expression was increased in the EC tissues. Compared with the normal group, miR-29b expression was down-regulated, while the mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were up-regulated in the other groups. Compared with the blank, pMIR-control and LNA-control groups, miR-29b expression was increased, while mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 were decreased in the pMIR-miR-29b group. The LNA-miR-29b inhibitors group exhibited elevated miR-29b expression and decreased mRNA and protein expressions of VEGFA, ERK, Akt, mTOR and Bcl-2 (All P < 0.05). Additionally, miR-29b expression was reduced in the LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups. In comparison to the normal group, MVD expression was elevated in the other groups. Compared with the blank, pMIR-control, LNA-control, LNA-miR-29b inhibitors + PD98059 and LNA-miR-29b inhibitors + wortmannin groups, MVD expression was decreased in the pMIR-miR-29b group but increased in the LNA-miR-29b inhibitors group., Conclusion: Our results indicate that miR-29b negatively modulates the MAPK/ERK and PI3K/Akt signaling pathways to inhibit angiogenesis in EC by targeting VEGFA., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

Background: Local tumor progression (LTP) in early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains high. Tumor feeding artery ablation (FAA) before target tumor ablation was reported to reduce LTP in patients with HCC >3 cm. The aim of our study is to investigate whether FAA before target tumor ablation may reduce LTP in HCC <3 cm., Methods: We retrospectively analysis the outcome of patients with HCC <3 cm undergoing FAA before target tumor ablation (N = 17) compared to direct RFA to target tumor alone (N = 35)., Results: FAA significantly reduces LTP (FAA vs. non-FAA: local tumor progression 17.6% vs. 48.6%, p = 0.038), but not in intrahepatic recurrence: 29.4% vs. 25.7%, p = 0.778; or in overall recurrence rate: 41.2% vs. 62.9%, p = 0.14). The cumulative 1-year and 2-year LTP rates in FAA group were 17.6% and 17.6%, while 11.4% and 42.9% in non-FAA group (p = 0.073), respectively. The cumulative overall recurrence rates at 1-year and 2-year were 29.4% and 35.3% in FAA group, while 14.3% and 57.1% in non-FAA group (p = 0.130), respectively., Conclusions: FAA before target tumor ablation may decrease LTP in HCC <3 cm. Further randomized control study will be helpful for validation., (Copyright © 2016 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Basing on analysis of own material (84 patients) and data of literature there was established, that vascular invasion by pancreatic tumors constitutes the main obstacle for conduction of the patients' radical treatment. Early diagnosis permits radical resectability of the patients, what constitutes the only one effective method of treatment. In vascular invasion by tumor a surgeon experience and professional preparation determines possibility of the extended operation performance with intervention on affected main vessel, enhancing the treatment radicalism.

Objective: To evaluate whether suppression of tumor microvasculature by double anti-angiogenic protein (DAAP) treatment could increase the extent of radiofrequency ablation (RFA)-induced coagulation in a murine renal cell carcinoma model., Materials and Methods: Renal cell carcinoma cell lines were implanted subcutaneously into 10 nude mice. Four mice received adenoviral DAAP treatment and 6 mice received sterile 0.9% saline solution as DAAP-untreated group. The effect of DAAP was evaluated according to the vascularity by contrast-enhanced ultrasound (CEUS) using microbubbles. Four DAAP-treated mice and 4 DAAP-untreated mice were then treated with RFA, resulting in 3 groups: no-therapy (n = 2), RFA only (n = 4), and RFA combined with DAAP treatment (n = 4). Immediately after RFA, the size of coagulation necrosis and mitochondrial enzyme activity were compared between the groups using analysis of variance (ANOVA) and post hoc test., Results: The contrast enhancement ratio for tumor vascularization on CEUS was significantly lower in the DAAP treated group than in DAAP-untreated group (30.2 ± 9.9% vs. 77.4 ± 17.3%; p = 0.021). After RFA, the mean coagulation diameter was 0 mm for no-therapy group, 6.7 ± 0.7 mm for the RFA only group and 8.5 ± 0.4 mm for the RFA with DAAP group (ANOVA, p < 0.001). The area of viable mitochondria within the tumor was 27.9 ± 3.9% in no-therapy group, 10.3 ± 4.5% in the RFA only group, and 2.1 ± 0.7% in the RFA with DAAP group (ANOVA, p < 0.001)., Conclusion: Our results suggest the potential value of combining RFA with anti-angiogenic therapy.

The prognostic significance of vascular invasion (VI) in nonmetastatic gastric cancer (GC) remains a matter of controversy. The purpose of this study was to assess the impact of VI on survival in this group of GC patients. We enrolled 361 GC patients without metastasis who underwent curative gastrectomy between 1996 and 2009 in Sun Yat-sen University Cancer Center. A retrospective analysis of the clinicopathological data was performed, focusing on the impact of VI detected by routine H&E staining on disease-free survival (DFS) and cancer-specific survival (CSS). The presence of VI was detected in 13.9% of our cohort. The VI status was significantly correlated with the tumor size, infiltration depth, and TNM stage (P < 0.05). Patients with VI showed significantly lower DFS and CSS compared with patients without VI (P < 0.0001 for both). The subgroup analysis indicated that the presence of VI was a negative predictor of DFS in all TNM stages and a predictor of lower CSS only in stage I (P < 0.05 for all). A multivariate Cox proportional analysis identified VI as an independent predictor of CSS (P = 0.022). The presence of VI is a risk factor for recurrence and an independent predictor of poor survival in nonmetastatic GC after curative resection. The VI status should be considered to stratify with this group of GC patients for adjuvant treatment and more effective follow-up protocol.

Malignant gliomas belong to the most threatening tumor entities and are hallmarked by rapid proliferation, hypervascularization and an invasive growth pattern. The primary obstacle in surgical treatment lies in differentiation between healthy and pathological tissue at the tumor margins, where current visualization methods reach their limits. Here, we report on a novel technique (vascular dual intraoperative visualization approach - vDIVA) enabling visualization of different tumor zones (TZ I-III) on the basis of angiogenic hotspots. We investigated glioblastoma patients who underwent 5-ALA fluorescence-guided surgery with simultaneous intraoperative ICG fluorescence angiography. This vDIVA technique revealed hypervascularized areas which were further histologically investigated. Neuropathological assessments revealed tissue areas at the resection margins corresponding to TZ II, and postoperative CD34- and Map2 immunostaining confirmed these angiogenic hotspots to be occupied by glioma cells. Hence, the vascular architecture in this transitional zone could be well differentiated from both primary tumor bulk and healthy brain parenchyma. These data demonstrate that ICG fluorescence angiography improves state-of-the-art glioma surgery techniques and facilitates the future characterization of polyclonal attributes of malignant gliomas.

This systematic review examined whether the available evidence justifies using hepatic resection (HR) during later stages of hepatocellular carcinoma (HCC), which contravenes treatment guidelines but is current practice at many medical centers.Official guidelines and retrospective studies recommend different roles for HR for patients with large/multinodular HCC or with HCC involving macrovascular invasion (MVI).Several databases were systematically searched for studies examining the safety and efficacy of HR for treating HCC involving a single large tumor (>5 cm) or multiple tumors, or for treating HCC involving MVI.We identified 50 studies involving 14, 808 patients that investigated the use of HR to treat large/multinodular HCC, and 24 studies with 4389 patients that investigated HR to treat HCC with MVI. Median in-hospital mortality for patients with either type of HCC was significantly lower in Asian studies (2.7%) than in non-Asian studies (7.3%, P < 0.001). Median overall survival (OS) was significantly higher for all Asian patients with large/multinodular HCC than for all non-Asian patients at both 1 year (81% vs 65%, P < 0.001) and 5 years (42% vs 32%, P < 0.001). Similar results were obtained for median disease-free survival at 1 year (61% vs 50%, P < 0.001) and 5 years (26% vs 24%, P < 0.001). However, median OS was similar for Asian and non-Asian patients with HCC involving MVI at 1 year (50% vs 52%, P = 0.45) and 5 years (18% vs 14%, P = 0.94). There was an upward trend in 5-year OS in patients with either type of HCC.HR is reasonably safe and effective at treating large/multinodular HCC and HCC with MVI. The available evidence argues for expanding the indications for HR in official treatment guidelines.

Background: Irreversible electroporation (IRE) has recently been added as an additional therapeutic ablative option in patients with locally advanced cancers (LAC) involving vital structures. IRE delivers localized electric current by peri-tumoral discrete probes to attain irreversible changes in cell membrane leading to cell death. The aim of this study was to evaluate the long-term effects of IRE in the treatment of locally advanced tumors., Methods: A prospective IRB approved evaluation of 107 consecutive patients from 7 institutions with tumors that had vascular invasion treated with IRE from 5/2010 to 1/2012. LAC was defined as primary tumor with <5 mm from major vascular structure based on pre-operative dynamic imaging or intra-operative criteria., Results: IRE as utilized in LAC in the liver (N = 42, 40%) and pancreas (N = 37, 35%), with a median number of lesions being 2 with a mean target size of 3 cm. IRE attributable morbidity rate was 13.3% (total 29.3%) with high-grade complications seen in 4.19% (total 12.6%). No significant vascular complications were seen, and of the high-grade complications, bleeding (2), biliary complications (3) and DVT/PE (3) were the most common. Complications were more likely with pancreatic lesions (p = 0.0001) and open surgery (p = 0.001). Calculated local recurrence free survival (LRFS) was 12.7 months with a median follow up of 26 months censured at last follow up. The tumor target size was inversely associated with recurrence free survival (b = 0.81, 95% CI: 1.6 to 4.7, p value = 0.02) but this did not have a significant overall survival impact., Conclusions: IRE represents a novel therapeutic option in patients with LAC involving vital structures that are not amenable to surgical resection. Acceptable to high local disease control and the long LRFS can be achieved with this therapy in combination with other multi-disciplinary therapies.

Background: Surgical therapies are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor metastasis after liver surgery remains a severe problem. We aim to investigate the roles and the underlying mechanism of YQ23, stabilized non-polymeric diaspirin cross-linked tetrameric hemoglobin, in liver tumor metastasis after major hepatectomy and partial hepatic ischemia reperfusion (I/R) injury., Methods: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Major hepatectomy for tumor-bearing lobe and partial hepatic I/R injury were performed at two weeks after orthotopic liver tumor implantation. YQ23 (0.2 g/kg) was administered at 1 hour before ischemia and immediately after reperfusion. Blood samples were collected at day 0, 1, 7, 14, 21 and 28 for detection of circulating endothelial progenitor cells (EPCs) and regulatory T cells (Tregs)., Results: Our results showed that YQ23 treatment effectively inhibited intrahepatic and lung metastases together with less tumor angiogenesis at 4 weeks after major hepatectomy and partial hepatic I/R injury. The levels of circulating EPCs and Tregs were significantly decreased in YQ23 treatment group. Furthermore, YQ23 treatment also increased liver tissue oxygenation during hepatic I/R injury. Up-regulation of HO1 and down-regulation of CXCR3, TNF-α and IL6 were detected after YQ23 treatment., Conclusions: YQ23 treatment suppressed liver tumor metastasis after major hepatectomy and partial hepatic I/R injury in a rat liver tumor model through increasing liver oxygen and reducing the populations of circulating EPCs and Tregs.

Objective: To evaluate the effects of mast cell count and angiogenesis on the prognosis of renal cell carcinoma., Methods: The retrospective study was conducted at the Harran University, Sanliurfa, Turkey, and included 64 cases with diagnosis of renal cell carcinoma between 2002 and 2012. Immunohistochemical analysis was performed on paraffin sections using the standard streptavidin-biotin immunoperoxidase method. CD31 antibodies were used to identify microvessels in tumoural tissues. The microvessel density was calculated using a serological method. The mean vascular density was equivalent to the vascular surface area (in mm2) per unit tissue volume (in mm3) (MVD = mm3). Mast cells tryptase antibody was used to evaluate the mast cell count in tumoural and non-tumoural tissues. The relationship between mast cell count and microvessel density was evaluated and compared with stage, grade, tumour diameter, and age., Results: The mast cell count in the tumoral tissue of renal cell carcinoma was significantly higher compared with non-neoplastic renal tissue (p < 0.001). A significant relationship was found between the mast cell count in tumoral tissue and stage, grade, and tumour diameter (p < 0.001). However, no relation was found with age (p > 0.05). The intratumoural mast cell count in clear cell renal carcinoma was significantly higher compared with non-clear variety (p = 0.001). No significant relationship was found between microvessel density, age, stage, diameter, or grade of the tumour and tumoral mast cell count (p > 0.05)., Conclusion: No significant association was found between the number of mast cells in tumoral tissue and microvessel density. Further studies are needed to demonstrate the effect of mast cells on angiogenesis in renal cell carcinoma.

Background: Cell-mediated angiogenic therapy for ischemic heart disease has had disappointing results. The lack of clinical translatability may be secondary to cell death and systemic dispersion with cell injection. We propose a novel tissue-engineered therapy, whereby extracellular matrix scaffold seeded with endothelial progenitor cells (EPCs) can overcome these limitations using an environment in which the cells can thrive, enabling an insult-free myocardial cell delivery to normalize myocardial biomechanics., Methods and Results: EPCs were isolated from the long bones of Wistar rat bone marrow. The cells were cultured for 7 days in media or seeded at a density of 5 × 10(6) cells/cm(2) on a collagen/vitronectin matrix. Seeded EPCs underwent ex vivo modification with stromal cell-derived factor-1α (100 ng/mL) to potentiate angiogenic properties and enhance paracrine qualities before construct formation. Scanning electron microscopy and confocal imaging confirmed EPC-matrix adhesion. In vitro vasculogenic potential was assessed by quantifying EPC cell migration and vascular differentiation. There was a marked increase in vasculogenesis in vitro as measured by angiogenesis assay (8 versus 0 vessels/hpf; P=0.004). The construct was then implanted onto ischemic myocardium in a rat model of acute myocardial infarction. Confocal microscopy demonstrated a significant migration of EPCs from the construct to the myocardium, suggesting a direct angiogenic effect. Myocardial biomechanical properties were uniaxially quantified by elastic modulus at 5% to 20% strain. Myocardial elasticity normalized after implant of our tissue-engineered construct (239 kPa versus normal=193, P=0.1; versus infarct=304 kPa, P=0.01)., Conclusions: We demonstrate restoration and normalization of post-myocardial infarction ventricular biomechanics after therapy with an angiogenic tissue-engineered EPC construct.

Introduction: The results of surgical outcomes of 20 gauge pars plana vitrectomy in Eales' disease are available in the scientific literature. However, all these studies have been done using the 20 gauge vitrectomy systems and most studies have been conducted in a retrospective manner., Objective: To evaluate the outcomes and safety of 23 gauge vitrectomy in complications of Eales' disease., Study Design: Consecutive interventional case series., Participants: Seventy-six eyes of 72 nonconsecutive patients undergoing 23-gauge vitrectomy for complications of Eales' disease were enrolled. The participants were followed up for a minimum of one year., Intervention: The participants underwent a complete demographic, medical and ophthalmic evaluation. A 23-gauge vitrectomy was performed. Endotamponade was used when necessary. Perioperative and postoperative events were recorded. Primary outcome measures were visual acuity and complications arising due to surgery., Results: Indication for surgery was non-clearing vitreous hemorrhage in 89.4% (68/76) and secondary retinal detachment in 10.6% (8). Visual acuity improved from Log Mar 1.80 ± 0.19 units preoperatively to Log Mar 0.47±0.59. Best-corrected visual acuity equivalent to Snellen 6/9 was achieved in 77. 6% of eyes. . Surgical failure was seen in 6.5% cases. Four cases were lost due to progression to neovascular glaucoma and 1 case was lost to severe residual retinal detachment. Iatrogenic portside retinal breaks occurred in 3.9% (3), post-vitrectomy retinal detachment 2.6% ( 2), hypotony 1.3% (1) and cataract in 38.1% (28) cases., Conclusion: 23-gauge sutureless vitrectomy in patients with Eales' disease is a safe and effective technique with acceptable level of risk and complications., (© NEPjOPH.)

A 60-year-old woman was admitted for the treatment of a gastric neuroendocrine tumor (NET) associated with type A chronic atrophic gastritis. The lesion measured 10 mm in diameter, and a computed tomography scan did not reveal any metastatic lesions. Endoscopic submucosal dissection (ESD) was subsequently performed. A histological examination revealed three gastric NETs, two of which exhibited vessel invasion. Endocrine cell micronests associated with a high risk of recurrence were also observed. Therefore, the patient underwent total gastrectomy with lymph node dissection. Because vessel invasion can occur in patients with small gastric NET G1, the use of ESD should be considered to carefully estimate the presence of invasion.

Children and adolescents represent 1-1.5% of all patients with thyroid cancer (TC). The vast majority of TC in children and adolescents is papillary TC; follicular TC (FTC) is exceedingly rare. In this study, we evaluate the clinical and pathological features of FTC in children and adolescents. We also report the risk factors for post-operative tumor recurrence and the associated outcomes. Twenty children and adolescents (under 21 years old) with FTC have been treated and followed at Noguchi Thyroid Clinic and Hospital Foundation since 1946. All patients underwent surgery (lobectomy, 11; subtotal thyroidectomy, 8; and total thyroidectomy, 1), and 8 patients received postoperative external beam radiation therapy. The incidence of FTC in children and adolescents was 1.9% among all FTC patients treated in our hospital. Histopathology revealed vascular and capsular invasion in 9 and 20 patients, respectively. The tumor recurrence rate in FTC with vascular invasion is significantly higher than in those without it (p = 0.038). No other factors were significant. Patients with recurrences were treated with completion thyroidectomy and ¹³¹I radioactive iodine therapy. There were no significant differences in the rates of disease-free survival or cause-specific survival when pediatric/adolescent FTC patients were compared to adults with FTC. FTC is very rare among children and adolescents, but the outcomes are similar to those observed among adults. Vascular invasion is poor prognostic indicator in pediatric/adolescent FTC patients.

Background: Anti-angiogenesis is a promising therapeutic strategy for locally advanced breast cancer. We performed this phase II trial to evaluate the anti-angiogenesis and anti-tumor effect of rh-endostatin combined with docetaxel and epirubicin in patients with locally advanced breast cancer by dynamic contrast-enhanced magnetic resonance imaging in 70 previously untreated locally advanced breast cancer patients., Methods: The study population was randomly assigned to neoadjuvant chemotherapy with docetaxel and epirubicin (neoadjuvant chemotherapy group) or neoadjuvant chemotherapy combining rh-endostatin with docetaxel and epirubicin (neoadjuvant chemotherapy+rh-endostatin group). The anti-angiogenic and anti-tumor effects of both regimens were evaluated by serial dynamic contrast-enhanced magnetic resonance imaging and microvessel density measurements after final surgery., Results: The results suggested a higher clinical objective response (90.9% vs. 67.7%, P = 0.021) and greater reductions in tumor size (67.2% vs. 55.9%, P = 0.000), Ki-67 proliferation index (32.79% vs. 12.47%, P = 0.000), tumor signal enhanced ratio (64% vs. 48%, P = 0.018), and K(trans) (67% vs. 39%, P = 0.026) in neoadjuvant chemotherapy+rh-endostatin group than those in neoadjuvant chemotherapy group. In addition, the microvessel density value in the neoadjuvant chemotherapy+rh-endostatin group was significantly lower than in the neoadjuvant chemotherapy group (18.67 ± 6.53 vs. 36.05 ± 9.64, P = 0.000). Moreover, the microvessel density value was significantly correlated with K(trans) after neoadjuvant chemotherapy+rh-endostatin treatment (r=0.88, P = 0.00)., Conclusions: The neoadjuvant chemotherapy+rh-endostatin treatment significantly repressed angiogenesis in locally advanced breast cancer and synergistically enhanced the anti-tumor effect of neoadjuvant chemotherapy. Serial dynamic contrast-enhanced magnetic resonance imaging data including reductions in tumor size and K(trans), could provide non-invasive evaluation for chemotherapeutic efficacy and, consequently, optimization of individual chemotherapy for locally advanced breast cancer patients.

Follicular thyroid carcinoma (FTC) is divided into two categories: minimally and widely invasive FTC. Generally, the prognosis of minimally invasive FTC is excellent, but patients showing certain characteristics have a dire prognosis. In this study, we investigated the prognostic factors of minimally invasive FTC using a series of 292 patients. On multivariate analysis, extensive (4 or more) vascular invasion, age ≥ 45 years, and tumor size > 4 cm were independent prognostic factors of patient disease-free survival (DFS). Distant metastasis at diagnosis (M1) was the strongest prognostic factor of cause-specific survival (CSS). Extensive vascular invasion and tumor size > 4 cm also independently affected patient carcinoma death. Capsular invasion was not related to patient prognosis. The ten-year DFS rate of patients with extensive vascular invasion was 80%, which was poorer than that of those having tumor size > 4 cm (91%) and aged 45 years or older (90%). These findings suggest that 1) M1 most strongly affects the CSS of patients, and 2) M0 patients with extensive vascular invasion may be candidates for completion total thyroidectomy and radioactive iodine ablation.

Purpose: We evaluated the morphologic changes in retinal structure after laser photocoagulation using supra- and subthreshold laser fluence., Methods: In a prospective cohort study 10 consecutive patients received scatter laser photocoagulation. Treatment was performed using a semiautomated patterned scanning laser system. In a study area adjacent to the temporal vessel arcades, 2 × 2 pattern laser spots were applied with halving the flux of the laser power in a stepwise manner starting from a power producing a typical grayish lesion. The study areas then were imaged on days one, three, and seven, and on months one, two, three, and six using color fundus photography, autofluorescence (AF), infrared (IR) imaging, and spectral domain optical coherence tomography (SD-OCT)., Results: The starting threshold power lesions each were visible on color fundus photography, IR, and AF in all patients, and showed characteristic changes on OCT throughout the follow-up period. The halved flux laser burns (first step) were undetectable ophthalmoscopically during the laser session, but during the follow-up always were detectable on IR and AF images, and sometimes on fundus photography. On OCT they showed changes similar to the suprathreshold laser scars, but were much smaller in diameter, and in some instances an inward migration of the photoreceptor layer was observed., Conclusions: Subthreshold laser burns with halved energy flux produced similar morphologic changes in the retina as threshold power, but with a smaller size. They induced less collateral damage to the neuroretina, and permit a level of reorganization in the outer retina. (ClinicalTrials.gov number, NCT00682240.).

Background: Radiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC., Methods: Using mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI., Results: Compared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density (VD), and vessel area fraction (VF) from qIHC. Although total hypoxic fractions ( HF) did not change, estimated acute hypoxia scores (AHS)--the proportion of hypoxia staining within 50 μm from perfusion staining--were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve (AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size (VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such modeling also detected tumor necrosis very strongly., Conclusions: DCE MRI reliably allows non-invasive assessment of tumors' vascular function. The findings of increased tumor vascularization after ADT encourage further studies into whether these changes are beneficial for combined RT, or if treatment with anti-angiogenic therapy may be a strategy to improve the therapeutic efficacy of ADT in advanced PC.

Background and Purpose: In cerebral gliomas, rCBV correlates with tumor grade and histologic findings of vascular proliferation. Moreover, ADC assesses water diffusivity and is inversely correlated with tumor grade. In the present work, we have studied whether combined rCBV and ADC values improve the diagnostic accuracy of MR imaging in the preoperative grading of gliomas., Materials and Methods: One hundred sixty-two patients with histopathologically confirmed diffuse gliomas underwent DWI and DSC. Mean rCBV and ADC values were compared among the tumor groups with the Student t test or ANOVA. ROC analysis was used to determine rCBV and ADC threshold values for glioma grading., Results: rCBV had significantly different values between grade II and IV gliomas and between grade III and IV tumors, but there were no significant differences between grade II and III gliomas (P > .05). Grade II and III tumors also did not differ when astrocytomas, oligodendrogliomas, and oligoastrocytomas were considered separately. ADC values were significantly different for all 3 grades. The ADC threshold value of 1.185 × 10(-3) mm(2)/s and the rCBV cutoff value of 1.74 could be used with high sensitivity in the characterization of high-grade gliomas. The area under the ROC curve for the maximum rCBV and minimum ADC was 0.72 and 0.75, respectively. The combination of rCBV and ADC values increased the area under the ROC curve to 0.83., Conclusions: ADC measurements are better than rCBV values for distinguishing the grades of gliomas. The combination of minimum ADC and maximum rCBV improves the diagnostic accuracy of glioma grading.

Rationale and Objectives: The aim of this study was to explore the effects of blood supply on high-intensity focused ultrasound (HIFU) applied to rabbit hepatic VX2 tumors of different ages., Materials and Methods: Eighteen rabbits with VX2 hepatic tumors were randomly divided into three groups according to the time of sacrifice after tumor implantation: 10, 15, or 20 days. Contrast-enhanced ultrasound was performed immediately before HIFU ablation. The same settings for HIFU dose parameters were used to ablate the central tumor area in each group, and the real-time temperature of the targeted site of the tumor was measured. After HIFU, the coagulation necrosis volumes of tumor tissue and the microvascular density of residual tumor tissue were determined., Results: Histopathologic analysis showed that the extent of a tumor's blood supply followed the order 10-day group > 15-day group > 20-day group (P < .01). Contrast-enhanced ultrasound showed the same results. There was no statistically significant difference among the three groups in terms of temperature-increase parameters during HIFU treatment (P > .05). However, there were statistically significant differences between the groups in terms of temperature-decrease parameters during HIFU treatment and in terms of necrosis volumes after HIFU treatment (P < .05). Necrosis volume was inversely related to absolute enhanced intensity (r = -0.823, P < .001)., Conclusions: The extent of a tumor's blood supply had a significant effect on the temperature-decrease phase but not on the temperature-increase phase during HIFU treatment. The longer the temperature-decrease phase, the more slowly heat dissipated after HIFU, resulting in larger coagulation necrosis volumes., (Copyright © 2012 AUR. Published by Elsevier Inc. All rights reserved.)

Objective: Increased vascularization is considered an important contributing factor for plaque vulnerability. Microvascular proliferative disease in patients with diabetes results in renal damage and visual loss. We assessed the hypothesis that vascularization in carotid atherosclerotic tissue is increased in diabetic patients, especially in the critical shoulder regions of the plaque., Methods: Carotid endarterectomy specimens, clinical data, and blood samples were collected from patients with symptomatic carotid artery stenosis (median 85 days after clinical event) and pharmacologic treatment for diabetes (n = 26) or no diabetes (n = 85). Plaques were fixed in formalin and transverse tissue sections prepared. Histopathology and immunohistochemistry were performed for detection of endothelial cells (anti-CD34), macrophages (anti-CD68), vascular endothelial growth factor (VEGF), and its receptor (VEGFR-2). Neovascularization was assessed as CD34(+) neovessel density in the entire section area and by the presence or absence of CD34(+) vessels in the shoulder and cap regions of the plaques., Results: The patient groups did not differ significantly in neovascularization in the entire transverse sections (2.0 vs 2.1 vessels/mm(2); P = .61) or in the fibrous cap (52% of the patients in both groups; P = .95). Neovascularization of the plaque shoulder regions was observed in 52% of the diabetic patients and in 26% of the nondiabetic patients (P = .028). VEGF-stained areas were similar in the two patient groups (0.4% and 0.2% of shoulder area; P = .61). Patients with diabetes had more VEGFR-2 (1.0% vs 0.2% of shoulder area; P < .016) and less CD68 staining (0.4% vs 3.6% of shoulder area; P < .008). Time from clinical event to surgery was positively associated with neovascularization of the plaque shoulder regions (≤90 days, 18% of patients; >90 days, 50% of patients; P = .002), independently of diabetes status., Conclusions: Diabetes was associated with increased vascularization of the shoulder regions in patients with symptomatic carotid atherosclerotic plaques. This was accompanied by increased expression of VEGFR-2. The increased vascularization of the plaque shoulder regions may help explain why patients with diabetes are at increased risk of atherosclerotic complications., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: The purpose of this study was to examine the prevalence and histopathologic correlates of pericardial delayed hyperenhancement (DHE) seen with cardiac magnetic resonance imaging (CMR) among patients with constrictive pericarditis (CP) undergoing pericardiectomy., Background: Constrictive pericarditis patients studied by CMR will occasionally demonstrate pericardial DHE following gadolinium contrast administration., Methods: We identified 25 CP patients who underwent pericardiectomy following CMR-gadolinium study. We also assessed 10 control subjects with no evidence of pericardial disease referred for cardiac viability imaging. A novel 14-segment pericardial model was used to determine pericardial DHE score and thickness score. Histopathology of pericardial specimens was reviewed and evaluated semiquantitatively on a 4-point scale for the extent of calcification, fibrosis, inflammation, and neovascularization., Results: DHE was present in 12 (48%) CP patients (DHE+ group), and absent in 13 CP patients (DHE- group) and all control patients. The DHE+ group had greater fibroblastic proliferation and neovascularization, as well as more prominent chronic inflammation and granulation tissue. Fibroblastic proliferation and chronic inflammation correlated with DHE presence quantitated by DHE score (Spearman r = 0.578, p < 0.002, and r = 0.590, p < 0.002, respectively), but not with pericardial thickness. Segmental analysis demonstrated no significant difference in the percentage of patients with different pericardial segmental thickness; however, overall, in each segment, the DHE+ group tended to have greater pericardial thickness., Conclusions: The presence of pericardial DHE on CMR is common in patients with CP, and its presence is associated with histological features of organizing pericarditis, which may be a target for future focused pharmacological interventions. Patients with CP without pericardial DHE had more pericardial fibrosis and calcification, as well as lesser degrees of pericardial thickening., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Single-stage posterior corpectomy for the management of spinal tumors has been well described. Anterior column reconstruction has been accomplished using polymethylmethacrylate (PMMA) or expandable cages (EC). The aim of this retrospective study was to compare PMMA versus ECs in anterior vertebral column reconstruction after posterior corpectomy for tumors in the lumbar and thoracolumbar spine. Between 2006 and 2009 we identified 32 patients that underwent a single-stage posterior extracavitary tumor resection and anterior reconstruction, 16 with PMMA and 16 with EC. There were no baseline differences in regards to age (mean: 58.2 years) or performance status. Differences between groups in terms of survival, estimated blood loss (EBL), kyphosis reduction (decrease in Cobb's angle), pain, functional outcomes, and performance status were evaluated. Mean overall survival and EBL were 17 months and 1165 ml, respectively. No differences were noted between the study groups in regards to survival (p = 0.5) or EBL (p = 0.8). There was a trend for better Kyphosis reduction in favor of the EC group (10.04 vs. 5.45, p = 0.16). No difference in performance status or VAS improvements was observed (p > 0.05). Seven patients had complications that led to reoperation (5 infections). PMMA or ECs are viable options for reconstruction of the anterior vertebral column following tumor resection and corpectomy. Both approaches allow for correction of the kyphotic deformity, and stabilization of the anterior vertebral column with similar functional and performance status outcomes in the lumbar and thoracolumbar area.

Background: Secretory meningiomas are known as a rare histological subtype within the meningioma family. In contrast to benign intracranial meningiomas, they are dreaded for causing an extensive perifocal cerebral tumor edema and life-threatening complications. The objective of the present study is a systematic, retrospective analysis of epidemiological, clinical, and radiological features of secretory meningiomas to predict potential patterns prior to surgery to reduce associated morbidity., Material and Methods: A systematic database search of PubMed with review of the literature was performed to identify clinical studies analyzing epidemiological, clinical, and radiological features of secretory meningiomas. Additionally, we supplemented our series of 17 patients with secretory meningiomas. Studies with available information for each patient were statistically metaanalyzed., Results: In summary, seven large series with a total number of 120 patients were identified, containing detailed information about epidemiological, clinical, and radiological features of secretory meningiomas. Epidemiologically, female predominance was a characteristic. Peritumoral brain edema occurred in about 70% of patients and holohemispheric in more than 50% of patients. Life-threatening complications and severe neurological deficits frequently occur potentially due to extensive peritumoral brain edema. At last, frontal location and age older than 66 years significantly correlated with the development of peritumoral brain edema., Conclusion: Secretory meningiomas are histologically benign tumors and are therefore associated with an excellent prognosis. Nevertheless, frequently life-threatening complications due to the development of an extensive peritumoral brain edema are documented. Predictive risk factors are frontal tumor location, increasing age, and visible pial tumor vessel supply. A careful preoperative evaluation, identification of risk factors, and a specific therapy might reduce perioperative morbidity.

Objective: To evaluate the safety, feasibility, and outcome following radical excision of thymoma with resection and reconstruction of invaded mediastinal vessels., Study Design: A retrospective study., Patients and Methods: Six patients with thymoma invading the superior vena cava (SVC) and/or the brachiocephalic veins (BCVs) were reviewed in this study. All the patients underwent radical excision of the tumor along with invaded mediastinal vessels followed by vessel reconstruction or repair. The clinical presentation, operative details, postoperative course, and follow-up were reviewed and analyzed., Results: Three patients presented with features suggestive of SVC syndrome. Contrast-enhanced computed tomography of the chest was the primary imaging modality, which detected a tumor with invasion of major mediastinal veins. WHO type B2 was the commonest histologic type, which was seen in 4 cases. Intraoperatively, SVC invasion, SVC and BCV invasion, and BCV invasions alone were seen in 1, 2, and 3 cases, respectively. The vessels were reconstructed with a prosthetic graft in 3 patients, and autologous pericardial tube graft was used in 1 patient. Two patients had primary repair of the wall of the involved vessel. Postoperative course was complicated by ventilator support requirement in 2, graft thrombosis in 2, acute renal failure in 1 and pneumonia in 1 patient. All patients are alive at the end of follow-up period ranging between 18 and 24 months., Conclusion: Thymoma excision with the reconstruction of SVC or BCV is safe and feasible in experienced hands.

Objective: To study the concentrations of vascular endothelial growth factor A (VEGF-A), soluble vascular endothelial growth factor receptors-1 and -2 (sVEGFR-1 and -2), angiogenin, and angiopoietin-2 (Ang-2) in serum and peritoneal fluid from healthy controls and women with advanced endometriosis. Further, we addressed the question of whether surgical removal of endometriotic lesions was associated with normalization of the serum concentrations of the same markers., Design: Patients with endometriosis before and after surgery were compared with control patients., Setting: University Hospital., Patient(s): Twenty-one healthy controls and 32 women with advanced endometriosis., Intervention(s): In women with endometriosis we performed surgical removal of endometriotic lesions using laparoscopy., Main Outcome Measure(s): Data on serum and peritoneal fluid concentrations of selected markers in healthy controls and women with endometriosis before surgery and in serum 5 to 7 days after surgery., Result(s): Women with endometriosis had elevated levels of VEGF-A, sVEGFR-1, and Ang-2 in serum and all studied markers in peritoneal fluid compared with healthy controls. Surgical removal of endometriotic lesions resulted in decreased serum levels of pro-angiogenic VEGF-A and increased levels of sVEGFR-2 that negatively regulates the action of VEGF., Conclusion(s): Women with advanced endometriosis have serum and peritoneal fluid concentrations of several factors involved in the regulation of angiogenesis that differ from those in healthy women, and these changes at least partly normalize within a week after surgical removal of the endometriotic lesions., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the possible roles of retinal photoreceptors in macular oedema and retinal angiogenesis with particular reference to the mode of action of laser therapy., Methods: (i) Studies in rats made hypoxic for 2 h by administering an oxygen/nitrogen mixture of reduced oxygen content, and growth factors determined by RT-PCR, western blotting, and immunohistochemistry. Assessment of blood-retinal barrier integrity using fluorescent and electron-dense tracers. (ii) Studies in pigs with one retina made hypoxic by selective embolisation of the retinal capillary circulation with fluorescent microspheres. (iii) Assessment of laser therapy in selected cases of retinal neovascularisation indicating a role for photoreceptors., Results: In the hypoxic retina, angiogenic and vascular permeability factors such as vascular endothelial growth factor (VEGF), nitric oxide synthases (NOSs), and insulin-like growth factor-1 are upregulated in retinal astrocytes and Müller cells but are also present in large amount in the photoreceptors. Hypoxia-inducible factor-1 (HIF-1) is upregulated in retinal glial cells but not in the photoreceptors, suggesting that growth factors in the photoreceptors may not have been generated there. The tracer dye, rhodium isothiocyanate, leaking from an abnormally permeable inner blood-retinal barrier in the hypoxic retina accumulates in the photoreceptors., Conclusions: The results indicate that laser treatment of macular oedema or retinal neovascularisation may obtain its effect not only by improving oxygen availability in the inner retina, but also by reducing the load of angiogenic/permeability factors that accumulate in the photoreceptors in hypoxic/ischaemic conditions.