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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.

Objectives: To investigate visual and anatomical outcomes of vitreoretinal surgeries in patients with Eales' disease., Materials and Methods: In this retrospective study, 22 eyes of 21 patients with vitreous hemorrhage (VH) or tractional retinal detachment (TRD) secondary to Eales' disease who underwent vitreoretinal surgery between January 1997 and December 2015 and had at least 1 year of follow-up were included., Results: The mean best corrected visual acuity (BCVA) was significantly higher at final visit (0.6±0.9 logMAR) than the preoperative values (1.8±1.1 logMAR) (p<0.001). After surgery, BCVA was stable in 4 eyes (18.2%), increased in 16 eyes (72.7%), and decreased in 2 eyes (9.1%). Although the mean BCVA was better in the VH group (0.3±0.34 logMAR) than the TRD group (0.9±1.1 logMAR), the difference was not statistically significant (p=0.1). Multivariable linear regression analyses revealed that final BCVA was negatively associated with preoperative or postoperative proliferative vitreoretinopathy grade C (PVR-C), preoperative retinal detachment involving the macula, postoperative neovascular glaucoma, and long preoperative duration of disease, and positively associated with preoperative BCVA. Final BCVA was not associated with preoperative retinal and disc neovascularization, rubeosis iridis, total posterior hyaloid detachment, preoperative retinal laser photocoagulation, indication of surgery, diameter of sclerotomy (20 or 23 gauge), preoperative lens status, preoperative or postoperative epimacular membrane, peroperative iatrogenic retinal breaks, postoperative hypotony, cystoid macular edema, and new or recurrent retinal detachment. The primary anatomic success rate was 81.8% and the final anatomic success rate was 90.9%., Conclusion: In Eales' disease, good visual results can be obtained with vitreoretinal surgery if the detachment area does not involve the macula and PVR-C does not develop pre- or postoperatively.

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.)

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.

Approximately 20% of patients have persistent unexplained pain after total knee arthroplasty (TKA). Currently available treatments are unsatisfactory. The present report describes four patients in whom transcatheter arterial embolization had a remarkable effect on pain after TKA. Abnormal neovessels were identified in all patients. For 48 h, one patient experienced remarkable postprocedural pain at the inner side of the knee that was subsided by level 1 analgesics and another patient development of a spontaneous skin ulceration resolving within 8 days. The mean Knee injury and Osteoarthritis Outcome Score pain subtotal had increased from 39 to 82 one month after treatment. Endovascular occlusion of neovascularization, decreasing chronic inflammation and the growth of unmyelinated sensory nerves may be treatment options for persistent unexplained pain following TKA.Level of Evidence IV, Case report.

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.

Purpose: To evaluate the effects of clinical features associated with enucleation in eyes with Coats disease., Methods: The medical records of all patients with Coats disease at the Ocular Oncology, Wills Eye Hospital from November 1, 1973, to July 31, 2018, were reviewed retrospectively. The clinical features pertaining to need for ultimate enucleation and time to enucleation were compared., Results: The records of 351 eyes were reviewed, of which 259 had follow-up at our center and 32 (12%) were managed with enucleation. Reasons for enucleation included neovascular glaucoma (n = 24 [75%]), possible tumor (6 [19%]), and phthisis bulbi (2 [6%]). Compared to nonenucleated eyes, enucleated eyes had more extensive clock hour involvement of telangiectasia (P < 0.001), light bulb aneurysms (P < 0.001), exudation (P < 0.001), and subretinal fluid (P < 0.001). On adjusted analysis by binomial logistic regression, variables predictive of enucleation included presence of iris neovascularization (P = 0.01), ultrasonographic retinal detachment (P = 0.004), open-funnel retinal detachment (P = 0.04), closed-funnel retinal detachment (P = 0.01), ultrasonographic elevation of subretinal fluid by millimeters (P = 0.001), and angiographic extent of light bulb aneurysms by clock hours (P = 0.02). By Kaplan-Meier analysis of 4-year cumulative risk of enucleation, risk factors for enucleation included presence of iris neovascularization (hazard ratio [HR] 31.0; P < 0.001), ultrasonographic retinal detachment (HR 56.2; P < 0.001), open-funnel retinal detachment (HR 2.7; P = 0.01), and closed-funnel retinal detachment (HR 4.5; P < 0.001)., Conclusions: Clinical features that predict risk of and time to enucleation in eyes with Coats disease include iris neovascularization, ultrasonographic presence and millimeter-elevation of retinal detachment, and angiographic extent of light bulb aneurysms., (Copyright © 2019 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

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.

Background and Purpose: Neovascularization (NV) is regarded to be one of the important features of vulnerable plaque. The purpose of this study was to evaluate associations between the presence of NV, detected using optical frequency domain imaging (OFDI), and ischemic events and the progress of carotid artery stenosis., Materials and Methods: Carotid artery plaques were evaluated using an OFDI system before angioplasty. NV was defined as no-signal tubuloluminal structures recognized on at least 3 consecutive images. The total number of NVs was compared between symptomatic and asymptomatic plaques and between progressive and nonprogressive plaques. Carotid plaque was diagnosed as "progressive" when peak systolic velocity increased between serial carotid duplex scans., Results: A total of 36 patients (17 symptomatic, 16 progressive) were included. The percentage of patients with smoking habits was significantly higher with progressive carotid plaque than with nonprogressive carotid plaque (P = 0.003). NV was detected in 34 patients (94%), and the total number of NVs was significantly higher with progressive carotid plaque (10.2 ± 4.8 vs. 3.7 ± 2.8; P < 0.0001). There was no relationship between the number of NVs and ischemic events (symptomatic 6.0 ± 5.1 vs. asymptomatic 7.1 ± 5.0; P = 0.47). In multivariate logistic regression analysis, the number of NVs was an independent predictor of progressive carotid plaque (odds ratio 1.64 per 1 increase [95% confidence interval 1.19-2.64]; P = 0.0005)., Conclusions: NV was more frequently observed in progressive carotid plaques. Evaluation of NV using OFDI may be useful in predicting progressive carotid plaques., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Objective: We aimed to assess the preoperative rectal cancer angiogenesis with Endorectal Power Doppler Ultrasonography by using the Power Doppler Vascularity Index (PDVI) calculated by imaging analysis software, and to compare it with the microvessel density (MVD) in surgical specimens PATIENTS AND METHODS: This study included 110 patients (39 females; mean age 61.5 years) with rectal cancer. Immunohistochemical staining of surgical specimens with anti-CD-31 antibody was used for MVD evaluation. The PDVI of each tumor was calculated using Endorectal Power Doppler with computer-assisted quantification of colour pixels., Results: Mean MVD - 163 ± 69 microvessels/mm2 (50-328) was used as a cutoff point, differentiating two groups of tumors with high (> 160 mm2) and low (≤ 160 mm2) angiogenic activity. Mean PDVI of 8.9 ± 6.0% (0-27.3) was used as a cutoff point, dividing two groups of tumors with high (> 8%) and low (≤ 8%) PDVI. The MVD and the PDVI showed a good positive correlation (r = 0.438, p = 0.002). Patients with low PDVI had 25 months longer overall survival (p < 0.05) than patients with high PDVI. Patients with low MVD had 36 months longer survival (p < 0.05)., Conclusions: Endorectal Power Doppler Ultrasonography is a reliable and noninvasive method for assessment of the extent of rectal cancer angiogenesis. Tumor angiogenesis assessed by the PDVI correlated with histological MVD determination and could predict survival rates. Endorectal Power Doppler examination is a useful and reproducible method for in vivo preoperative quantitative assessment of tumor vascularization.

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.

Background: We report the case of a 40-year-old patient with a large, World Health Organization grade III oligodendroglioma in the left parietal lobe., Case Description: Presurgical planning included functional magnetic resonance imaging (fMRI) localization of language, motor, and somatosensory processing. fMRI results for motor and somatosensory tasks revealed activation in perilesional regions near the surgical resection as well as deactivation in the tumor for the sensory task, suggesting decreased autoregulation in the region owing to the glioma. fMRI results showed left-hemisphere dominance for language and activation in perilesional regions for all 3 speech tasks (i.e., word reading, picture naming, and semantic questions). In addition, the results demonstrated that the high vascularity of the lesion altered the blood oxygen level-dependent function, resulting in false-positive and false-negative activation in the semantic questions and leg/foot rubbing task, respectively. Intraoperative direct cortical stimulation was conducted in the regions corresponding to fMRI activation while the patient performed motor, sensory, and language tasks and showed no loss of function. Follow-up fMRI revealed that there was no longer activation in the tumor or in perilesional regions, presumably owing to the resection of the vascularized tumor., Conclusions: This case highlights the importance of presurgical fMRI to inform the neurosurgical approach and emphasizes the need for careful interpretation of fMRI data, especially in cases of malignant glioma, which can decrease autoregulation in surrounding regions, affecting fMRI blood oxygen level-dependent signal., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Aim: To integrate various criteria for borderline resectable pancreatic cancer (BRPC) based on radiological parameters using classification tree analysis., Materials and Methods: The institutional review board approved this retrospective study and waived the requirement for informed consent. Two hundred and thirty-five tumour-vein interfaces and 67 tumour-artery interfaces in 245 patients with surgically confirmed pancreatic ductal adenocarcinoma who underwent both preoperative computed tomography (CT) and magnetic resonance imaging (MRI) were assessed by two independent readers. Radiological parameters for evaluation of the tumour-vascular interface were boundary, length of interface, degree of circumferential interface, and contour deformity of affected vessels. Classification tree analysis was performed to determine parameters associated with vascular invasion using pathological and surgical results as the reference standard., Results: In the classification tree analysis for the tumour-vein interface, contour deformity and degree of circumferential interface were the first and second determining factors, respectively, for both surgical and pathological vascular invasion. For the tumour-artery interface, boundary and degree of circumferential interface were the first and second determining factors for surgical invasion, while contour deformity and length of interface were the first and second determining factors for pathological invasion. The BRPC group of modified criteria arbitrarily formed based on the results had similar surgical (74.1-81.6%) and pathological (54.3-63.3%) venous invasion compared to that of the National Comprehensive Cancer Network (NCCN) criteria, and the lowest surgical (33.3%) and pathological (6.7%) arterial invasion compared with those in previously established criteria for BRPC (43.3-55.6% and 22.2-26.1%, respectively)., Conclusion: Various criteria for BRPCs were integrated using classification tree analysis, and a modified criterion for BRPC, which provides satisfactory results, was established., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

OBJECTIVE Quantitative assessment of tumor microvascularity has the potential to improve prognostication, advance understanding of tumor biology, and help narrow potential molecular therapies. While the role of tumor microvascularity has been widely studied in meningiomas, this study examines both the role of automated measurements and the impact on surgical outcome. METHODS Two hundred seven patients with Grade I meningiomas underwent surgery between 1996 and 2011. Tissue samples from each patient were retrospectively evaluated for histopathological measures of microvascularity, including staining for von Willebrand factor (vWF), CD31, CD105, hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor, glucose transporter 1, and carbonic anhydrase IX. Manual methods of assessing microvascularity were supplemented by a computational analysis of the microvascular patterns by means of fractal analysis. MIB-1 proliferation staining was also performed on the same tumors. These measures were compared with various patient characteristics, tumor volume, estimated blood loss (EBL) during surgery, progression-free survival (PFS), and overall survival (OS). RESULTS The mean patient age was 55.4 ± 14.8 years, and 63 (30.4%) patients were male. Patients harboring tumors ≥ 3 cm were significantly older (56.9 ± 15.2 years vs 53.1 ± 13.6 years; p = 0.07), more frequently male (40.8% vs 14.6%; p = 0.0001), and had greater EBL (446.5 ± 532.2 ml vs 185.4 ± 197.2 ml; p = 0.0001), greater tumor volume (33.9 ± 38.1 ml vs 29.4 ± 23.5 ml; p = 0.0001), higher MIB-1 index values (3.0% ± 5.4% vs 1.7% ± 1.7%; p = 0.03), higher vWF levels (85.6% ± 76.9% vs 54.1% ± 52.4%; p = 0.001), lower HIF-1 expression (1.4 ± 1.3 vs 2.2 ± 1.4; p = 0.004), and worse OS (199.9 ± 7.6 months vs 180.8 ± 8.1 months; p = 0.05) than patients with tumors < 3 cm. In the multivariate logistic regression, MIB-1 (OR 1.14; p = 0.05), vWF (OR 1.01; p = 0.01), and HIF-1 (OR 1.54; p = 0.0001) significantly predicted tumor size. Although multiple factors were predictive of EBL in the univariate linear regression, only vWF remained significant in the multivariate analysis (β = 0.39; p = 0.004). Lastly, MIB-1 was useful via Kaplan-Meier survival analysis for predicting patients with disease progression, whereby an MIB-1 cutoff value of ≥ 3% conferred a 36% sensitivity and 82.5% specificity in predicting disease progression; an MIB-1 value ≥ 3% showed significantly shorter mean PFS (140.1 ± 11.7 months vs 179.5 ± 7.0 months; log-rank test, p = 0.05). The Cox proportional hazards model showed a trend for MIB-1 in predicting disease progression in a hazards model (OR 1.08; 95% CI 0.99-1.19; p = 0.08). CONCLUSIONS These results support the importance of various microvascularity measures in predicting preoperative (e.g., tumor size), intraoperative (e.g., EBL), and postoperative (e.g., PFS and OS) outcomes in patients with Grade I meningiomas. An MIB-1 cutoff value of 3% showed good specificity for predicting tumor progression. The predictive ability of various measures to detect aberrant tumor microvasculature differed, possibly reflecting the heterogeneous underlying biology of meningiomas. It may be necessary to combine assays to understand angiogenesis in meningiomas.

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.

Background: Mesenchymal stem cell transplantation is demonstrated to improve neurological performance in neurodegenerative diseases including Alzheimer's disease., Objective: The objective of this study is to understand the underlying mechanism of such improvement., Methods: Amyloid β (Aβ) peptide was infused into the lateral ventricle of adult Wister rats using the osmotic pump. After 15 days of continuous infusion, a mesenchymal stem cell line (B10) was transplanted in the lateral ventricle. Learning-related behavior was evaluated by 2-way shuttle avoidance test. Fifteen days after B10 transplantation, pathological and expressional changes were evaluated., Results: Compared to sham group, learning-related behavior was significantly decreased in Aβ-infused non-transplanted group, but not in B10-transplanted group. Nissl staining results demonstrated that the number of hippocampal pyramidal neurons in CA1 area in B10-transplanted group was similar to the sham group, whereas that was decreased in Aβ-infused non-transplanted group. Aβ mainly deposited in the vessels of the brains of Aβ-infused non-transplanted rats, which was decreased by B10 transplantation. Moreover, B10 transplantation increased vessel density as well as endoglin positive cells. The number of astrocyte and microglia was decreased in Aβ-infused non-transplanted group, which was returned to the level of sham animals by B10 transplantation. Real-time PCR and immunostaining results showed that B10 transplantation significantly increased IL-1β mRNA and protein expression., Conclusion: Thus, our result showed that MSC transplantation effectively decreased Aβ deposition in the cerebral vessel and increased angiogenesis, which could be a possible cause of improved neurological performance in Aβ-infused AD model rats., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Major portal vein invasion (MVI) by hepatocellular carcinoma (HCC) carries an extremely poor prognosis. Our aim was to clarify the indications of hepatic resection in the presence of MVI by HCC. Between 2001 and 2015, 1,306 patients undergoing primary treatment for HCC were analyzed (866 hepatic resections and 440 transarterial therapies). Significant prognostic factors were identified by retrospectively analyzing tumor status, liver function and treatment. Overall survival was compared in terms of the degree of vascular invasion and treatment. The 5-year survival rates according to the degree of vascular invasion (Vp) were Vp0: 51.9%, Vp1: 33.0%, Vp2: 16.7%, Vp3: 21.8%, and Vp4: 0%, respectively. Overall survival (OS) did not differ significantly between patients with Vp3 and Vp4 MVI (p = 0.153). Median survival following hepatic resection of Vp3 cases was significantly better than that for Vp4 cases (1,913 vs. 258 days, p = 0.014), while OS following transarterial therapy was not significantly different (164 vs. 254 days in Vp3 vs. Vp4, p = 0.137). Multivariate analysis revealed hepatic resection (Odds: 2.335 [95%CI: 1.236-4.718], p = 0.008) and multiple tumors (1.698 [1.029-2.826], p = 0.038) as independent predictors of survival. Hepatic resection in HCC patients with MVI should be indicate in patients with Vp3 invasion.

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.

Radiofrequency ablation (RFA) for liver tumors is a minimally invasive procedure that uses electrical energy and heat to destroy cancer cells. One of the critical factors that impedes its successful outcome is the thermal heat sink effects from complex vascular systems that give rise to incomplete destruction of the target tumor tissue, resulting in therapy failure. To better understand the thermal influence of the complex vascular system during RFA, this work proposes the employment of two 3D fractal tree-like branched networks to investigate which key factors of the tree-like vascular system impact heating process. A three-dimensional finite difference analysis is employed to simulate the RFA treatment. Based on the data acquired from the measured experiments, the simulated results derived from combining the Pennes bioheat model and the boundary condition-enforced immersed boundary method (IBM) have demonstrated close agreement with experimental data with a maximum discrepancy of ±8.3%. We employed the orthogonal design approach to analyze 3 factors, namely, the blood vessel's volume, the average distance between probe center and the blood vessel system and the number of the selected part's branches at three different levels. Results have revealed that the distance between RFA probe and blood vessel plays a major role during the heating process compared with the other two factors. In addition, both the ablating rates and the volume of damaged tissue are slightly reduced with increasing number of blood vessel branches., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

Purpose: To describe a new approach for the treatment of cyclitic vascularized pupillary membranes., Patients and Methods: A retrospective interventional case series describing 3 patients undergoing a novel interventional treatment at a single institutional center., Results: This technique allows successful completion of laser membranectomy to create a pupillary aperture. This aperture resulted in improved vision and an enhanced ability to examine for and treat ischemic retinal disease., Conclusions: This technique describes a new use for bevacizumab that enables the surgeon to treat recalcitrant and recurrent cyclitic vascularized pupillary membranes.

Background/aims: To identify cell surface markers selectively expressed by tumor cells and tumor vasculature is the current goal for tumor therapy. One such marker is nerve/glial antigen 2 (NG2), which is a transmembrane glycoprotein. We aimed to investigate the expression of NG2 in colorectal cancer (CRC) and its association with clinicopathological parameters., Methods: Immunohistochemical staining of NG2, vascular endothelial growth factor, and CD34 in 65 patients diagnosed with CRC over a 5-year period was performed. NG2 expression in both tumor cells and tumor vasculature was scored according to the German Reactive Scoring System. The association between NG2 and patient and tumor characteristics was analyzed., Results: NG2 was expressed by tumor cells in 56.9%, tumor vasculature in 43%, and simultaneously by both in 27.6% of the cases. Tumor cell NG2 was more common in elderly patients (p = 0.023) and vascular NG2 was associated with better tumor differentiation (p = 0.035). Notably, vascular NG2 was expressed in half of the patients with left colon cancer, although it was not expressed in a majority of those with right colon cancer (50.9 vs. 17.7%, p = 0.041)., Conclusion: Both tumor cell and vascular NG2 expression were shown to be present in a significant number of patients with CRC and this makes NG2 a double target for anti-tumor therapies. Such therapies might be more effective for elderly patients with well-differentiated left colon cancer., (© 2017 S. Karger AG, Basel.)

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.)

Because of the spread to different anatomical regions, craniofacial tumors (CFTs) usually receive blood supply from several arterial systems, and CFT removal is often accompanied by abundant blood loss., Purpose: The study purpose was to develop an algorithm of diagnostic angiography for planning surgical treatment of CFT patients., Material and Methods: Complex preoperative angiography was performed in 72 patients with craniofacial tumors, aged 10 to 78 years (mean age, 45.5 years), who underwent surgical treatment at the Burdenko Neurosurgical Institute in the period from 2012 to 2015. At the first stage, blood supply to tumors was quantified using SCT perfusion. Then, depending on an assessed degree of tumor vascularization, direct angiography or modern minimally invasive angiographic techniques (3D TOF HR MR angiography, SCT angiography) were applied., Results: In 12 cases of hypervascular tumors, accessible afferents were preoperatively embolized through the external carotid artery, which was accompanied by an increase in the blood supply to tumors via alternative routes of the external and internal carotid arteries. The obtained data were used to plan the surgical approach. A comparative analysis of the SCT perfusion data and the expression level of endothelial markers in histological specimens revealed no significant correlation., Conclusion: The study demonstrated the importance of a comprehensive assessment of the blood supply to CFTs in planning of the surgical treatment and enabled the development of algorithms for preoperative angiographic diagnosis, depending on the baseline clinical and radiological data.

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.)

Retinal capillary hemangioma (RCH) is strongly associated with von Hippel-Lindau (VHL) disease. Treatment of this sight-threatening condition is often unsatisfactory despite multiple treatment options available. We here describe an interesting case of a 50-year-old male with RCH located in the perifoveal region of the left eye. Subretinal bleed, exudation, and macular edema resulted in progressive deterioration of visual acuity. Fundus photography, fluorescein angiography, and optical coherence tomography (OCT) were used to serially monitor the lesion. After ruling out systemic lesions of VHL disease, the patient was subjected to direct laser photocoagulation of the lesion which resulted in further loss in vision with increase in bleed and exudation. Subsequently, the patient was given 2 monthly intravitreal injections of bevacizumab followed by laser photocoagulation of feeder arteriole. This combination therapy resulted in resolution of exudation, bleed, and macular edema with improvement in visual acuity. Thus, vision-threatening RCH may be safely and effectively treated by means of a combination therapy comprising of intravitreal bevacizumab and feeder vessel treatment.

Tumor vaccination depending on specific antigens, autologous tumor vaccination involving wide range of antigens, immunomodulating cytokines and bacterial agents have been studied extensively with the purpose of stimulating the antitumor immune response. Unfortunately these therapies showed disappointing results mainly due to undesirable mechanisms tending to dampen the antitumor immune response. We will discuss a novel approach of autologous tumor immunization using a surgical technique: autologous tumor immunizing devascularization (ATID). This approach involves complete surgical devascularization of a tumor which is then left isolated in situ in the body. The stressing pathophysiological condition of the completely isolated tumor provokes a generalized immune response which, as shown from clinical cases, leads to the elimination of the devascularized tumor and distant metastases without causing sepsis. Until now no clinical study was properly executed. The possible significance of this method which resides in its curative potential has thus escaped attention in the field of cancer therapy. This article will hypothesize optimal physiological criteria and necessary clinical conditions for ATID to be performed effectively. The main criteria are (1) complete isolation of the tumor from the vascular system, (2) sufficient devascularized tumor load to trigger a sustained generalized immune response to cancer antigens until elimination of all cancer loci, (3) tumor cell killing rate corresponding to the elicited immune response is higher than the tumor cell growth rate, and (4) patients with an uncompromised immune system. Future studies have to be performed under the indicated conditions in order to confirm the efficacy and safety of ATID as a novel approach in the treatment of cancer., (Copyright © 2016 Elsevier Ltd. 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.

Currently there is no consensus how to reduce the risk of hemorrhage in spinal decompression surgery of hypervascu- lar spinal tumors. A retrospective study of 128 patients oper- ated in our institute was held in the period between 2003 and 2014. There were 80 male and 48 female patients with extradural hypervascular spinal tumor. The study included 71 patients with metastases of renal cell carcinoma, 28 - with multiple myeloma, 18 - with plasmacytoma and 11 - with aggressive hemangioma. The first group included 59 patients who underwent preoperative tumor embolization. The second group consisted of 69 patients who were treated surgically using intraoperative local hemostatic agents. We performed 2 types of treatment options: palliative decompression and total spondylectomy. We did not get evidence that embolization was more effective than using local hemostatic agents for patients with hypervascular spinal tumors who underwent palliative decompression. In the same time efficiency of embolization for patients with total spondylectomy was significantly higher.

Vascular anomalies, as described by the Adachi classification, are an inevitable issue for gastric cancer surgery. Here, we report a safe technique for laparoscopic lymph node dissection in a patient with Adachi typeⅥ vascular anomaly. The patient is a 72-year-old woman, who presented with a submucosal gastric cancer located on the lesser curvature of the stomach. Preoperative MDCT revealed Adachi type Ⅵ vascular anomaly. At laparoscopic surgery, we first identified the portal vein. Then, dissection of the hepatoduodenal and No. 8a lymph nodes was performed from the location near the portal vein at the superior portion of the hepatoduodenal ligament to that near the splenic vein superior to the pancreas. This avoids the disorientation that may result from anomalous vessels and prevents error that can lead to vascular complications. Subsequently, she underwent D1 plus gastrectomy. Her postoperative course was uneventful. Our surgical technique offers a safe approach for laparoscopic gastrectomy in the patient with Adachi type Ⅵ vascular anomaly.

Background: Autologous fat grafts are rich in adipose-derived stem cells, providing optimal soft-tissue replacement and significant quantities of angiogenic growth factor. Although fat grafts (FG) are used in several clinical conditions, the use of FG in urethral repairs and the effects of FG to urethral repairs have not yet been reported., Objective: An experimental study was performed to evaluate the effect of FG on urethral angiogenesis and tissue growth factor (GF) levels., Study Design: Sixteen Wistar albino, adult, male rats were allocated into two groups: the control group (CG) (n = 8) and the experiment group (EG) (n = 8). After anesthetization of all rats, 3-mm vertical incisions were made on the urethras, and then sutured with interrupted 5/0 vicryl sutures. The operations were performed under a stereo dissecting microscope under magnification (×20). In the CG, no additional procedure was performed. In the EG after the same surgical procedure, 1 mm(3) FG was removed from the inguinal region by sharp dissection with a knife. The grafts were trimmed to 1 × 1 mm dimensions on millimeter paper. The FGs were placed on the repaired urethras. The skin was then closed. Samples from urethral and penile skin were taken 21 days after surgery in both groups. Density and intensity of staining with vascular-endothelial GF (VEGF), VEGF-receptor, and endothelial-GF receptor (EGFR) in the endothelial and mesenchymal cells of the penile urethral vessels were immunohistochemically evaluated. Data obtained from immunohistochemical evaluations were analyzed with SPSS 15.0. The P-values lower than 0.05 were considered as significant., Results: Density of VEGF staining was significantly decreased in the vascular endothelium of the EG compared to the CG (P < 0.05). Density of the EGFR staining was significantly decreased in the vascular endothelium of the EG compared to the CG (P < 0.05) (Table). Intensity of VEGF, VEGF-R and EGFR staining was not significantly different between the two groups. There were no significant differences between groups regarding to VEGFR staining and mesenchymal examination., Discussion: Decreased density was found in the VEGF staining in the vascular endothelium. This could be explained by the day that the tissues were harvested or because autologous fat grafts might cause decreased growth factor levels, which is contrary to the literature data., Conclusion: Fat grafting has an immunohistochemical effect on the growth factor levels that are related to angiogenesis after urethral repair. It is difficult to make a firm conclusion about the role of fat grafting on urethral healing. Therefore, future studies are needed to see if FG can be used as an alternative to other procedures in order to avoid complications., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Nanoparticle based image-guided therapy is an emerging technology for cancer in recent years. Here, we report simultaneous photoacoustic (PA)- and magnetic resonance (MR)-guided photothermal ablation (PTA) therapy using multifunctional superparamagnetic iron oxide-containing gold nanoshells (SPIO@AuNS). Based on the intrinsic high near-infrared optical absorbance and strong magnetic property of SPIO@AuNS, we carried out in vivo dual-modality PA-MR imaging of mouse tumors. PA- and MR-guided imaging can monitor therapeutic effect after photothermal therapy mediated by our multifunctional nanomaterial. In addition, using our pulsed laser PA technique, we also observe a clearer structure of the tumor vasculature after intravenously administration SPIO@AuNS. The novel dual PA-MRI image-guided PTA therapy provides a promising new platform for cancer diagnosis and treatment simultaneously.

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.

Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear., Methods: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS)., Results: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis., Conclusion: The presence of VI is not an independent predictor of outcome in WDTC.

Background and Purpose: To more safely resect pathological lesions during spinal vascular lesion surgery, it is most important to understand local abnormal hemodynamics in detail. New devices or techniques that make out intraoperative local hemodynamics have been awaited. To introduce a resourceful method, we present a case of spinal hemangioblastoma for which temporary arterial occlusion during near-infrared intraoperative indocyanine green (ICG) videoangiography gives useful assessment of the main and minor feeders easily., Methods: A 36-year-old female suffered progressive paresthesia of both lower extremities for 12 months and gait disturbance for 2 weeks. A neurological examination revealed T10 myelopathy. Magnetic resonance imaging (MRI) of the thoracic spine showed an intramedullary tumor at the T8 level and severe spinal cord edema with a flow void in the extended dorsal spinal veins. Spinal angiography showed a hemangioblastoma at the T8 level, with two main feeders and minor feeders., Results: She underwent total resection of the tumor by a posterior approach. During the intraoperative ICG videoangiography, temporary arterial occlusion of the two main feeders and FLOW(®)800 analysis enabled clear understanding of the vasculature, especially of the two minor feeders. At the 9-month follow-up, her neurological manifestation was partially resolved, and post-operative MRI showed total removal of the tumor and disappearance of the spinal cord edema., Conclusions: Temporary clipping of the main feeders during intraoperative ICG videoangiography is very useful for easily determining the minor feeding arteries, and helpful for maintaining normal perfusion of the spinal cord in spinal hemangioblastoma surgery. Furthermore, the FLOW 800 analysis, especially the false color-coded variation, increased our understanding of the hemodynamics.