Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma.

PURPOSE: Antiangiogenic agents have been used for many years as a first-line systemic treatment for advanced HCC. Embolization with cytostatic drugs on the other hand is the first-line treatment for intermediate HCC. The two types of drugs have not been combined for intraarterial delivery yet. The loading and release dynamics and the in vitro effect of their combination are tested in this experimental study. MATERIALS AND METHODS: Drug-eluting beads were loaded with doxorubicin, sunitinib and sunitinib analogue piperazine (SAP) alone and with their combinations. Diameter change, loading, release, and effect in cellular proliferation were assessed. RESULTS: The average microsphere diameter after loading was 473.7 µm (µm) for Doxorubicin, 388.4 µm for Sunitinib, 515.5 µm for SAP, 414.8 µm for the combination Doxorubicin/Sunitinib and 468.8 µm for the combination Doxorubicin /SAP. Drug release in 0.9% NaCl was 10% for Doxorubicin, 49% for Sunitinib, 25% for SAP, 20%/18% for the combination Doxorubicin/Sunitinib, and 18%/23% for the combination Doxorubicin/SAP whereas in human plasma it was 56%, 27%, 13%, 76%/63% and 62%/15%, respectively. The mean concentration of Doxorubicin that led to inhibition of 50% of cellular proliferation in an HCC Huh7 cell line was 163.1 nM (nM), for Sunitinib 10.3 micromolar (µΜ), for SAP 16.7 µΜ, for Doxorubicin/Sunitinib 222.4 nM and for Doxorubicin/SAP 275 nM. CONCLUSIONS: Doxorubicin may be combined with antiangiogenic drugs with satisfactory in vitro loading and release outcomes and effect on cellular lines.

Exploring the latest findings on endovascular treatments for giant aneurysms: a review.

Giant intracranial aneurysms represent a very challenging aspect of aneurysmal pathophysiology with very high mortality and morbidity if left untreated. Their variety in clinical presentation (subarachnoid hemorrhage, cranial nerve palsy, etc.) and pathological and imaging properties (location, anatomy, presence of collateral circulation) pose serious questions regarding the best treatment option. Admirable advances have been achieved in surgical techniques, while endovascular modalities with flow diversion techniques have become widely used. However, there is still lack of data regarding whether a single endovascular technique can be the universal treatment for such cases. In this review, we aim to summarize the current funds of knowledge concerning giant intracranial aneurysms and the role of endovascular management in their treatment.

Moyamoya Disease: Clinical and Radiological Characteristics in Adult Greek Patients.

BACKGROUND AND PURPOSE: The aim of our study is to present, for the first time, the clinical, radiological, and neurocognitive characteristics of Greek adult patients with Moyamoya disease (MMD). METHODS: We analyzed prospectively collected data of 12 patients referred to our department from 2004 to 2019. All patients underwent a thorough diagnostic work up, including extensive clinical, neuroradiological, and neurocognitive assessment. RESULTS: Our study population consisted of 7 females and the median age at the time of the diagnosis was 43.5 years. No patient had a positive family history of the disease and roughly 50% were hypertensives. Ten patients presented with transient or permanent cerebrovascular ischemia and two patients suffered from hemorrhagic complications. The median NIHSS was 7.5 (0-23) and clinical status remained stable during follow-up with conservative treatment in most of the patients. The majority (83.3%) had bilateral disease confirmed by DSA. All lesions exclusively affected the anterior circulation, with 50% of patients presenting with stenoocclusive changes. No aneurysm or AVM were revealed. The most common neurocognitive deficits were in the executive and language domains. CONCLUSIONS: Our MMD patients had a later onset of the disease and an absence of familial occurrence. The most common manifestation was ischemia, transient or permanent, and all lesions affected the anterior circulation, whereas no vascular malformations (AVM, aneurysms) were demonstrated in brain imaging. These findings in Greek patients imply a probable different, Mediterranean phenotype.

Artificial intelligence-driven ASPECTS for the detection of early stroke changes in non-contrast CT: a systematic review and meta-analysis.

BACKGROUND: Recent advances in machine learning have enabled development of the automated Alberta Stroke Program Early CT Score (ASPECTS) prediction algorithms using non-contrast enhanced computed tomography (NCCT) scans. The applicability of automated ASPECTS in daily clinical practice is yet to be established. The objective of this meta-analysis was to directly compare the performance of automated and manual ASPECTS predictions in recognizing early stroke changes on NCCT. METHODS: The MEDLINE, Scopus, and Cochrane databases were searched. The last database search was performed on March 10, 2022. Studies reporting the diagnostic performance and validity of automated ASPECTS software compared with expert readers were included. The outcomes were the interobserver reliability of outputs between ASPECTS versus expert readings, experts versus reference standard, and ASPECTS versus reference standard by means of pooled Fisher's Z transformation of the interclass correlation coefficients (ICCs). RESULTS: Eleven studies were included in the meta-analysis, involving 1976 patients. The meta-analyses showed good interobserver reliability between experts (ICC 0.72 (95% CI 0.63 to 0.79); p<0.001), moderate reliability in the correlation between automated and expert readings (ICC 0.54 (95% CI 0.40 to 0.67); p<0.001), good reliability between the total expert readings and the reference standard (ICC 0.62 (95% CI 0.52 to 0.71); p<0.001), and good reliability between the automated predictions and the reference standard (ICC 0.72 (95% CI 0.61 to 0.80); p<0.001). CONCLUSIONS: Artificial intelligence-driven ASPECTS software has comparable or better performance than physicians in terms of recognizing early stroke changes on NCCT.

Vena cava balloon occlusion for pulmonary embolism prevention during resection of giant uterus fibroids.

We report the case of a single 46-year-old woman presenting with huge uterine fibroids growing for the last 12 years, resulting in a recent common iliac vein thrombosis. Due to the high risk for pulmonary embolism, an occluding balloon was inserted through the right jugular vein before the abdominal incision and occluded the vena cava just inferior to the renal veins. The tumor was easily mobilized, and the vena cava bifurcation was exposed and controlled until the uterus with the masses was resected. We recommend this method for oncovascular surgeries involving deep vein thrombosis and vein thromboembolism.

Radiomics/Radiogenomics in Lung Cancer: Basic Principles and Initial Clinical Results.

Lung cancer is the leading cause of cancer-related deaths worldwide, and elucidation of its complicated pathobiology has been traditionally targeted by studies incorporating genomic as well other high-throughput approaches. Recently, a collection of methods used for cancer imaging, supplemented by quantitative aspects leading towards imaging biomarker assessment termed "radiomics", has introduced a novel dimension in cancer research. Integration of genomics and radiomics approaches, where identifying the biological basis of imaging phenotypes is feasible due to the establishment of associations between molecular features at the genomic-transcriptomic-proteomic level and radiological features, has recently emerged termed radiogenomics. This review article aims to briefly describe the main aspects of radiogenomics, while discussing its basic limitations related to lung cancer clinical applications for clinicians, researchers and patients.

CurveletTransform-Based Texture Analysis of Carotid B-mode Ultrasound Images in Asymptomatic Men With Moderate and Severe Stenoses: A Preliminary Clinical Study.

The curvelet transform, which represents images in terms of their geometric and textural characteristics, was investigated toward revealing differences between moderate (50%-69%, n = 11) and severe (70%-100%, n = 14) stenosis asymptomatic plaque from B-mode ultrasound. Texture features were estimated in original and curvelet transformed images of atheromatous plaque (PL), the adjacent arterial wall (intima-media [IM]) and the plaque shoulder (SH) (i.e., the boundary between plaque and wall), separately at end systole and end diastole. Seventeen features derived from the original images were significantly different between the two groups (4 for IM, 3 for PL and 10 for SH; 9 for end diastole and 8 for end systole); 19 of 234 features (2 for IM and 17 for SH; 8 for end systole and 11 for end diastole) derived from curvelet transformed images were significantly higher in the patients with severe stenosis, indicating higher magnitude, variation and randomness of image gray levels. In these patients, lower body height and higher serum creatinine concentration were observed. Our findings suggest that (a) moderate and severe plaque have similar curvelet-based texture properties, and (b) IM and SH provide useful information about arterial wall pathophysiology, complementary to PL itself. The curvelet transform is promising for identifying novel indices of cardiovascular risk and warrants further investigation in larger cohorts.

Endovascular Treatment of Intracranial Aneurysms.

Traditionally, surgical clipping was the only available treatment modality for intracranial aneurysms. However, in the last few decades, the endovascular therapy of intracranial aneurysms (IAs) has seen a tremendous evolution and development. From coiling to flow diversion and flow disruptor devices, endovascular treatment modalities have increased in number and received broader indications throughout the years. In this review article, the treatment modalities for the endovascular management of IAs are presented, emphasizing newer devices and technologies.

Leiomyoma of the Retzius space in a male patient: A case report and a diagnostic approach to Retzius space diseases.

Retzius space is a small anatomical compartment located directly posterior to the pubic symphysis and anterior to the urinary bladder. Diseases developing primarily in this space are rare; only 7 cases of leiomyomas of the Retzius space have been reported in the literature so far, all of them in female patients. We present a unique case of a leiomyoma of the Retzius space in a male patient. An imaging-based diagnostic approach to Retzius space disease is proposed.

Reversal of Acute Mesenteric Ischemia by Salvation of the Meandering Mesenteric Artery with Stenting of the Left Internal Iliac Artery.

The presence of the meandering mesenteric artery, which is a nonconstant tortuous arterial component unifying the peripheral intestinal circulation, is evidence of chronic occlusive disease of the main intestinal arteries. This collateral intestinal arterial pathway, when present, must be preserved in any abdominal intervention, as it is often the only remaining arterial supply of the intestine; its ligation can be accompanied by intestinal ischemia. We present herein, the case of a 42-year-old man, heavy smoker, who had chronic mesenteric ischemia without particular clinical manifestations till the hospitalization for acute myocardial infarction for which he underwent balloon angioplasty and stenting of the left circumflex coronary artery. Three days later, he experienced acute-on-chronic intestinal ischemia with crescendo clinical manifestations; intra-arterial angiography revealed the presence of a meandering mesenteric artery in a milieu of celiac, superior and inferior mesenteric, and right internal iliac artery occlusion accompanied by a tight stenosis of the left internal iliac artery. Successful stenting of the orifice of the left internal iliac artery was followed by a well-defined dilatation of the meandering artery, revascularization of the peripheral branches of the inferior-through the superior hemorrhoidal artery-and superior mesenteric arteries and complete resolution of the acute mesenteric ischemia. Thus, time was gained for the patient in order to have, if needed, a future elective open revascularization of the mesenteric artery, when the perioperative risk of mortality from the recent myocardial infarction and the coronary angioplasty and stenting will be minimal.

Pharmacokinetics, Safety, and Efficacy of Chemoembolization with Doxorubicin-Loaded Tightly Calibrated Small Microspheres in Patients with Hepatocellular Carcinoma.

PURPOSE: This study examines safety, efficacy, and pharmacokinetics of chemoembolization with loadable microspheres ≤100 µm for hepatocellular carcinoma. MATERIALS AND METHODS: A pilot safety study was performed in 19 patients with size and dose escalation and then 52 patients were enrolled prospectively and randomly assigned to chemoembolization with TANDEM™ loaded with 150 or 100 mg of doxorubicin. RESULTS: The mean diameter of the tumors was 7.28 ± 2.09 cm (range 4-12) and distribution dominant/multiple 51.9/48.1 %. Child A/B distribution was 32/20 (61.5/38.5 %) and etiology HBV/HCV/HBV/HCV-hemochromatosis was 61.6/9.6/9.6/15.4 %. Twenty-five patients were assigned in the low and 27 in the high loading group. There was 1.92 % thirty-day mortality due to lesion rupture. Biliary damage was seen in 3 patients (5.7 %) in the high loading. Mean maximum plasma concentration of doxorubicin C max ± SD was 284.9 ± 276.2 ng/mL for the high and 108.5 ± 77.6 ng/mL for the low loading (p < 0.001). According to m-RECIST overall objective response after two sessions reached 61.22 and 63.82 % at 6 months. Notably, complete target lesion response (CR) after the second session was observed in 28.57 % and maintained in 23.40 % at 6 months. No statistical differences in the local response rates were observed between the two loading groups. Overall survival (OS) at 6 months, 1 , 2, and 3 years was 98.08, 92.3, 88.46, and 82.6 %, respectively. OS and Progression-Free Survival did not demonstrate statistical significance between the two loading groups. CONCLUSION: Initial evidence shows that (a) TANDEM™ achieves high rates of local response and mid-term survival, (b) high loading provides no clinical benefit and is associated with biliary toxicity.

Ultrasound and Biochemical Diagnostic Tools for the Characterization of Vulnerable Carotid Atherosclerotic Plaque.

Stroke is a leading cause of morbidity and mortality worldwide, and characterization of vulnerable carotid plaque remains the spearhead of scientific research. Plaque destabilization, the key factor that induces the series of events leading to the clinical symptoms of carotid artery disease, is a consequence of complex mechanical, structural and biochemical processes. Novel imaging and molecular markers have been studied as predictors of disease outcome with promising results. The aim of this review is to present the current state of research on the association between ultrasound-derived echogenicity indices and blood parameters indicative of carotid plaque stability and activity. Bibliographic research revealed that there are limited available data. Among the biomarkers studied, those related to oxidative stress, lipoproteins and diabetes/insulin resistance are associated with echolucent plaques, whereas adipokines are associated with echogenic plaques. Biomarkers of inflammation and coagulation have not exhibited any conclusive relationship with plaque echogenicity, and it is not possible to come to any conclusion regarding calcification-, apoptosis- and neo-angiogenesis-related parameters because of the extremely limited bibliographic data.

Childhood central nervous system tumour mortality and survival in Southern and Eastern Europe (1983-2014): Gaps persist across 14 cancer registries.

AIM: Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region. METHODS: Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants. RESULTS: Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4). CONCLUSION: Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe.

Chemoembolization of hepatocellular carcinoma with HepaSphere 30-60 µm. Safety and efficacy study.

BACKGROUND: This study examined the safety, pharmacokinetics, and efficacy of transarterial chemoembolization of hepatocellular carcinoma (HCC) using a newly developed size of a superabsorbent polymer drug-eluting embolic material. METHODS: Forty-five patients with documented HCC (Child-Pugh score A/B: 55.5 %/44.5 %) were embolized with HepaSphere microspheres 30-60 µm with escalation of lesion, dose, and frequency of re-embolization. Local response was evaluated with modified response evaluation criteria in solid tumors (mRECIST). Plasma levels of doxorubicin were measured in 24 patients at baseline and at 5, 20, 40, 60, and 120 min, at 6, 24, and 48 h, and at 7 days, respectively, to determine doxorubicin in plasma (Cmax) and area under the curve (AUC). Measurements of three patients who underwent lipiodol-based conventional chemoembolization (c-TACE) were also performed. RESULTS: TACE with HepaSphere was well tolerated with an acceptable safety profile and no 30-day mortality. Response rates were calculated on intention-to-treat basis with complete response (CR) in 17.8 % reaching 22.2 % for the target lesion. Overall partial response (PR) was seen in 51.1 %, stable disease in 20 %, and progressive disease in 11.1 % of patients. Overall objective response (CR + PR), including patients treated at all dosages of doxorubicin, was seen in 68.9 % of cases. After a median follow-up of 15.6 months, 1-year survival is 100 %. Doxorubicin AUC was significantly lower in patients with HepaSphere 30-60 µm (35,195 ± 27,873 ng × min/ml) than in patients with conventional TACE (103,960 ± 16,652 ng × min/ml; p = 0.009). Cmax was also significantly lower with HepaSphere 30-60 µm (83.9 ± 32.1 ng/ml) compared with c-TACE (761.3 ± 58.8 ng/ml; p = 0.002). CONCLUSION: HepaSphere 30-60 µm is an effective drug-eluting embolic material with a favourable pharmacokinetic profile.

Long term recurrence analysis post drug eluting bead (deb) chemoembolization for hepatocellular carcinoma (hcc).

UNLABELLED: BACKROUND-AIMS: To determine long term outcomes, regarding recurrence and survival, in patients with HCC that achieved complete response after initial treatment with drug eluting beads (DEB) using DC Bead loaded with doxorubicin (DEB-DOX). METHODOLOGY: Forty-five patients with HCC, not suitable for curative treatments that exhibited complete response (EASL criteria) to initial DEB-DOX treatment were retrospectively analyzed after a median follow up period of 63 months. Child-Pugh class was A/B (62.2/37.8%) and mean lesion diameter 5.36 ± 1.1 cm. Lesion morphology was one dominant ≤5cm (53.3%), one dominant >5cm (31.1%) and multifocal (15.6%). RESULTS: At 5 years, overall survival was 62.2% and recurrence-free survival 8.9%. All deaths that occurred were related to tumor progression (31.1%) or complications of underlying liver disease (28.9%). Median time of initial recurrence from baseline treatment was 18 months (range 8-52). When recurrence occurred, a mean time interval between additional DEB-DOX procedures less than 9 months was correlated to a poorer prognosis (p=0.025). Multivariate analysis identified Child-Pugh class at baseline (p=0.048), combined therapy of recurrences with local ablation (p=0.03) and number of DEB-DOX procedures (p=0.037) as significant prognostic factors of 5-year survival. Lesion morphology displayed significance for recurrence-free survival (p=0.014). Child-Pugh class at baseline, additional local ablation, pattern of initial recurrence and initial sum of recurrent tumor diameters all displayed statistical significance for post-recurrence survival (median 40 months), with the first two variables maintaining statistical significance in multivariate analysis (p=0.015 and p=0.014 respectively). CONCLUSION: Initial complete response to DEB-DOX ensures a favorable prognosis. However, management of recurrent tumors, which occur frequently mostly as new lesions, and preservation of underlying liver function appear to play a key role in prolonging survival.

Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis.

PURPOSE: The purpose of this study was to report on the 5-year survival of hepatocellular carcinoma (HCC) patients treated with DC Bead loaded with doxorubicin (DEB-DOX) in a scheduled scheme in up to three treatments and thereafter on demand. MATERIALS AND METHODS: 173 HCC patients not suitable for curable treatments were prospectively enrolled (mean age 70.4 ± 7.4 years). Child-Pugh (Child) class was A/B (102/71 [59/41 %]), Okuda stage was 0/1/2 (91/61/19 [53.2/35.7/11.1 %]), and mean lesion diameter was 7.6 ± 2.1 cm. Lesion morphology was one dominant ≤5 cm (22 %), one dominant >5 cm (41.6 %), multifocal ≤5 (26 %), and multifocal >5 (10.4 %). RESULTS: Overall survival at 1, 2, 3, 4, and 5 years was 93.6, 83.8, 62, 41.04, and 22.5 %, with higher rates achieved in Child class A compared with Child class B patients (95, 88.2, 61.7, 45, and 29.4 % vs. 91.5, 75, 50.7, 35.2, and 12.8 %). Mean overall survival was 43.8 months (range 1.2-64.8). Cumulative survival was better for Child class A compared with Child class B patients (p = 0.029). For patients with dominant lesions ≤5 cm 1-, 2-, 3-, 4-, and 5-year survival rates were 100, 95.2, 71.4, 66.6, and 47.6 % for Child class A and 94.1, 88.2, 58.8, 41.2, 29.4, and 23.5 % for Child class B patients. Regarding DEB-DOX treatment, multivariate analysis identified number of lesions (p = 0.033), lesion vascularity (p < 0.0001), initially achieved complete response (p < 0.0001), and objective response (p = 0.046) as significant and independent determinants of 5-year survival. CONCLUSION: DEB-DOX results, with high rates of 5-year survival for patients, not amenable to curative treatments. Number of lesions, lesion vascularity, and local response were significant independent determinants of 5-year survival.

Intimal aortic sarcoma mimicking ruptured thoracoabdominal type IV aneurysm. A rare case report and review of the literature.

Primary intimal aortic sarcoma represents a very rare and highly lethal medical entity. Diagnosis is made either by embolic events caused by the tumor or by surrounding tissue symptoms such as pain. Herein we report an extremely rare case of a 51-year-old man previously operated for ascending aortic aneurysm, who presented with clinical and radiological findings suggestive of a ruptured thoracoabdominal type IV aneurysm. The patient underwent radical resection of the aorta and surrounding tissue with placement of a composite 4-branched graft. The diagnosis was made by frozen section and regular histopathologic examination of the specimen and the patient received adjuvant chemotherapy. Nine months after surgery the patient is still alive and has no signs of recurrence. We review the literature and discuss the option of postoperative chemotherapy.

Differential effect of Pistacia vera extracts on experimental atherosclerosis in the rabbit animal model: an experimental study.

BACKGROUND: Lipid-enriched diets and oxidative stress are risk factors for the development of atherosclerosis. The effects of the methanolic (ME) and cyclohexane (CHE) extracts of the Pistacia vera nut, often included in the Mediterranean diet, were studied in the rabbit model of atherosclerosis. METHODS AND RESULTS: Twenty-four New Zealand White rabbits received atherogenic diet (Control Group), supplemented with ME (Group ME) or CHE (Group CHE) for 3 months. Previously, a GC-MS and a UHPLC LC-DAD-ESI(-)-HRMS/MS method were developed to investigate the extracts' chemical profiles. Blood samples at baseline and monthly determined lipid profile, lipid peroxidation and liver function. The aorta, myocardium and liver were examined histologically at 3 months.Groups ME and CHE had significantly higher HDL- and non-significantly lower LDL-cholesterol median % changes from baseline than the Control Group. Triacylglycerol was significantly higher in Group CHE vs. Control. MDA values were significantly lower in Group ME vs. Control and CHE. ALT and AST were significantly higher in Group CHE vs. Control. gamma-GT was lower in Group ME vs. Control. Aortic intimal thickness was significantly less in Groups ME and CHE vs. Control; Group ME atherosclerotic lesions were significantly less extensive vs. Groups Control and CHE. Only Group CHE had significant liver fatty infiltration. CONCLUSIONS: During short-term administration concomitantly with atherogenic diet, both P. vera extracts were beneficial on HDL-, LDL-cholesterol and aortic intimal thickness. The ME additionally presented an antioxidant effect and significant decrease of aortic surface lesions. These results indicate that P. vera dietary inclusion, in particular its ME, is potentially beneficial in atherosclerosis management.