Posterior Cerebral Artery Angle and the Rupture of Basilar Tip Aneurysms

Since the initial publication of the International Study of Unruptured Intracranial Aneurysms (ISUIA), management of unruptured intracranial aneurysms has been mainly based on the size of the aneurysm. The contribution of morphological characteristics to treatment decisions of unruptured aneurysms has not been well studied in a systematic and location specific manner. We present a large sample of basilar artery tip aneurysms (BTA) that were assessed using a diverse array of morphological variables to determine the parameters associated with ruptured aneurysms. Demographic and clinical risk factors of aneurysm rupture were obtained from chart review. CT angiograms (CTA) were evaluated with Slicer, an open source visualization and image analysis software, to generate 3-D models of the aneurysms and surrounding vascular architecture. Morphological parameters examined in each model included aneurysm volume, aspect ratio, size ratio, aneurysm angle, basilar vessel angle, basilar flow angle, and vessel to vessel angles. Univariate and multivariate analyses were performed to determine statistical significance. From 2008–2013, 54 patients with BTA aneurysms were evaluated in a single institution, and CTAs from 33 patients (15 ruptured, 18 unruptured) were available and analyzed. Aneurysms that underwent reoperation, that were associated with arteriovenous malformations, or that lacked preoperative CTA were excluded. Multivariate logistic regression revealed that a larger angle between the posterior cerebral arteries (P1-P1 angle, p = 0.037) was most strongly associated with aneurysm rupture after adjusting for other morphological variables. In this location specific study of BTA aneurysms, the larger the angle formed between posterior cerebral arteries was found to be a new morphological parameter significantly associated with ruptured BTA aneurysms. This is a physically intuitive parameter that can be measured easily and readily applied in the clinical setting.     

Morphological and Hemodynamic Discriminators for Rupture Status in Posterior Communicating Artery Aneurysms

Background and Purpose

The conflicting findings of previous morphological and hemodynamic studies on intracranial aneurysm rupture may be caused by the relatively small sample sizes and the variation in location of the patient-specific aneurysm models. We aimed to determine the discriminators for aneurysm rupture status by focusing on only posterior communicating artery (PCoA) aneurysms.

Materials and Methods

In 129 PCoA aneurysms (85 ruptured, 44 unruptured), clinical, morphological and hemodynamic characteristics were compared between the ruptured and unruptured cases. Multivariate logistic regression analysis was performed to determine the discriminators for rupture status of PCoA aneurysms.

Results

While univariate analyses showed that the size of aneurysm dome, aspect ratio (AR), size ratio (SR), dome-to-neck ratio (DN), inflow angle (IA), normalized wall shear stress (NWSS) and percentage of low wall shear stress area (LSA) were significantly associated with PCoA aneurysm rupture status. With multivariate analyses, significance was only retained for higher IA (OR = 1.539, p < 0.001) and LSA (OR = 1.393, p = 0.041).

Conclusions

Hemodynamics and morphology were related to rupture status of intracranial aneurysms. Higher IA and LSA were identified as discriminators for rupture status of PCoA aneurysms.     

Analysis of Morphological Parameters to Differentiate Rupture Status in Anterior Communicating Artery Aneurysms

In contrast to size, the association of morphological characteristics of intracranial aneurysms with rupture has not been established in a systematic manner. We present an analysis of the morphological variables that are associated with rupture in anterior communicating artery aneurysms to determine site-specific risk variables. One hundred and twenty-four anterior communicating artery aneurysms were treated in a single institution from 2005 to 2010, and CT angiograms (CTAs) or rotational angiography from 79 patients (42 ruptured, 37 unruptured) were analyzed. Vascular imaging was evaluated with 3D Slicer© to generate models of the aneurysms and surrounding vasculature. Morphological parameters were examined using univariate and multivariate analysis and included aneurysm volume, aspect ratio, size ratio, distance to bifurcation, aneurysm angle, vessel angle, flow angle, and parent-daughter angle. Multivariate logistic regression revealed that size ratio, flow angle, and parent-daughter angle were associated with aneurysm rupture after adjustment for age, sex, smoking history, and other clinical risk factors. Simple morphological parameters such as size ratio, flow angle, and parent-daughter angle may thus aid in the evaluation of rupture risk of anterior communicating artery aneurysms.     

Correlation Between the Rupture Risk and 3D Geometric Parameters of Saccular Intracranial Aneurysms

The purpose of this study is to evaluate the association of the location and geometric parameters of intracranial aneurysm with the risk of rupture. A retrospective study consisted of 284 patients diagnosed with saccular intracranial aneurysm between January 2009 and May 2013 at Wuxi Third People’s Hospital was conducted. 3D digital subtraction angiography images from all patients (240 ruptured, 44 unruptured) were obtained and analyzed. The location of the aneurysms and the 3D geometric parameters including the aneurysm depth, the neck size, diameter of the parent artery, aneurysm angle, aspect radio, size ratio, and the neck-to-parent-artery ratio (NPR) were compared between ruptured and unruptured groups. Results: In ruptured group, anterior communicating artery, posterior communicating artery (PCoA), and the bifurcation of internal carotid artery (ICA) were the top three locations for aneurysm occurrence, accounting for 40.00, 30.42, and 12.08 % respectively. While in the unruptured group, top three locations were PCoA (36.36 %), posterior cerebral circulation (18.18 %), and the bifurcation of the ICA (15.91 %). Distribution of aneurysm location is significantly different (p < 0.05) between ruptured and unruptured aneurysms. For the 3D geometric parameters characterizing aneurysm, aneurysm depth (p < 0.05), parent artery diameter (p < 0.05), aneurysm angle (p < 0.01), aspect ratio (p < 0.01), and size ratio (p < 0.01) all showed a significant difference between ruptured and unruptured group. No difference was found in the neck size and the NPR ratio between the two groups. 3D geometric parameters such as aneurysm depth, parent artery diameter, aneurysm angle, aspect ratio, and size ratio can be helpful in evaluating the rupture risk of saccular intracranial aneurysm for a better prevention and prognosis.     

Morphometry and hemodynamics of posterior communicating artery aneurysms: Ruptured versus unruptured

Posterior communicating artery (PCoA) aneurysms frequently rupture in small size (<7 mm). The aim of the study is to demonstrate morphometric and hemodynamic analyses in ruptured and unruptured PCoA aneurysms to improve predictive accuracy for rupture. Geometrical models were reconstructed from rotational DSA images of 57 ruptured and 22 unruptured side-wall PCoA aneurysms, which were classified into four two-dimensional (2D) groups by a combination of H/D and H/S ratios (H: dome height, D: dome diameter, and S: semi-axis height). Surface area ratio (SAR) of low time-averaged wall shear stress (TAWSS, ≤4 dynes cm⁻²) and high oscillatory shear index (OSI, ≥0.15) were computed in aneurysms. We hypothesized that a two-step analysis method, i.e., one-dimensionally morphometric and hemodynamic analyses in each 2D group, can enhance accuracy of PCoA aneurysm rupture evaluation. There was the highest incidence of H/D > 1 and H/S ≤ 2 with the largest surface area and SAR-TAWSS, but the lowest incidence of H/D ≤ 1 and H/S > 2 with the smallest surface area and SAR-TAWSS in ruptured PCoA aneurysms. PCoA aneurysms of H/D > 1 and H/S ≤ 2 with surface area > 70 mm², H/D ≤ 1 and H/S > 2 with neck diameter > 2.3 mm, H/D ≤ 1 and H/S ≤ 2 with aneurysmal height/parent diameter ratio > 1.0, and H/D > 1 and H/S > 2 with aneurysmal angle > 115° need special attention for clinical diagnosis and treatment. The study highlighted the importance of the two-step analysis method for clinical evaluation of PCoA aneurysm rupture.     

Flow instability detected in ruptured versus unruptured cerebral aneurysms at the internal carotid artery

Flow instability has emerged as a new hemodynamic metric hypothesized to have potential value in assessing the rupture risk of cerebral aneurysms. However, diverse findings have been reported in the literature. In the present study, high-resolution hemodynamic simulations were performed retrospectively on 35 aneurysms (10 ruptured & 25 unruptured) located at the internal carotid artery (ICA). Simulated hemodynamic parameters were statistically compared between the ruptured and unruptured aneurysms, with emphasis on examining the correlation of flow instability with the status of aneurysm rupture. Pronounced flow instability was detected in 20% (2 out of 10) of the ruptured aneurysms, whereas in 44% (11 out of 25) of the unruptured aneurysms. Statistically, the flow instability metric (quantified by the temporally and spatially averaged fluctuating kinetic energy over the aneurysm sac) did not differ significantly between the ruptured and unruptured aneurysms. In contrast, low wall shear stress area (LSA) and pressure loss coefficient (PLC) exhibited significant correlations with the status of aneurysm rupture. In conclusion, the present study suggests that the presence of flow instability may not correlate closely with the status of aneurysm rupture, at least for ICA aneurysms. On the other hand, the retrospective nature of the study and the small sample size may have to some extent compromised the reliability of the conclusion, and therefore large-scale prospective studies would be needed to further address the issue.     

Difference in Aneurysm Characteristics between Patients with Familial and Sporadic Aneurysmal Subarachnoid Haemorrhage

ObjectPatients with familial intracranial aneurysms (IA) have a higher risk of rupture than patients with sporadic IA. We compared geometric and morphological risk factors for aneurysmal rupture between patients with familial and sporadic aneurysmal subarachnoid hemorrhage (aSAH) to analyse if these risk factors contribute to the increased rupture rate of familial IA.MethodsGeometric and morphological aneurysm characteristics were studied on CT-angiography in a prospectively collected series of patients with familial and sporadic aSAH, admitted between September 2006 and September 2009, and additional patients with familial aSAH retrieved from the prospectively collected database of familial IA patients of our center. Odds ratios (OR) with corresponding 95% confidence intervals (95% CI) were calculated to compare the aneurysm characteristics between patients with familial and sporadic aSAH.ResultsWe studied 67 patients with familial and 184 with sporadic aSAH. OR’s for familial compared with sporadic aSAH were for oval shape 1.16(95%CI:0.65–2.09), oblong shape 0.26(95%CI:0.03–2.13), irregular shape 0.83(95%CI:0.47–1.49), aspect ratio ≥ 1.6 0.94(95%CI:0.54–1.66), contact with the perianeurysmal environment (PAE) 1.15(95%CI:0.56–2.40), deformation by the PAE 1.05(95%CI:0.47–2.35) and for dominance of the posterior communicating artery (PCoA) in case of PCoA aneurysms 1.97(95% CI:0.50–7.83).ConclusionsThe geometric and morphological risk factors for aneurysm rupture do not have a higher prevalence in familial than in sporadic aSAH and thus do not explain the increased risk of IA rupture in patients with familial IA. We recommend further search for other potential risk factors for rupture of familial IA, such as genetic factors.     

Aneurysm Characteristics Associated with the Rupture Risk of Intracranial Aneurysms: A Self-Controlled Study

This study analyzed the rupture risk of intracranial aneurysms (IAs) according to aneurysm characteristics by comparing the differences between two aneurysms in different locations within the same patient. We utilized this self-controlled model to exclude potential interference from all demographic factors to study the risk factors related to IA rupture. A total of 103 patients were diagnosed with IAs between January 2011 and April 2015 and were enrolled in this study. All enrolled patients had two IAs. One IA (the case) was ruptured, and the other (the control) was unruptured. Aneurysm characteristics, including the presence of a daughter sac, the aneurysm neck, the parent artery diameter, the maximum aneurysm height, the maximum aneurysm width, the location, the aspect ratio (AR, maximum perpendicular height/average neck diameter), the size ratio (SR, maximum aneurysm height/average parent diameter) and the width/height ratio (WH ratio, maximum aneurysm width/maximum aneurysm height), were collected and analyzed to evaluate the rupture risks of the two IAs within each patient and to identify the independent risk factors associated with IA rupture. Multivariate, conditional, backward, stepwise logistic regression analysis was performed to identify the independent risk factors associated with IA rupture. The multivariate analysis identified the presence of a daughter sac (odds ratio [OR], 13.80; 95% confidence interval [CI], 1.65–115.87), a maximum aneurysm height ≥7 mm (OR, 4.80; 95% CI, 1.21–18.98), location on the posterior communicating artery (PCOM) or anterior communicating artery (ACOM; OR, 3.09; 95% CI, 1.34–7.11) and SR (OR, 2.13; 95% CI, 1.16–3.91) as factors that were significantly associated with IA rupture. The presence of a daughter sac, the maximum aneurysm height, PCOM or ACOM locations and SR (>1.5±0.7) of unruptured IAs were significantly associated with IA rupture.     

Reconstruction of Saccular and Dissected Intracranial Aneurysms Using Solitaire? AB Stents

Introduction

We aimed to evaluate the feasibility, safety, efficacy, and predictors for outcome of reconstructive treatment with Solitaire™ AB stent(s) based on 54 cases of saccular aneurysms and 14 of acute symptomatic dissecting aneurysms.

Methods

Fifty-eight consecutive patients (M/F = 28/30; median age, 53 years) harbouring 68 aneurysms (ruptured/unruptured = 12/56) underwent treatment with Solitaire™ AB stent(s) implantation between April 2010 and August 2011 in our institution. The data were retrospectively reviewed and analysed.

Results

The technical success rate of Solitaire™ AB stenting was 100%. The rates of the overall and the treatment-related adverse events were 9% (6/68) and 6% (4/68), respectively, and the recurrent rate was 1% (1/68). All of the adverse events (n = 6) occurred in tiny (n = 1, ≤3 mm) or small (n = 5, >3 to ≤10 mm) aneurysms. The majority (75%, 3/4) of thromboembolic events (thrombus, n = 2; infarction, n = 2) occurred in ruptured lesions, and 2 intraprocedural aneurysm ruptures occurred in the course of coiling when the stent(s) was/were applied within 6 months. Subarachnoid haemorrhages (SAH, p<0.05) and immediate occlusion grades (p<0.05) were predictors for overall adverse events by univariate analysis. Compared with the immediate post-treatment angiographic results, the follow-up angiographic imaging (mean, 13 months; range, 6–25 months) revealed that stent(s) implantation enhanced the rate of class I occlusion from 34% (23/68) to 93% (63/68). SAH was the only predictor for unfavourable outcomes (the modified Rankin Scale score [mRS], 2–6) during the mean 19-month (range, 12–27 months) of clinical follow-ups (p<0.05).

Conclusions

Although the complete obliteration of tiny and small aneurysms without complications remains a challenge, stent(s) implantation could lead to further occlusion of incompletely coiled aneurysms. SAH and the occlusion grade were the primary predictors for adverse events. SAH was the only predictor for unfavourable outcomes by univariate analysis.     

Sleepiness,Long Distance Commuting and Night Work as Predictors of Driving Performance

Few studies have examined the effect of working night shift and long distance commuting. We examined the association between several sleep related and demographic variables, commuting distance, night work and use of mobile phones on driving performance. We used a prospective design to recruit participants and conducted a telephone survey (n = 649). The survey collected demographic and journey details, work and sleep history and driving performance concerning the day the participant was recruited. Participants also completed the Karolinska Sleepiness Scale and the Epworth Sleepiness Scale. Night workers reported significantly more sleepiness, shorter sleep duration and commuting longer distances. Seven variables were significant predictors of lane crossing. The strongest predictor was acute sleepiness (OR = 5.25, CI, 1.42–19.49, p<0.01) followed by driving ≥150 kms (OR = 3.61, CI, 1.66–7.81, p<0.001), obtaining less than 10 hours sleep in the previous 48 hours (OR = 2.58, CI, 1.03–6.46, p<0.05), driving after night shift (OR = 2.19, CI, 1.24–3.88, p<0.001), being <43 years old (OR = 1.95, CI, 1.11–3.41, p<0.05) and using mobile phones during the journey (OR = 1.90, CI, 1.10–3.27, p<0.05). Sleep related variables, long-distance commuting and night work have a major impact on lane crossing. Several interventions should be considered to reduce the level of sleepiness in night workers.     

miR-141 and miR-200c as Markers of Overall Survival in Early Stage Non-Small Cell Lung Cancer Adenocarcinoma

Background

Several treatments in non-small cell lung cancer (NSCLC) are histology-dependent, and the need for histology-related markers is increasing. MicroRNAs (miRNAs) are promising molecular markers in multiple cancers and show differences in expression depending on histological subtype. The miRNA family miR-200 has been associated with the regulation of epithelial-mesenchymal (EMT)/mesenchymal-epithelial transition (MET). EMT involves profound phenotypic changes that include the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties that facilitates metastasis. A dual role for the miR-200 family in the prognosis of several tumors has been related to tumor cell origin. However, the prognostic role and function of miR-200 family in early-stage NSCLC adenocarcinoma and squamous cell carcinoma (SCC) have not been well established.

Methods

miRNA expression was determined using TaqMan assays in 155 tumors from resected NSCLC patients. Functional studies were conducted in three NSCLC cell lines: H23, A-549 and HCC-44.

Results

High miR-200c expression was associated with shorter overall survival (OS) in the entire cohort (p = 0.024). High miR-200c (p = 0.0004) and miR-141 (p = 0.009) expression correlated with shorter OS in adenocarcinoma – but not in SCC. In the multivariate analysis, a risk score based on miR-141 and miR-200c expression emerged as an independent prognostic factor for OS in the entire cohort (OR, 2.787; p = 0.033) and in adenocarcinoma patients (OR, 10.649; p = 0.002). Functional analyses showed that miR-200c, was related to mesenchymal-epithelial transition (MET) and affected cell migration and E-cadherin levels, while overexpression of miR-141 reduced KLF6 protein levels and produced an increase of secretion of VEGFA in vitro (H23, p = 0.04; A-549, p = 0.03; HCC-44, p = 0.02) and was associated with higher blood microvessel density in patient tumor samples (p<0.001).

Conclusion

High miR-141 and miR-200c expression are associated with shorter OS in NSCLC patients with adenocarcinoma through MET and angiogenesis.     

Emergent Endovascular vs. Open Surgery Repair for Ruptured Abdominal Aortic Aneurysms: A Meta-Analysis

Objectives

To systematically review studies comparing peri-operative mortality and length of hospital stay in patients with ruptured abdominal aortic aneurysms (rAAAs) who underwent endovascular aneurysm repair (EVAR) to patients who underwent open surgical repair (OSR).

Methods

The Medline, Cochrane, EMBASE, and Google Scholar databases were searched until Apr 30, 2013 using keywords such as abdominal aortic aneurysm, emergent, emergency, rupture, leaking, acute, endovascular, stent, graft, and endoscopic. The primary outcome was peri-operative mortality and the secondary outcome was length of hospital stay.

Results

A total of 18 studies (2 randomized controlled trials, 5 prospective studies, and 11 retrospective studies) with a total of 135,734 rAAA patients were included. rAAA patients who underwent EVAR had significantly lower peri-operative mortality compared to those who underwent OSR (overall OR = 0.62, 95% CI = 0.58 to 0.67, P<0.001). rAAA patients with EVAR also had a significantly shorter mean length of hospital stay compared to those with OSR (difference in mean length of stay ranged from −2.00 to −19.10 days, with the overall estimate being −5.25 days (95% CI = −9.23 to −1.26, P = 0.010). There was no publication bias and sensitivity analysis showed good reliability.

Conclusions

EVAR confers significant benefits in terms of peri-operative mortality and length of hospital stay. There is a need for more randomized controlled trials to compare outcomes of EVAR and OSR for rAAA.     

Non-Enhanced MR Imaging of Cerebral Aneurysms: 7 Tesla versus 1.5 Tesla

Purpose

To prospectively evaluate 7 Tesla time-of-flight (TOF) magnetic resonance angiography (MRA) in comparison to 1.5 Tesla TOF MRA and 7 Tesla non-contrast enhanced magnetization-prepared rapid acquisition gradient-echo (MPRAGE) for delineation of unruptured intracranial aneurysms (UIA).

Material and Methods

Sixteen neurosurgical patients (male n = 5, female n = 11) with single or multiple UIA were enrolled in this trial. All patients were accordingly examined at 7 Tesla and 1.5 Tesla MRI utilizing dedicated head coils. The following sequences were obtained: 7 Tesla TOF MRA, 1.5 Tesla TOF MRA and 7 Tesla non-contrast enhanced MPRAGE. Image analysis was performed by two radiologists with regard to delineation of aneurysm features (dome, neck, parent vessel), presence of artifacts, vessel-tissue-contrast and overall image quality. Interobserver accordance and intermethod comparisons were calculated by kappa coefficient and Lin''s concordance correlation coefficient.

Results

A total of 20 intracranial aneurysms were detected in 16 patients, with two patients showing multiple aneurysms (n = 2, n = 4). Out of 20 intracranial aneurysms, 14 aneurysms were located in the anterior circulation and 6 aneurysms in the posterior circulation. 7 Tesla MPRAGE imaging was superior over 1.5 and 7 Tesla TOF MRA in the assessment of all considered aneurysm and image quality features (e.g. image quality: mean MPRAGE7T: 5.0; mean TOF7T: 4.3; mean TOF1.5T: 4.3). Ratings for 7 Tesla TOF MRA were equal or higher over 1.5 Tesla TOF MRA for all assessed features except for artifact delineation (mean TOF7T: 4.3; mean TOF1.5T 4.4). Interobserver accordance was good to excellent for most ratings.

Conclusion

7 Tesla MPRAGE imaging demonstrated its superiority in the detection and assessment of UIA as well as overall imaging features, offering excellent interobserver accordance and highest scores for all ratings. Hence, it may bear the potential to serve as a high-quality diagnostic tool for pretherapeutic assessment and follow-up of untreated UIA.     

Angiotensin-Induced Abdominal Aortic Aneurysms in Hypercholesterolemic Mice: Role of Serum Cholesterol and Temporal Effects of Exposure

Objective

Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E^−/− mice.

Approach

A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.

Results

The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (−0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86).

Conclusions

These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.     

Diagnostic and Prognostic Impact of Circulating YKL-40, IL-6, and CA 19.9 in Patients with Pancreatic Cancer

Purpose

We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival.

Patients and Methods

In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (n = 448) and Germany (n = 111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay.

Results

Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: OR = 2.28, 95% CI 1.97 to 2.68, p<0.0001, AUC = 0.94; YKL-40: OR = 4.50, 3.99 to 5.08, p<0.0001, AUC = 0.87; IL-6: OR = 3.68, 3.08 to 4.44, p<0.0001, AUC = 0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HR = 2.51, 1.22–5.15, p = 0.013; IL-6: HR = 2.03, 1.11 to 3.70, p = 0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HR = 1.30, 1.03 to 1.64, p = 0.029; IL-6: HR = 1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HR = 1.54, 1.06 to 2.24, p = 0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months).

Conclusions

Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.     

Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression and Survival in Operable Squamous-Cell Laryngeal Cancer

Introduction

Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin-like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression.

Patients and Methods

We identified all patients with localized TNM stage I–III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS).

Results

Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p<0.0001), subglottic/transglottic localization (HR = 1.756, p = 0.0438) and IGF1R-alpha protein overexpression (HR = 1.475, p = 0.0504).

Conclusion

IGF1R-alpha protein overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of the IGF1R-alpha prognostic utility is warranted.     

3D Contrast Enhancement-MR Angiography for Imaging of Unruptured Cerebral Aneurysms: A Hospital-Based Prevalence Study

Background and Purpose

Contrast enhanced MRA (CE-MRA) can help to overcome the limitations of other techniques to clearly display the details of cerebral aneurysms at 1.5-T MR system. We investigated the prevalence of unruptured cerebral aneurysms (UCAs) using three dimensional (3D) CE-MRA in a tertiary comprehensive hospital in China.

Materials and Methods

The cases were prospectively recorded at our hospital between February 2009 and October 2010. 3D CE-MRA, interpreted by 2 observers blinded to the participants’ information, was used to identify the location and size of UCAs and to estimate the overall, age-specific, and sex-specific prevalence.

Results

Of the 3993 patients (men: women = 2159∶1834), 408 UCAs were found in 350 patients (men: women = 151∶199). The prevalence was 8.8% overall (95% CI, 8.0–10.0%), with 7.0% for men (CI, 6.0–8.0%) and 10.9% for women (CI, 9.0–12.0%). The overall prevalence of UCAs was higher in women than in men (P<0.001) and increased with age both in men and women. Prevalence peaked at age group 75–80 years. Forty-two patients (11.7%) had multiple aneurysms, including 10 (2.9%) male patients and 32 (9.1%) female patients. The most common site of aneurysm was the carotid siphon, and most lesions (71.3%) had a maximum diameter of 3−5 mm.

Conclusion

This hospital-based prevalence study suggested a high prevalence (8.8%) of UCAs and most lesions (71.3%) had a maximum diameter of 3–5 mm observed by 3D CE-MRA. Because the rupture of small cerebral aneurysms was not uncommon, an appropriate follow-up care strategy must be formulated.     

Herpes Virus Infection Is Associated with Vascular Remodeling and Pulmonary Hypertension in Idiopathic Pulmonary Fibrosis

Background

Pulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed.

Methods

Lung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice.

Results

A higher frequency of virus positive cases was found in IPF patients than in controls (p = 0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p = 0.01), poorer performance in the six minute walking test (6MWT; p = 0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p = 0.02). Increased arterial thickening, particularly of the intimal layer (p = 0.002 and p = 0.004) and higher TGF-β expression (p = 0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p = 0.03), poorer performance in the 6MWT (p = 0.008) and PGD (p = 0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients.

Conclusion

Herpesviral infections may contribute to the development of PH in IPF patients.     

Group B Streptococcal Infection of the Choriodecidua Induces Dysfunction of the Cytokeratin Network in Amniotic Epithelium: A Pathway to Membrane Weakening

Early events leading to intrauterine infection remain poorly defined, but may hold the key to preventing preterm delivery. To determine molecular pathways within fetal membranes (chorioamnion) associated with early choriodecidual infection that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of a Group B Streptococcus (GBS) choriodecidual infection on chorioamnion in a nonhuman primate model. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118–125 days gestation (term = 172 days) received choriodecidual inoculation of either GBS (n = 5) or saline (n = 5). Cesarean section was performed in the first week after GBS or saline inoculation. RNA extracted from chorioamnion (inoculation site) was profiled by microarray. Single gene, Gene Set, and Ingenuity Pathway Analysis results were validated using qRT-PCR (chorioamnion), Luminex (amniotic fluid, AF), immunohistochemistry, and transmission electron microscopy (TEM). Despite uterine quiescence in most cases, significant elevations of AF cytokines (TNF-α, IL-8, IL-1β, IL-6) were detected in GBS versus controls (p<0.05). Choriodecidual infection resolved by the time of cesarean section in 3 of 5 cases and GBS was undetectable by culture and PCR in the AF. A total of 331 genes were differentially expressed (>2-fold change, p<0.05). Remarkably, GBS exposure was associated with significantly downregulated expression of multiple cytokeratin (CK) and other cytoskeletal genes critical for maintenance of tissue tensile strength. Immunofluorescence revealed highly significant changes in the CK network within amniocytes with dense CK aggregates and retraction from the cell periphery (all p = 0.006). In human pregnancies affected by PPROM, there was further evidence of CK network retraction with significantly shorter amniocyte foot processes (p = 0.002). These results suggest early choriodecidual infection results in decreased cellular membrane integrity and tensile strength via dysfunction of CK networks. Downregulation of CK expression and perturbations in the amniotic epithelial cell intermediate filament network occur after GBS choriodecidual infection, which may contribute to PPROM.