Early ischemic recurrence in acute spontaneous cervical artery dissection.

BACKGROUND AND PURPOSE: Early ischemic recurrence (EIR) following the diagnosis of acute spontaneous cervical artery dissection (CeAD) has been little investigated. We aimed to determine the prevalence and determinants on admission of EIR in a large single-center retrospective cohort study of patients with CeAD. METHODS: EIR was defined as any ipsilateral clinical or radiological cerebral ischemia or intracranial artery occlusion, not present on admission and occurring within 2 weeks. CeAD location, degree of stenosis, circle of Willis support, presence of intraluminal thrombus, intracranial extension, and intracranial embolism were analyzed on initial imaging by 2 independent observers. Uni- and multivariate logistic regression was used to determine their association with EIR. RESULTS: Two hundred thirty-three consecutive patients with 286 CeAD were included. EIR was observed in 21 patients (9%,95%CI=5-13%) with a median time from diagnosis of 1.5 days (range:0.1-14.0 days). No EIR was observed in CeAD without ischemic presentation or with less than 70% stenosis. In the remaining cases, poor circle of Willis (OR=8.5, CI95%=2.0-35.4, p = 0.003), CeAD extending to other intracranial arteries than just V4 (OR=6.8, CI95%=1.4-32.6, p = 0.017), cervical artery occlusion (OR=9.5, CI95%=1.2- 39.0, p = 0.031), and cervical intraluminal thrombus (OR=17.5, CI95%=3.0-101.7, p = 0.001) were independently associated with EIR. CONCLUSIONS: Our results suggests that EIR is more frequent than previously reported, and that its risk might be stratified on admission with a standard workup. In particular, the presence of a poor circle of Willis, intracranial extension (other than just V4), cervical occlusion, or cervical intraluminal thrombus are associated with high risk of EIR, for which specific management should be further evaluated.

Mechanical thrombectomy in a pediatric patient with sedation aided by contralateral intra-arterial propofol injection: feasibility in an extreme condition.

Pediatric patients undergoing mechanical thrombectomy may be challenging for the anesthesiologists as regards the best anesthetic choice, especially if concomitant to severe comorbidities such as heart failure. A 16-year-old patient affected by arrhythmogenic right ventricle dysplasia/cardiomyopathy underwent mechanical thrombectomy. He was not eligible for deep sedation or general anesthesia since he has been suffering from severe heart failure. The patient stillness was obtained by intra-arterial injection of propofol from the contralateral internal carotid artery. The procedure has been well tolerated, without cardiorespiratory impairment. The case stresses the growing importance to tailor a proper anesthesiologic plan during mechanical thrombectomy, especially in extreme conditions.

Intensive therapies of delayed cerebral ischemia after subarachnoid hemorrhage: a propensity-matched comparison of different center-driven strategies.

BACKGROUND: Intensive therapies of delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) have still controversial and unproven benefit. We aimed to compare the overall efficacy of two different center-driven strategies for the treatment of DCI respectively with and without vasospasm angioplasty. METHODS: Two hundred consecutive patients with aSAH were enrolled in each of two northern European centers. In an interventional center, vasospasm angioplasty was indicated as first line rather than rescue treatment of DCI using distal percutaneous balloon angioplasty technique combined with intravenous milrinone. In non-interventional center, induced hypertension was the only intensive therapy of DCI. Radiological DCI (new cerebral infarcts not visible on immediate post-treatment imaging), death at 1 month, and favorable outcome at 6 months (modified Rankin scale score ≤ 2) were retrospectively analyzed by independent observers and compared between two centers before and after propensity score (PS) matching for baseline characteristics. RESULTS: Baseline characteristics only differed between centers for age and rate of smokers and patients with chronic high blood pressure. In the interventional center, vasospasm angioplasty was performed in 38% of patients with median time from bleeding of 8 days (Q1 = 6.5;Q3 = 10). There was no significant difference of incidence of radiological DCI (9% vs.14%, P = 0.11), death (8% vs. 9%, P = 0.4), and favorable outcome 74% vs. 72% (P = 0.4) between interventional and non-interventional centers before and after PS matching. CONCLUSIONS: Our results suggest either that there is no benefit, or might be minimal, of one between two different center-driven strategies for intensive treatment of DCI. Despite potential lack of power or unknown confounders in our study, these results question the use of such intensive therapies in daily practice without further optimization and validation.

Continuous stellate ganglion block in delayed cerebral ischemia: A possible supplementary approach to traditional therapy?

Delayed Cerebral Ischemia (DCI) is a major contributor to morbidity and mortality after SAH. Currently the prevention of vasospasm and DCI relies on nimodipine administration and on maintaining an adequate cerebral perfusion pressure. We report a patient with initial DCI after SAH in which stellate ganglion block (SGB) was performed after nimodipine administration. Firstly the procedure was characterized by a iv and intra-arterial nimodipine administration which did not result into a normal perfusion pattern. Therefore a single-shot stellate ganglion block was performed, as suggested in literature. Because of the not sufficient but promising perfusion improvement, we decided to deliver a continuous ganglion block (cSGB) for 5 days. Consequently a further improvement of the cerebral perfusion on CTPerfusion and Real Time Angiographic Perfusion Assessment was registered. In order to treat cerebral vasospasm, SGB is known to be a further valuable treatment, despite its temporary effect. However the continuous use of SGB during initial DCI has never been described before.

Intracranial stenting after tumor exeresis complicated by delayed kinking of the middle cerebral artery.

During intracranial tumor resection, the delayed kinking of a major encased vessel has never been described in literature. We present a case which required urgent endovascular treatment performed through a stent positioning. A patient was hospitalized with symptomatic sphenoid meningioma in the left middle cranial fossa. Twelve days after surgery, right-sided hemiplegia and aphasia occurred. Digital subtraction arteriography revealed a kinking of the M1 segment of the left middle cerebral artery and diffuse vasospasm. At first, intra-arterial nimodipine has been administered, obtaining the remission of the vasospasm. Secondly, a stent was positioned to treat the kinking, achieving a complete flow restoration.

Remote Training of Neurointerventions by Audiovisual Streaming : Experiences from the European ESMINT-EYMINT E-Fellowship Program.

BACKGROUND: Remote access of trainees to training centers via video streaming (tele-observership, e­fellowship) emerges as an alternative to acquire knowledge in endovascular interventions. Situational awareness is a summary term that is also used in surgical procedures for perceiving and understanding the situation and projecting what will happen next. A high situational awareness would serve as prerequisite for meaningful learning success during tele-observerships. We hypothesized that live perception of the angiographical procedures using streaming technology is feasible and sufficient to gain useful situational awareness of the procedure. METHODS: During a European tele-observership organized by the European Society of Minimally Invasive Neurological Therapy (ESMINT) and its trainee association (EYMINT), a total of six neurointerventional fellows in five countries observed live cases performed by experienced neurointerventionalists (mentors) in six different high-volume neurovascular centers across Europe equipped with live-streaming technology (Tegus Medical, Hamburg, Germany). Cases were prospectively evaluated during a 12-month period, followed by a final questionnaire after completion of the course. RESULTS: A total of 102/161 (63%) cases with a 1:1 allocation of fellow and mentor were evaluated during a 12-month period. Most frequent conditions were ischemic stroke (27.5%), followed by embolization of unruptured aneurysms (25.5%) and arteriovenous malformations (AVMs) (15.7%). A high level of situational awareness was reported by fellows in 75.5% of all cases. After finishing the program, the general improvement of neurointerventional knowledge was evaluated to be extensive (1/6 fellows), substantial (3/6), and moderate (2/6). The specific fields of improvement were procedural knowledge (6/6 fellows), technical knowledge (3/6) and complication management (2/6). CONCLUSION: Online streaming technology facilitates location-independent training of complex neurointerventional procedures through high levels of situational awareness and can therefore supplement live hands-on-training. In addition, it leads to a training effect for fellows with a perceived improvement of their neurointerventional knowledge.

Impact of atrial fibrillation on the treatment effect of bridging thrombolysis in ischemic stroke patients undergoing endovascular thrombectomy: a multicenter international cohort study.

BACKGROUND: The role of bridging intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) in the treatment of acute ischemic stroke (AIS) remains debatable. Atrial fibrillation (AF) associated strokes may be associated with reduced treatment effect from IVT. This study compares the effect of bridging IVT in AF and non-AF patients. METHODS: This retrospective cohort study comprised anterior circulation large vessel occlusion (LVO) AIS patients receiving EVT alone or bridging IVT plus EVT within 6 hours of symptom onset. Primary outcome was good functional outcome defined as modified Rankin Scale (mRS) 0-2 at 90 days. Secondary outcomes were successful reperfusion defined as expanded Thrombolysis In Cerebral Infarction (eTICI) grading ≥2b flow, symptomatic intracerebral hemorrhage (sICH), and in-hospital mortality. RESULTS: We included 705 patients (314 AF and 391 non-AF patients). The mean age was 68.6 years and 53.9% were male. The odds of good functional outcomes with bridging IVT was higher in the non-AF (adjusted odds ratio (aOR) 2.28, 95% CI 1.06 to 4.91, P=0.035) compared with the AF subgroups (aOR 1.89, 95% CI 0.89 to 4.01, P=0.097). However, this did not constitute a significant effect modification by the presence of AF on bridging IVT (interaction aOR 0.12, 95% CI -1.94 to 2.18, P=0.455). The rate of successful reperfusion, sICH, and mortality were similar between bridging IVT and EVT for both AF and non-AF patients. CONCLUSION: The presence of AF did not modify the treatment effect of bridging IVT. Further individual patient data meta-analysis of randomized trials may shed light on the comparative efficacy of bridging IVT in AF versus non-AF LVO strokes.

SOFIA Nonwire Advancement techniKE 35 Technique: A Minimalist Approach to Stroke Thrombectomy.

BACKGROUND: The Soft Torqueable Catheter Optimized for Intracranial Access (SOFIA) is a catheter designed to enable intracranial access, allowing for advancement, at least partially, without a microcatheter by a technique called SOFIA Nonwire Advancement techniKE (SNAKE). We propose a variation of this technique, called SOFIA Nonwire Advancement techniKE 35 (SNAKE35), in which the catheter is navigated by the intracatheter support of a 0.035-inch guidewire, allowing for rapid, distal intracranial access through a biaxial technique. OBJECTIVE: To assess the performance of a modified navigation technique in the setting of acute stroke thrombectomy. METHODS: Consecutive patients who underwent a thrombectomy procedure between January 2017 and February 2019 were retrospectively identified at our institution. The primary end point was defined as successful positioning of the catheter at the proximal end of the occlusion with the sole use of the SNAKE35 technique. Secondary end points were defined as complications, reperfusion times, and thrombolysis in cerebral infarction scores. RESULTS: Among 140 patients, SNAKE35 was attempted in 79 patients (SNAKE35 group), while traditional navigation was used in the remaining 61 patients (conventional group). Of the total 79 cases, SNAKE35 was successful in positioning the catheter at the proximal end of the occlusion in 66 cases (84%). Of these, 54 cases were completed solely with aspiration techniques. Groin puncture to revascularization time averaged 26 minutes in the SNAKE35 group and 37 minutes in the conventional group ( P < .05), despite older age ( P < .001) and increased use of conscious sedation ( P < .001) in the SNAKE35 group. CONCLUSION: SNAKE35 is an effective and safe technique for SOFIA navigation up to the site of intracranial occlusion in the anterior circulation leading to significant decrease of procedural times.

Distribution of symptomatic cerebral vasospasm following subarachnoid hemorrhage assessed using cone-beam CT angiography.

BACKGROUND AND PURPOSE: Cone-beam CT angiography (CB-CTA) provides a three-dimensional spatial resolution which is, so far, unmatched in clinical practice compared with other conventional techniques such as two-dimensional digital subtracted angiography. We aimed to assess the distribution of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) using CB-CTA. METHODS: 30 consecutive patients with aSAH undergoing vasospasm percutaneous balloon angioplasty (PBA) were recruited and underwent CB-CTA in this single-center prospective cohort series. Intracranial arteries were systematically analyzed by two independent observers from the large trunks to the distal cortical branches and perforators using a high-resolution reconstruction protocol. Intermediate and severe cerebral vasospasm was defined as 30-50% and >50% narrowing in the diameter of the vessel, respectively. RESULTS: 35 arterial cervical artery territories were analyzed, of which 80% were associated with clinical or radiological signs of delayed cerebral ischemia. The median spatial resolution was 150 µm (range 100-250 µm). Intermediate or severe vasospasm was observed in the proximal (86%, 95% CI 74% to 97%), middle (89%, 95% CI 78% to 99%), and distal (60%, 95% CI 44% to 76%) segments of the large trunks, as well as the cortical branches (11%, 95% CI 1% to 22%). No vasospasm was observed in basal ganglia or cortical perforators, or in arteries smaller than 900 µm. Vasospasm was more severe in middle or distal segments compared with proximal segments in 43% (95% CI 26% to 59%) of cases. CONCLUSIONS: Our study demonstrated that symptomatic cerebral vasospasm following aSAH did not involve arteries smaller than 900 µm, and frequently predominated in middle or distal segments. These results offer new insights into the potential management options for vasospasm using PBA.

Computed tomography angiography for quantification of cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

PURPOSE: The purpose of this study was to assess the accuracy of computed tomography angiography (CTA) for quantification of cerebral vasospasm following aneurysmal subarachnoid hemorrhage in proximal and middle segments of intracranial arteries. MATERIALS AND METHODS: Twenty consecutive patients (7 men, 13 women; mean age, 47 ± 7 [SD] years; age range: 27-78 years) with aneurysmal subarachnoid hemorrhage who underwent CTA and digital subtracted angiography (DSA) with a 6-hour window at baseline and during vasospasm period were included. Twelve artery segments were analyzed in each patient. Vasospasm was blindly quantified on CTA and digital subtracted angiography (DSA) by two independent readers with discordance > 10% resolved by open data consensus. Inter-reader and inter-test correlations with DSA as reference, and causes of discordant readings were analyzed. The best sensitivity and specificity of CTA for determination of vasospasm ≥ 50% on DSA was determined using receiver operating curve analysis. RESULTS: Two-hundred-and-ten arterial segments were analyzed after exclusion of 30 segments with missing data or metallic artifacts. An inter-reader discordance >10% was observed in 82 segments (82/210; 39% [95% CI: 32-46]). Inter-test discordances >10% were observed respectively in 115 segments (115/210; 55% [95% CI: 49-62]) with the junior reader and in 73 segments (73/210; 35% [95% CI: 29-42]) with the senior reader. They were related to reader error in 55 (55/210; 26% [95% CI: 20-32]) with the junior reader and 13 (13/210; 6% [95% CI: 3-9]) with the senior reader, as well systematic biases in 8 (8/210; 4% [95% CI: 1-6]), and intrinsic limitation in 52 (52/210; 25% [95% CI: 19-31]). Best sensitivity and specificity of CTA were observed for a threshold value of 30% (sensitivity = 88% [95% CI: 78-97%]; specificity = 84% [95% CI: 77-90%]; area under curve = 0.92 [95% CI: 0.86-0.97]). On a patient basis, sensitivity was 100% (specificity = 60% [95% CI: 38-81%]; area under curve = 0.97 [95% CI: 89-100%] for this same threshold. CONCLUSION: Our study shows a moderate accuracy of CTA for the quantification of cerebral vasospasm, mostly related to challenging interpretation and intrinsic limitations. CTA may rule-out angiographic vasospasm ≥ 50% when no segment has vasospasm over than 30%.

Early Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage Is Associated with Prior Global Cerebral Hypoperfusion.

BACKGROUND AND PURPOSE: Early cerebral infarction (ECI) is an independent factor associated with poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). We aimed to test the association between ECI and prior global impairment of cerebral perfusion. METHODS: We performed a retrospective cohort study of consecutive patients admitted for aSAH in 2 centers. ECI was defined as any radiological cerebral infarction identified within 3 days from the onset of bleeding and not related to aneurysm repair. Global impairment of cerebral perfusion was defined as clinical or transcranial Doppler signs of brain hypoperfusion together with circulatory failure or intracranial hypertension in keeping with guidelines. The association between ECI and prior occurrence of global impairment of cerebral perfusion was tested using binary logistic regression adjusted for confounders identified in the univariate analysis. RESULTS: Seven hundred fifty-three patients with aSAH were included. ECI was observed in 40 patients (5.3%; 95% CI = 3.7%-6.9%). Prior global impairment of cerebral perfusion occurred in 90% of them (60% in-hospital) versus in 11% of patients without ECI (P < 0.001). In the multivariate analysis, World Federation of Neurological Surgeons grade (OR = 2.3, 95% CI = 1.5-3.6, P<0.001), global impairment of cerebral perfusion due to circulatory failure (OR = 4.7, 95% CI = 1.8-11, P = 0.001), or intracranial hypertension (OR = 11.1, 95% CI = 3.8-32.3, P<0.001) was an independent risk factor for ECI. CONCLUSIONS: Our study demonstrated that ECI is strongly associated with the prior occurrence of global impairment of cerebral perfusion, independent of World Federation of Neurological Surgeons grade. These patients may benefit from more intensive and systematic prevention of impaired cerebral perfusion, particularly in poor-grade patients.

P2Y12 inhibitors for the neurointerventionalist.

The use of antiplatelets is widespread in clinical practice. However, for neurointerventional procedures, protocols for antiplatelet use are scarce and practice varies between individuals and institutions. This is further complicated by the quantity of antiplatelet agents which differ in route of administration, dosage, onset of action, efficacy and ischemic and hemorrhagic complications. Clarifying the individual characteristics for each antiplatelet agent, and their associated risks, will increasingly become relevant as the practice of mechanical thrombectomy, stenting, coiling and flow diversion procedures grows. The aim of this review is to summarize the existing literature for the use of P2Y12 inhibitors in neurointerventional procedures, examine the quality of the evidence, and highlight areas in need of further research.

Glycoprotein IIb/IIIa inhibitors for the neurointerventionalist.

Antiplatelet therapies are commonly used in neurointerventional procedures. However, specific guidelines for their use in these settings is lacking and it can often be difficult to balance the potential risks and benefits of these medications. Considering the continued growth and adoption of neurointerventional procedures, it is crucial to understand the properties of these agents in order to use them safely. Large-scale clinical trials are still needed to clarify many of these aspects for this emerging field. However, the existing literature already provides insight into which antiplatelet drugs are of benefit to the neurointerventionalist as well as their associated risks of ischemic and hemorrhagic complications. Hence, this review focuses on the applications of GPIIb/IIIA inhibitors to neurointerventional procedures.

Hand-compression pressure cooker: an innovative variation of an existing technique with two example cases.

The pressure cooker technique was originally ideated to obtain wedge-flow conditions during arteriovenous malformation or arteriovenous fistula embolisation. The anti-reflux plug created with coils or glue around the tip of a detachable microcatheter enables a continuous injection with a more in-depth penetration. Here we describe two illustrative cases performed with a variation of the technique that we describe as the hand-compression pressure cooker technique.

Aneurysms of the communicating segment of the internal carotid artery with posterior communicating artery agenesis are associated with perforator infarction after embolization.

BACKGROUND: While anatomic features associated with the risk of posterior communicating artery (PcoA) occlusion after embolization of aneurysms of the PcoA segment of the internal carotid artery (ICA) are well known, the link between perforator origin and perforator infarction has only been reported following neurosurgical clipping. The aim of this study was to determine the origin of anterior thalamic perforators and correlate it with risk of perforator infarction after embolization of PcoA segment aneurysms. METHODS: One-hundred-and-ninety consecutive patients treated for PcoA segment aneurysms between 2017 and 2019 were included. PcoA and anterior thalamic perforator origin anatomy was assessed with computed tomography (CT) angiography, digital subtracted angiography, and high-resolution three-dimensional rotational cone-beam CT angiography (CBCT-A) by two independent interventional neuroradiologists. The presence of perforator infarction after embolization was ascertained from the patient's notes and follow-up imaging. RESULTS: CBCT-A was superior in demonstrating the origin of perforators (P<0.001). The prevalence of perforator origin was estimated at 86% (95% CI 81%-92%) for PcoA, 8% (95% CI 4%-13%) for aneurysm wall, and 5% (95% CI 2%-9%) for ICA. The aneurysm wall origin was exclusively associated with PcoA agenesis, as well as higher risk of perforator infarction after aneurysm coiling compared with other variants (OR=14, 95% CI 2-88, P=0.006). CONCLUSIONS: Our study suggests that anterior thalamic perforators may arise from aneurysm wall when there is no PcoA. Anatomic association between PcoA agenesis and perforator arising from ICA could underlie such findings, and careful consideration is essential before aneurysm repair to anticipate the risk of thalamic infarction in such cases.

Greater Occipital Nerve Block as a Tool to Diagnose Spontaneous Intracranial Hypotension Before Epidural Blood Patch: A Case Report.

Spontaneous intracranial hypotension (SIH) has been increasingly characterized in recent years. A definitive diagnostic algorithm remains controversial because several symptoms are often found to be nonspecific. When neuroimaging fails to identify a cerebrospinal fluid leak and symptoms are atypical, an epidural blood patch (EBP) may be performed but not without risks. Our case shows how greater occipital nerve block (GONB) can expedite SIH diagnosis in a man with atypical presentation by reducing the sensory input from the posterior cranial fossa. The relief provided by GONB allowed to diagnose SIH promptly and the patient underwent a curative EBP.

18F-Fluorodeoxyglucose Positron Emission Tomography-Magnetic Resonance Monitoring of Brain Metabolic Changes in a Case of Arteriovenous Malformation-Related Steal Phenomenon Symptoms.

BACKGROUND: Unruptured brain arteriovenous malformations (AVMs) represent a complex disease in young healthy adults. Most often AVMs are clinically silent but also can display a neurologic syndrome due to hypoperfusion/hypometabolism in perilesional brain tissue called steal phenomenon. CASE DESCRIPTION: A 34-year-old woman was admitted to a secondary neurologic center complaining of a right hemiparesis and secondarily generalized seizures. Computed tomography scan and magnetic resonance imaging of the brain showed a left prerolandic AVM without signs of acute or previous bleedings. Digital subtraction angiography confirmed a left juxta-central AVM, with a diffuse pattern, fed by hypertrophic rolandic branches from the left middle cerebral artery. An 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance imaging scan was performed 3 days after the critical episode. A significant hypometabolism in parenchymal regions ipsilaterally to the AVM was detected. Two embolization sessions were performed by means of N-butyl cyanoacrylate glue. At the end of the second procedure, a decrease of the shunt-flow and AVM size was observed. Six months later, 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance imaging scan showed persistent hypometabolism located in the AVM area, with a significant improvement of the cortical hemispheric hypometabolism. The patient was asymptomatic and was sent to stereotactic radiosurgery to complete the treatment. CONCLUSIONS: In clinical practice, irritative symptoms in patients with unruptured AVMs could lead to erroneous evaluations. In case of fluctuating clinical syndromes, like our case, establishing that symptoms are related to a steal phenomenon is usually difficult.

Serpinb3 is overexpressed in the liver in presence of iron overload.

Iron overload results in cellular toxicity, tissue injury, organ fibrosis and increased risk of neoplastic transformation. SerpinB3 is a serine protease inhibitor overexpressed in the liver in oxidative stress conditions, able to induce fibrosis and increased risk of malignant transformation. Aim of the present study was to assess the effect of iron overload on SerpinB3 expression in the liver using in vivo and in vitro models.The expression of Serpinb3 was assessed in the liver of hemojuvelin knockout mice (Hjv-/-), an established model of hereditary hemochromatosis, and of wild type control mice, following dietary or pharmacological iron manipulation. To assess the direct effect of iron in vitro, cell lines were treated with different concentration of hemin or with an iron chelator.Hepatic Serpinb3 mRNA and protein were highly expressed in Hjv-/- mice, but not in wild type controls fed with a standard diet. Serpinb3 became detectable in wild type mice fed with a high iron diet or injected with iron dextran; these treatments further induced Serpinb3 expression in Hjv-/- mice. Livers expressing Serpinb3 showed a positive staining also for HIF-2α in the same areas. Hemin promoted induction of SerpinB3 mRNA in HeLa and HA22T/VGH cells, but a mild stimulation of SerpinB3 promoter activity in HeLa and Huh7 cells. In conclusion, Serpinb3 is strongly induced by iron in the mouse liver. The molecular link between iron, ROS and SerpinB3 seems to be HIF-2α, which is induced by iron overload and was previously found capable of up-regulating SerpinB3 at the transcriptional level.