Unexpected Severe Cerebral Edema after Cranioplasty : Case Report and Literature Review

This report details a case of unexpected, severe post-operative cerebral edema following cranioplasty. We discuss the possible pathological mechanisms of this complication. A 50-year-old female was admitted to our department with sudden onset of stuporous consciousness. A brain computed tomography (CT) revealed a subarachnoid hemorrhage with intracranial hemorrhage and subdural hematoma. Emergency decompressive craniectomy and aneurysmal neck clipping were performed. Following recovery, the decision was made to proceed with an autologous cranioplasty. The cranioplasty procedure was free of complications. An epidural drain was placed and connected to a suction system during skin closure to avoid epidural blood accumulation. However, following the procedure, the patient had a seizure in the recovery room. An emergency brain CT scan revealed widespread cerebral edema, and the catheter drain was clamped. The increased intracranial pressure and cerebral edema were controlled with osmotic diuretics, corticosteroids, and antiepileptic drugs. The edema slowly subsided, but new low-density areas were noted in the brain on follow-up CT 1 week later. We speculated that placing the epidural drain on active suction may have caused an acute decrease in intracranial pressure and subsequent rapid expansion of the brain, which impaired autoregulation and led to reperfusion injury.     

Clinical Utility of an Automated Pupillometer in Patients with Acute Brain Lesion

ObjectiveThe purpose of this study was to evaluate the clinical utility and validity of using a pupillometer to assess patients with acute brain lesions.MethodsPupillary examinations using an automated pupillometer (NeurOptics®NPi™-100 Pupillometer) were performed every 4 hours and were simultaneously assessed using the Glasgow Coma Scale (GCS) and for intracranial pressure (ICP), from admission to discharge or expire in neuro-intensive care unit (NICU). Manual pupillary examinations were also recorded for comparison. By comparing these data, we evaluated the validity of using automated pupillometers to predict clinical outcomes.ResultsThe mean values of the Neurologic Pupillary index (NPi) were different in the groups examined manually. The GCS correlated well with NPi values, especially in severe brain injury patients (GCS below 9). However, the NPi values were weakly correlated with intracranial pressure (ICP) when the ICP was lower than 30 cm H₂O. The NPi value was not affected by age or intensity of illumination. In patients with a "poor" prognosis who had a Glasgow Outcome Scale (GOS) of 1 or 2, the mean initial NPi score was 0.88±1.68, whereas the value was 3.89±0.97 in patients with a "favorable" prognosis who had a GOS greater than 2 (p<0.001). For predicting clinical outcomes, the initial NPi value of 3.4 had the highest sensitivity and specificity.ConclusionAn automated pupillometer can serve as a simple and useful tool for the accurate measurement of pupillary reactivity in patients with acute brain lesions.     

Comparative Cost Analysis for Surgical and Endovascular Treatment of Unruptured Intracranial Aneurysms in South Korea

Objective

A cost comparison of the surgical clipping and endovascular coiling of unruptured intracranial aneurysms (UIAs), and the identification of the principal cost determinants of these treatments.

Methods

This study conducted a retrospective review of data from a series of patients who underwent surgical clipping or endovascular coiling of UIAs between January 2011 and May 2014. The medical records, radiological data, and hospital cost data were all examined.

Results

When comparing the total hospital costs for surgical clipping of a single UIA (n=188) and endovascular coiling of a single UIA (n=188), surgical treatment [mean±standard deviation (SD) : ₩8,280,000±1,490,000] resulted in significantly lower total hospital costs than endovascular treatment (mean±SD : ₩11,700,000±3,050,000, p<0.001). In a multi regression analysis, the factors significantly associated with the total hospital costs for endovascular treatment were the aneurysm diameter (p<0.001) and patient age (p=0.014). For the endovascular group, a Pearson correlation analysis revealed a strong positive correlation (r=0.77) between the aneurysm diameter and the total hospital costs, while a simple linear regression provided the equation, y (₩)=6,658,630+855,250x (mm), where y represents the total hospital costs and x is the aneurysm diameter.

Conclusion

In South Korea, the total hospital costs for the surgical clipping of UIAs were found to be lower than those for endovascular coiling when the surgical results were favorable without significant complications. Plus, a strong positive correlation was noted between an increase in the aneurysm diameter and a dramatic increase in the costs of endovascular coiling.     

Brain Activation Evoked by Sensory Stimulation in Patients with Spinal Cord Injury : Functional Magnetic Resonance Imaging Correlations with Clinical Features

Objective

The purpose of this study is to determine whether the changes of contralateral sensorimotor cortical activation on functional magnetic resonance imaging (fMRI) can predict the neurological outcome among spinal cord injury (SCI) patients when the great toes are stimulated without notice.

Methods

This study enrolled a total of 49 patients with SCI and investigated each patient''s preoperative fMRI, postoperative fMRI, American Spinal Injury Association (ASIA) score, and neuropathic pain occurrence. Patients were classified into 3 groups according to the change of blood oxygenation level dependent (BOLD) response on perioperative fMRI during proprioceptive stimulation with repetitive passive toe movements : 1) patients with a response of contralateral sensorimotor cortical activation in fMRI were categorized; 2) patients with a response in other regions; and 3) patients with no response. Correlation between the result of fMRI and each parameter was analyzed.

Results

In fMRI data, ASIA score was likely to show greater improvement in patients in group A compared to those belonging to group B or C (p<0.001). No statistical significance was observed between the result of fMRI and neuropathic pain (p=0.709). However, increase in neuropathic pain in response to the signal change of the ipsilateral frontal lobe on fMRI was statistically significant (p=0.030).

Conclusion

When there was change of BOLD response at the contralateral sensorimotor cortex on perioperative fMRI after surgery, relief of neurological symptoms was highly likely for traumatic SCI patients. In addition, development of neuropathic pain was likely to occur when there was change of BOLD response at ipsilateral frontal lobe.     

Association of Carotid Intraplaque Hemorrhage and Territorial Acute Infarction in Patients with Acute Neurological Symptoms Using Carotid Magnetization-Prepared Rapid Acquisition with Gradient-Echo

Objective

The purpose of our study was to assess prevalence of carotid intraplaque hemorrhage (IPH) and associations between territorial acute infarction and IPH on magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) in patients with acute neurologic symptoms.

Methods

83 patients with suspected acute neurologic symptoms were evaluated with both brain diffusion weighted imaging (DWI) and carotid MPRAGE sequences. Carotid plaque with high signal intensity on MPRAGE of >200% that of adjacent muscle was categorized as IPH. We analyzed the prevalence of IPH and its correlation with territorial acute infarction.

Results

Of 166 arteries, 39 had a carotid artery plaque. Of these arteries, 26 had carotid artery stenosis less than 50%. In all carotid arteries, MR-depicted IPH was found in 7.2% (12/166). High-signal intensity on DWI was found in 17.5% (29/166). Combined lesion with ipsilateral high-signal intensity on DWI and IPH on carotid MPRAGE sequence was found in 6 lesions (6/166, 3.6%). Of patients with carotid artery plaque, MR-predicted IPH was found in 30.8% (12/39) and match lesions with high-signal intensity on DWI and MPRAGE was found in 15.4% (6/39). MR-predicted IPH was significantly higher prevalence in high-grade stenosis group (p=0.010). Relative risk between carotid MPRAGE-positive signal and ipsilateral high-signal intensity on DWI in arteries with carotid artery plaques was 6.8 (p=0.010).

Conclusion

Carotid MPRAGE-positive signal in patients was associated with an increased risk of territorial acute infarction as detected objectively by brain DWI. The relative risk of stroke was increased in high-grade stenosis categories.     

Hepatic radiofrequency ablation: in vivo and ex vivo comparisons of 15-gauge (G) and 17-G internally cooled electrodes

Objective:

To compare the performance of the 15-G internally cooled electrode with that of the conventional 17-G internally cooled electrode.

Methods:

A total of 40 (20 for each electrode) and 20 ablation zones (10 for each electrode) were made in extracted bovine livers and in in vivo porcine livers, respectively. Technical parameters, three dimensions [long-axis diameter (Dl), vertical-axis diameter (Dv) and short-axis diameter (Ds)], volume and the circularity (Ds/Dl) of the ablation zone were compared.

Results:

The total delivered energy was higher in the 15-G group than in the 17-G group in both ex vivo and in vivo studies (8.78 ± 1.06 vs 7.70 ± 0.98 kcal, p = 0.033; 11.20 ± 1.13 vs 8.49 ± 0.35 kcal, p = 0.001, respectively). The three dimensions of the ablation zone had a tendency to be larger in the 15-G group than in the 17-G group in both studies. The ablation volume was larger in the 15-G group than in the 17-G group in both ex vivo and in vivo studies (29.61 ± 7.10 vs 23.86 ± 3.82 cm³, p = 0.015; 10.26 ± 2.28 vs 7.79 ± 1.68 cm³, p = 0.028, respectively). The circularity of ablation zone was not significantly different in both the studies.

Conclusion:

The size of ablation zone was larger in the 15-G internally cooled electrode than in the 17-G electrode in both ex vivo and in vivo studies.

Advances in knowledge:

Radiofrequency ablation of hepatic tumours using 15-G electrode is useful to create larger ablation zones.Radiofrequency ablation (RFA) is the most widely used local ablation technique for the management of primary and metastatic liver tumours. However, previous studies have reported that RFA showed a relatively higher local tumour progression rate than did hepatic resection.^1,2 One of the most important factors affecting local tumour progression was insufficient tumour-free ablation margin of hepatic parenchyma around the tumour margin.^3–6Several strategies have been developed to obtain sufficient ablation margin. In the aspect of RFA techniques, overlapping technique and combined treatment with transcatheter arterial chemoembolization can be used.^7–9 Another strategy is to use switching monopolar, bipolar or multipolar modes to deliver radiofrequency (RF) energy more efficiently.^10,11 Sufficient ablation margin can also be achieved by more efficient electrodes: internally cooled electrode increases the size of ablation zone by preventing charring around the electrode tip.^12,13 Perfusion electrodes can also enlarge the ablation zone by increasing electrical conductance and thermal conductivity.^14–16The diameter of an electrode is also known to be associated with the size of the ablation zone. Theoretically, as the diameter of an electrode becomes larger, the contact surface of the electrode with the surrounding tissue becomes bigger, thereby increasing the active electric field.^17,18 As a result, an electrode with a larger diameter is likely to create a larger ablation zone. In a previous study, Goldberg et al¹⁷ reported that the extent of coagulation necrosis by RFA increases as the diameter of an electrode increases through an in vivo experimental study. However, this study was performed with an electrode without an internal cooling system. Recently, a clinical study comparing therapeutic efficacy and safety between 15-G and 17-G internally cooled electrodes of RFA for hepatocellular carcinoma was published.¹⁹ According to that study, the 15-G internally cooled electrode created a larger ablation volume than did the 17-G electrode. However, the study was limited by selection bias owing to the retrospective study design. In addition, the ablation protocol was not exactly the same between the two groups. Therefore, the issue whether an internally cooled electrode with a larger diameter creates a larger ablation volume should be verified with ex vivo and in vivo experimental studies.The purpose of this experimental study was to compare the performance of the 15-G internally cooled RF electrode with that of the conventional 17-G electrode in both ex vivo and in vivo studies.     

门静脉高压巨脾大部切除后残脾神经分布与定量研究

目的：观察门静脉高压巨脾大部切除后残脾神经纤维分布与密度变化,评估残脾保留的价值。 方法：选取门静脉高压脾肿大行脾大部切除并残脾腹后固定术患者13例,收集患者术后切取的巨脾组织,以及术后8年穿刺获取的残脾组织,另取外伤性脾组织13例为正常对照。采用免疫组化法检测脾神经肽Y（NPY）和神经丝蛋白200（NF 200）阳性神经纤维分布及密度。 结果：3组脾组织NPY和NF200阳性神经纤维的分布部位大致相同,但两者在巨脾组织中的密度明显较高。红髓部分的定量分析显示,巨脾组织NPY与NF200阳性神经纤维密度均明显高于残脾组织和正常脾组织（均P<0.05）,而两种阳性神经纤维密度在残脾组织与正常脾组织间差异无统计学意义（均P>0.05）。 结论：巨脾大部切除术后残脾神经纤维分布及含量与正常脾大致相同,提示解除高压环境后,残脾神经功能能逐渐恢复正常。     

Adrenal cortical carcinoma initially presented with overwhelming disseminated intravascular coagulation

We report a 54-year-old man who had adrenal cortical carcinoma initially manifested as features of overwhelming disseminated intravascular coagulation (DIC). In the initial diagnostic work-up, an adrenal mass was detected with venous thrombi in the abdominal imaging study, but the radiologic diagnosis was a hematoma arising from the adrenal gland and a biopsy was not possible due to a bleeding tendency. A lot of platelets and plasma products were transfused, but the bleeding tendency and other DIC features persisted. Finally, he expired because of newly developed massive pulmonary thromboembolism. To our knowledge, this is the first reported case of adrenal cortical carcinoma complicated with bleeding tendency caused by DIC as an initial manifestation. This suggests that adrenal cortical carcinoma should be considered in a patient with an adrenal mass and DIC features.     

Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.     

Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4B^G12D), and nontransforming cytosolic double mutant (BirA-KRAS4B^G12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRAS^G12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

A total of 60,430 new cases of pancreatic cancer were estimated for 2021, and the 5-y relative survival rate has consistently remained below 11% (1). About 85% of these pancreatic cancer tumors are pancreatic ductal adenocarcinoma (PDAC) (2). Poor outcomes of PDAC cases result from late diagnoses leading to unresectable and heterogeneous tumors as well as ineffective therapies, which only prolong survival on the order of months (3–5). Mutations in the KRAS proto-oncogene are present in over 90% of PDAC cases and are associated with a poor prognosis (6). Furthermore, mice expressing mutant KRAS in the pancreas develop precursor lesions, which sporadically progress into frank PDAC. This progression is accelerated when combined with other mutations or deletion of tumor suppressor genes (7–11). Additionally, independent studies have shown that the maintenance of murine PDAC cells require KRAS (12–14).As a RAS GTPase, KRAS acts as a molecular switch at the plasma membrane that relays growth factor signaling from receptor tyrosine kinases to downstream pathways such as RAF/MEK and PI3K/AKT (15). GTP binding alters the conformation of the KRAS G domain, thereby creating binding sites for downstream effectors to trigger enzymatic cascades that promote cell transformation (16–19). Intrinsically, KRAS slowly hydrolyzes GTP into GDP to halt signaling; however, GTPase activating proteins (GAPs) such as neurofibromin 1(NF1) catalyze this process (20). In contrast, guanine nucleotide exchange factors, such as son of sevenless homolog 1 (SOS1), catalyze the exchange of GTP for bound GDP. In most PDAC cases, KRAS is mutated at the 12th residue located in the G domain from glycine to either a valine (G12V), or more commonly, aspartate (G12D). These mutations sterically prevent the “arginine finger domain” of GAPs from entering the GTPase site, thereby blocking extrinsic allosteric GTPase activation and stabilizing RAS-GTP (21, 22). Activating mutations in KRAS constitutively trigger RAF/MEK and PI3K/AKT pathways leading to increased cell proliferation as well as other prooncogenic behaviors (15). KRAS signaling not only relies on the G domain but also the C-terminal hypervariable domain (HVR), which is required to stabilize KRAS on membranes where signaling is most efficient (23–26). Independent studies suggest that specific biochemical and cellular consequences of KRAS activation are attributed to the unique properties of the HVR of the predominant splice form KRAS4B, namely the polybasic domain and the lipid anchor (27–30). Localization of RAS proteins to the plasma membrane requires the prenylation of the CAAX motif (23). Additionally, for KRAS4B, the hypervariable region contains a highly polybasic domain consisting of several consecutive lysines, which can interact with the negative charges on the polar heads of phospholipids and stabilize protein interactions (31). Structural and biochemical characterization of the HVR and G domain has contributed to a better understanding of the signaling outputs of KRAS and led to KRAS-targeting strategies.Various approaches to inhibit KRAS include direct inhibition, expression interference, mislocalization, and targeting of downstream effectors (32). Thus far, direct inhibitors against KRAS have only successfully targeted the G12C mutant, which comprises 2.9% of KRAS mutant PDAC (21, 33). For other KRAS mutants, targeting downstream effectors of KRAS in pancreatic cancer remains an alternative approach. Unfortunately, dual inhibition of MEK and AKT pathways was ineffective in PDAC patients (34). Difficulty in targeting KRAS due to adaptive resistance and feedback regulation motivates a better understanding of KRAS biology (35). For example, although PDAC typically features a mutant KRAS, there may be a role for its wild-type (WT) counterpart as well as WT RAS paralogs (HRAS and NRAS), which are GAP sensitive and subject to signaling feedback. While oncogenic KRAS has been shown to activate WT HRAS and NRAS via allosteric stimulation of SOS1 (36), WT KRAS has been proposed to be a tumor suppressor in some KRAS mutant cancers based on the commonly observed mutant-specific allele imbalance that occurs throughout tumor progression (37). Additionally, the reintroduction of WT KRAS abolished tumor T cell acute lymphoblastic leukemia development and impaired tumor growth in KRAS mutant lung cancer cells in vivo (37–39). The discovery of novel KRAS protein interactors involved in downstream signaling or feedback and compensatory pathways may elucidate why inhibition of downstream pathways have had limited clinical impact in PDAC. Here, we perform proximity labeling experiments by expressing a fusion of BirA^R118G biotin ligase and KRAS in PDAC cells, which, in the presence of high concentrations of biotin, generates reactive biotinoyl-AMP that labels lysines of nearby proteins, such as interactors of its fusion partner KRAS (40–42). The biotinylated interactor proteins can be isolated by streptavidin pulldown and analyzed by proteomics to identify novel protein interactors (43–45). Because covalent labeling occurs in living cells, enzymatic labeling may potentially identify transient interactors and protein complexes.Two recent studies used proximity-dependent biotin identification (BioID) labeling methods to identify KRAS interactors in 293T and colon cancer cells (46, 47). These studies uncovered and validated the functional relevance of PIP5KA1 and mTORC2 in PDAC cells. However, BirA-KRAS screens in PDAC models have not yet been performed. Since the tumor context may determine protein expression and relevant interactions, we sought to perform a BirA-KRAS screen in PDAC cells. We hypothesize that proximity labeling with BioID presents a means for identifying new mutant KRAS-specific interactions in PDAC, which may unveil new insights into therapeutic design for this malignancy.