Circadian rhythm and aneurysmal subarachnoid hemorrhage: Is there an alarm clock for the rupture timing?

BACKGROUND AND PURPOSE: Data on the temporal distribution of the bleeding time of intracranial aneurysms are limited to a few small studies. With this study, the aim was to analyze time patterns of the occurrence of aneurysmal subarachnoid hemorrhage (SAH), particularly focusing on the impact of patients' socio-demographic and clinical characteristics on the ictus timing. METHODS: The study is based on an institutional SAH cohort with 782 consecutive cases treated between January 2003 and June 2016. Data were collected on the ictus time, patients' socio-demographic and clinical characteristics, as well as the initial severity and outcome. Univariate and multivariate analyses were performed on the bleeding timeline. RESULTS: There were two peaks in the circadian rhythm of SAH, one in the morning (7-9 a.m.) and the other in the evening (7-9 p.m.). The strongest alterations in the bleeding time patterns were observed for weekdays, patients' age, sex and ethnicity. Individuals with chronic alcohol and painkiller consumption showed a higher bleeding peak between 1 and 3 p.m. Finally, the bleeding time showed no impact on the severity, clinically relevant complications and the outcome of SAH patients. CONCLUSIONS: This study is one of the very few detailed analyses of the impact of specific socio-demographic, ethnic, behavioral and clinical characteristics on the rupture timing of aneurysms. Our results point to the possible relevance of the circadian rhythm for the rupture event, and therefore might be useful in the elaboration of preventive measures against aneurysm rupture.

Central nervous system cavernous malformations: cross-sectional study assessing rebleeding risk after a second haemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the 5-year risk of a third bleeding event in cavernous malformations (CMs) of the central nervous system. METHODS: Patients with cerebral or spinal CMs treated between 2003 and 2021 were screened using our institutional database. Patients with a complete magnetic resonance imaging dataset, clinical baseline characteristics, and history of two bleeding events were included. Patients who underwent surgical CM removal were excluded. Neurological functional status was obtained using the modified Rankin Scale score at the second and third bleeding. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for a third haemorrhage. RESULTS: Forty-two patients were included. Cox regression analysis adjusted for age and sex did not identify risk factors for a third haemorrhage. 37% of patients experienced neurological deterioration after the third haemorrhage (p = 0.019). The cumulative 5-year risk of a third bleeding was 66.7% (95% confidence interval [CI] 50.4%-80%) for the whole cohort, 65.9% (95% CI 49.3%-79.5%) for patients with bleeding at initial diagnosis, 72.7% (95% CI 39.3%-92.7%) for patients with a developmental venous anomaly, 76.9% (95% CI 55.9%-90.3%) for patients with CM localization to the brainstem and 75% (95% CI 50.6%-90.4%) for patients suffering from familial CM disease. CONCLUSIONS: During an untreated 5-year follow-up after a second haemorrhage, a significantly increased risk of a third haemorrhage compared to the known risk of a first and second bleeding event was identified. The third bleeding was significantly associated with neurological deterioration. These findings may justify a surgical treatment after a second bleeding event.

Benign peripheral nerve sheath tumors: an interdisciplinary diagnostic and therapeutic challenge.

A benign peripheral nerve sheath tumor (bPNST) is a rare lesion associated with peripheral nerval structures. Symptoms may be heterogeneous, complicating diagnosis finding. Additionally, management concepts of bPNST may vary. In some cases, initial misdiagnosis leads to mistreatment resulting in severe functional deficits and chronic pain syndromes. Therefore, we analyzed patients treated for bPNST in our specialized institution with a primary focus on prior misdiagnosis and possible mistreatment. Patients with bPNSTs (schwannomas, neurofibromas, hybrid nerve sheath tumors, and perineuriomas) treated at the Neurosurgical Department between January 1, 2015, and July 31, 2021, were included. Assessment of demographics, tumor entity, tumor location, symptoms, the interval between the onset of symptoms and surgery, involved medical specialties, and outpatients' treatment, with particular focus on initial misdiagnosis and inappropriate medical treatment, was performed. Eighty-five patients were included in the final analysis with schwannoma being the most prevalent histopathological diagnosis (schwannoma (75.3%, n=64), neurofibroma (12.9%, n=11), hybrid nerve sheath tumor (5.9%, n=5), and perineurioma (5.9%, n=5)). An incorrect primary diagnosis was detected in 44.7% (n=38), leading to suboptimal or insufficient treatment in these cases. Of those, 28.9% (n=11/38) were treated suboptimal, while 18.5% (n=7/38) underwent unnecessary invasive diagnostics. Inappropriate surgery based on prior misdiagnosis, which led to severe neurological deficits in all these cases, was reported in 26.3% (n=10/38). For the first time, our data shows the quantity and impact of incorrect initial diagnosis in bPNST causing a delay in causative treatment or resulting in unnecessary or potentially harmful treatment.

The value of ventricular measurements in the prediction of shunt dependency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Chronic hydrocephalus requiring shunt placement is a common complication of aneurysmal subarachnoid hemorrhage (SAH). Different risk factors and prediction scores for post-SAH shunt dependency have been evaluated so far. We analyzed the value of ventricle measurements for prediction of the need for shunt placement in SAH patients. METHODS: Eligible SAH cases treated between 01/2003 and 06/2016 were included. Initial computed tomography scans were reviewed to measure ventricle indices (bifrontal, bicaudate, Evans', ventricular, Huckman's, and third ventricle ratio). Previously introduced CHESS and SDASH scores for shunt dependency were calculated. Receiver operating characteristic analyses were performed for diagnostic accuracy of the ventricle indices and to identify the clinically relevant cut-offs. RESULTS: Shunt placement followed in 221 (36.5%) of 606 patients. In univariate analyses, all ventricular indices were associated with shunting (all: p<0.0001). The area under the curve (AUC) ranged between 0.622 and 0.662. In multivariate analyses, only Huckman's index was associated with shunt dependency (cut-off at ≥6.0cm, p<0.0001) independent of the CHESS score as baseline prediction model. A combined score (0-10 points) containing the CHESS score components (0-8 points) and Huckman's index (+2 points) showed better diagnostic accuracy (AUC=0.751) than the CHESS (AUC=0.713) and SDASH (AUC=0.693) scores and the highest overall model quality (0.71 vs. 0.65 and 0.67), respectively. CONCLUSIONS: Ventricle measurements are feasible for early prediction of shunt placement after SAH. The combined prediction model containing the CHESS score and Huckman's index showed remarkable diagnostic accuracy regarding identification of SAH individuals requiring shunt placement. External validation of the presented combined CHESS-Huckman score is mandatory.

Functional outcome after pediatric cerebral cavernous malformation surgery.

The purpose of this study was to investigate the functional outcome following surgical resection of cerebral cavernous malformations (CCM) in pediatric patients. We screened our institutional database of CCM patients treated between 2003 and 2021. Inclusion regarded individuals younger or equal than 18 years of age with complete clinical baseline characteristics, magnetic resonance imaging dataset, and postoperative follow-up time of at least three months. Functional outcome was quantified using the modified Rankin Scale (mRS) score and assessed at admission, discharge, and last follow-up examination. The primary endpoint was the postoperative functional outcome. As a secondary endpoint, predictors of postoperative functional deterioration were assessed. A total of 49 pediatric patients with a mean age of 11.3 ± 5.7 years were included for subsequent analyses. Twenty individuals (40.8%) were female. Complete resection of the lesion was achieved in 44 patients (89.8%), and two patients with incomplete resection were referred for successive remnant removal. The mean follow-up time after surgery was 44 months (IQR: 13 - 131). The mean mRS score was 1.6 on admission, 1.7 at discharge, and 0.9 at the latest follow-up. Logistic regression analysis adjusted to age and sex identified brainstem localization (aOR = 53.45 [95%CI = 2.26 - 1261.81], p = .014) as a predictor of postoperative deterioration. This study indicates that CCM removal in children can be regarded as safe and favorable for the majority of patients, depending on lesion localization. Brainstem localization implies a high risk of postoperative morbidity and indication for surgery should be balanced carefully. Minor evidence indicates that second-look surgery for CCM remnants might be safe and favorable.

Natural course of cerebral and spinal cavernous malformations: a complete ten-year follow-up study.

Knowledge of the bleeding risk and the long-term outcome of conservatively treated patients with cavernous malformations (CM) is poor. In this work, we studied the occurrence of CM-associated hemorrhage over a 10-year period and investigated risk factors for bleeding. Our institutional database was screened for patients with cerebral (CCM) or intramedullary spinal cord (ISCM) CM admitted between 2003 and 2021. Patients who underwent surgery and patients without completed follow-up were excluded. Analyses were performed to identify risk factors and to determine the cumulative risk for hemorrhage. A total of 91 CM patients were included. Adjusted multivariate logistic regression analysis identified bleeding at diagnosis (p = 0.039) and CM localization to the spine (p = 0.010) as predictors for (re)hemorrhage. Both risk factors remained independent predictors through Cox regression analysis (p = 0.049; p = 0.016). The cumulative 10-year risk of bleeding was 30% for the whole cohort, 39% for patients with bleeding at diagnosis and 67% for ISCM. During an untreated 10-year follow-up, the probability of hemorrhage increased over time, especially in cases with bleeding at presentation and spinal cord localization. The intensity of such increase may decline throughout time but remains considerably high. These findings may indicate a rather aggressive course in patients with ISCM and may endorse early surgical treatment.

Morphometric Study of the Initial Ventricular Indices to Predict the Complications and Outcome of Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Acute hydrocephalus is a common complication in patients with aneurysmal subarachnoid hemorrhage (SAH). Several ventricular indices have been introduced to enable measurements of ventricular morphology. Previously, researchers have showed their diagnostic value for various neurological disorders. In this study, we evaluated the association between ventricular indices and the clinical course, occurrence of complications and outcome of SAH. METHODS: A total of 745 SAH patients with available early admission computed tomography scans were included in the analyses. Six ventricular indices (bifrontal, bicaudate, ventricular and third ventricle ratios and Evans' and Huckman's indices) were measured. Primary endpoints included the occurrence of cerebral infarctions, in-hospital mortality and a poor outcome at 6 months. Secondary endpoints included different adverse events in the course of SAH. Clinically relevant cut-offs for the indices were determined using receiver operating curves. Univariate analyses were performed. Multivariate analyses were conducted on significant findings in a stepwise backward regression model. RESULTS: The higher the values of the ventricular indices were and the older the patient was, the higher the WFNS and Fisher's scores were, and the lower the SEBES score was at admission. Patients with larger ventricles showed a shorter duration of intracranial pressure increase > 20 mmHg and required decompressive craniectomy less frequently. Ventricular indices were independently associated with the parameters of inflammatory response after SAH (C-reactive protein in serum and interleukin-6 in cerebrospinal fluid and fever). Finally, there were independent correlations between larger ventricles and all the primary endpoints. CONCLUSIONS: The lower risk of intracranial pressure increase and absence of an association with vasospasm or systemic infections during SAH, and the poorer outcome in individuals with larger ventricles might be related to a more pronounced neuroinflammatory response after aneurysmal bleeding. These observations might be helpful in the development of specific medical and surgical treatment strategies for SAH patients depending on the initial ventricle measurements.

Parkinson's disease may disrupt overlapping subthalamic nucleus and pallidal motor networks.

There is an ongoing debate about differential clinical outcome and associated adverse effects of deep brain stimulation (DBS) in Parkinson's disease (PD) targeting the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi). Given that functional connectivity profiles suggest beneficial DBS effects within a common network, the empirical evidence about the underlying anatomical circuitry is still scarce. Therefore, we investigate the STN and GPi-associated structural covariance brain patterns in PD patients and healthy controls. We estimate GPi's and STN's whole-brain structural covariance from magnetic resonance imaging (MRI) in a normative mid- to old-age community-dwelling cohort (n = 1184) across maps of grey matter volume, magnetization transfer (MT) saturation, longitudinal relaxation rate (R1), effective transversal relaxation rate (R2*) and effective proton density (PD*). We compare these with the structural covariance estimates in patients with idiopathic PD (n = 32) followed by validation using a reduced size controls' cohort (n = 32). In the normative data set, we observed overlapping spatially distributed cortical and subcortical covariance patterns across maps confined to basal ganglia, thalamus, motor, and premotor cortical areas. Only the subcortical and midline motor cortical areas were confirmed in the reduced size cohort. These findings contrasted with the absence of structural covariance with cortical areas in the PD cohort. We interpret with caution the differential covariance maps of overlapping STN and GPi networks in patients with PD and healthy controls as correlates of motor network disruption. Our study provides face validity to the proposed extension of the currently existing structural covariance methods based on morphometry features to multiparameter MRI sensitive to brain tissue microstructure.

Development of multiple intracranial aneurysms: beyond the common risk factors.

OBJECTIVE: The prevalence of multiple intracranial aneurysms (MIAs) has increased over the last decades. Because MIAs have been identified as an independent risk factor for formation, growth, and rupture of intracranial aneurysms (IAs), a more profound understanding of the underlying pathophysiology of MIAs is needed. Therefore, the authors' extensive institutional aneurysm database was analyzed to elucidate differences between patients with a single IA (SIA) and those with MIAs. METHODS: A total of 2446 patients seen with or for IAs at the University Hospital of Essen, Essen, Germany, from January 2003 to June 2016 were included in this retrospective cohort study and were separated into MIA and SIA subgroups. Patient data were screened for sociodemographic and radiographic parameters, preexisting medical conditions, and results of blood examinations. These parameters were analyzed for their correlations with MIAs and absolute number of IAs. RESULTS: MIAs were identified in 853 (34.9%) patients. In multivariable analysis, MIAs were independently associated with female sex (p = 0.001), arterial hypertension (p = 0.023), tobacco abuse (p = 0.009), AB blood group (p = 0.010), and increased admission values for C-reactive protein (p = 0.006), mean corpuscular volume (p = 0.009), and total serum protein (p = 0.034), but not with diagnostic modality (3D vs 2D digital subtraction angiography, p = 0.912). Absolute number of IAs was independently associated with female sex (p < 0.001), arterial hypertension (p = 0.014), familial predisposition to IA (p = 0.015), tobacco consumption (p = 0.025), increased mean corpuscular volume (p = 0.002), and high platelet count (p = 0.007). CONCLUSIONS: In this sizable consecutive series of patients with IAs, the authors confirmed the impact of common IA risk factors on the genesis of MIAs. In addition, specific hemorheological and hemocytological features may also contribute to the development of MIAs.

Blood pressure and outcome after aneurysmal subarachnoid hemorrhage.

Blood pressure management is crucial in the treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). Possible association between the blood pressure increase and the risk of delayed cerebral ischemia (DCI) and different systemic complications after aSAH is still a matter of debate. This study aims to elucidate the influence of blood pressure levels on the outcome of aSAH. All consecutive aSAH patients (n = 690) treated between 01/2003 and 06/2016 were included. The mean value of the mean arterial pressure (MAP) during 14 days after ictus was calculated for each individual. According to the institutional standards of vasospasm management, the mean 14 days MAP ≥ 95 mmHg was referred as increased (IMAP) and the patients with and without vasospasm were analyzed separately. Study endpoints were the occurrence of DCI on computed tomography scans, development of cardiac and nephrological complications, and poor outcome 6 months after aSAH (mRS > 2). Associations were tested in univariable/multivariable binary logistic regression analysis. IMAP was documented in 474 (68.7%) cases and was more common in individuals with poor neurological conditions at admission (p < 0.001), severe amount of intracranial blood (p = 0.001) and premorbid hypertension (p < 0.001). IMAP was independently associated with the occurrence of DCI (p = 0.014; aOR = 2.97; 95% CI 1.25-7.09) and poor functional outcome (p = 0.020; aOR = 3.14; 95% CI 1.20-8.22) in patients with vasospasm, but not in counterparts without vasospasm (p = 0.113/p = 0.086). IMAP had no influence on cardiac or nephrological complications. In aSAH individuals with cerebral vasospasm, sustained increase of blood pressure exceeding the therapeutic targets is strongly associated with the risk of DCI and poor outcome. Therefore, such an intrinsic increase of blood pressure might reflect the autoregulatory mechanisms against the impending cerebral ischemia in patients with cerebral vasospasm.Trial registration number: German clinical trial registry (DRKS, Unique identifier: DRKS00008749, 06/09/2015).

Lipomas as an Extremely Rare Cause for Brachial Plexus Compression: A Case Series and Systematic Review.

Introduction Brachial plexus lipomas are extremely rare benign tumors that may cause slow progression of neurological deficits leading to thoracic outlet syndrome. Up to now, surgery remains challenging. The aim of this study is to present our surgical treatment regime and long-term neurological outcome in three cases of giant brachial plexus lipomas and to show results of systematic review. Patients and Methods Retrospective analysis of our database "peripheral nerve lesion" to identify patients suffering from brachial plexus lipomas between January 1, 2012, and December 31, 2019. Systematic review was performed for literature published until March 31, 2020, analyzing PubMed, Google Scholar, Scopus, and the Cochrane Collaboration Library independently by two authors. Results Over the past years, three patients suffering from giant brachial plexus lipomas attended to our neurosurgical department. All patients underwent preoperative magnetic resonance imaging (MRI), ultrasound examinations, and electrophysiological testing. Tumors were removed microsurgically via anterior/posterior, supraclavicular/infraclavicular, and combined approaches. The patients were accessed postoperatively by MRI and clinical follow-up. Systematic review of the literature revealed 22 cases, which were analyzed in regard to demographics, surgical treatment, and neurological outcome. Conclusion Brachial plexus lipomas are an extremely rare cause for brachial plexus compression. Total microsurgical removal with intraoperative electrophysiological monitoring is the treatment of choice with excellent long-term MRI and clinical outcome.

PaCO2-management in the neuro-critical care of patients with subarachnoid hemorrhage.

The partial pressure of carbon dioxide (PaCO2) in the arterial blood is a strong vasomodulator affecting cerebral blood flow and the risk of cerebral edema and ischemia after acute brain injury. In turn, both complications are related to poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to analyze the effect of PaCO2 levels on the course and outcome of aSAH. All patients of a single institution treated for aSAH over 13.5 years were included (n = 633). Daily PaCO2 values from arterial blood gas measurements were recorded for up to 2 weeks after ictus. The study endpoints were: delayed cerebral ischemia (DCI), need for decompressive craniectomy due to increased intracranial pressure > 20 mmHg refractory to conservative treatment and poor outcome at 6-months follow-up (modified Rankin scale > 2). By correlations with the study endpoints, clinically relevant cutoffs for the 14-days mean values for the lowest and highest daily PaCO2 levels were defined by receiver operating characteristic curve analysis. Association with the study endpoints for the identifies subgroups was analyzed using multivariate analysis. The optimal range for PaCO2 values was identified between 30 and 38 mmHg. ASAH patients with poor initial condition (WFNS 4/5) were less likely to show PaCO2 values within the range of 30-38 mmHg (p < 0.001, OR = 0.44). In the multivariate analysis, PaCO2 values between 30 and 38 mmHg were associated with a lower risk for decompressive craniectomy (p = 0.042, aOR = 0.27), DCI occurrence (p = 0.035; aOR = 0.50), and poor patient outcome (p = 0.004; aOR = 0.42). The data from this study shows an independent positive association between low normal mean PaCO2 values during the acute phase of aSAH and patients' outcome. This effect might be attributed to the reduction of intracranial hypertension and alterations in the cerebral blood flow.

Predictive Value of Intraoperative Neuromonitoring in Brainstem Cavernous Malformation Surgery.

OBJECTIVE: To evaluate the predictive value of intraoperative neuromonitoring (IONM) in brainstem cavernous malformation (BSCM) surgery. METHODS: Surgically treated patients with BSCM were included. All patients received IONM consisting of motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SSEPs). Neurologic examination was conducted preoperatively and at discharge and follow-up >3 months after BSCM removal. Demographic, radiographic, and clinical features were assessed. Study end points were new motor or somatosensory deficits and functional disability. RESULTS: A total of 62 patients were included. MEP decrease was associated with new motor deficits at discharge (P = 0.022), and SSEP decrease was associated with new somatosensory deficits at discharge (P < 0.001) and follow-up (P < 0.001). Sensitivity and specificity values for MEPs (discharge: 31% and 93%; follow-up: 33% and 91%) and SSEPs (discharge: 82% and 80%; follow-up: 85% and 79%) were calculated, respectively. Receiver operating characteristic analyses with area under the curve (AUC) metrics revealed acceptable performance of MEPs (AUC, 0.75; P = 0.022) and SSEPs (AUC, 0.72; P = 0.004) in predicting early deficits. Intraoperative decrease of MEPs (P = 0.047) and SSEPs (P = 0.017) was associated with early functional disability. Surgery-related subdural air accumulation impaired IONM reliability in predicting early (P = 0.048) and long-term (P = 0.013) deficits. CONCLUSIONS: Established IONM warning criteria may be valid for BSCM removal. However, surgical approaches in the sitting position significantly limit the predictive value of IONM, to some extent because of intraoperative pneumocephalus.

Seizures at the onset of aneurysmal SAH: epiphenomenon or valuable predictor?

OBJECTIVE: Seizures at the onset (SAO) of aneurysmal subarachnoid hemorrhage (aSAH) occur in up to one of every five cases. To date, there is no consensus on causal background and clinical value of these early bleeding-related seizures. This study aimed to analyze the predictors and the impact of SAO in aSAH. METHODS: All aSAH patients from the institutional observational cohort (01/2003-06/2016) were retrospectively reviewed. Patients' charts and emergency protocols from first responders were screened for the occurrence of seizures in the first 24 h after aSAH. Patients' baseline characteristics and occurrence of post-hemorrhagic complications were analyzed. Outcome endpoints included in-hospital mortality and poor outcome at 6-month follow-up (modified Rankin Scale > 3). RESULTS: Of 984 patients included in the final analysis, SAO occurred in 93 cases (9.5%) and were independently associated with younger age (< 51 years, p < 0.001), WFNS grade ≥ 4 (p < 0.001), aneurysm characteristics (location at the proximal branch of the anterior cerebral artery [p = 0.037] and irregular sac [p = 0.019]) and admission body temperature > 38.3 â„ƒ (p = 0.008). There was an association between SAO and early complications (early infarcts [p = 0.004] and primary decompressive craniectomy [p = 0.024]). Only in the subgroup analysis restricted to the younger individuals, SAO independently predicted poor outcome of aSAH (p = 0.002). SIGNIFICANCE: Onset seizures following aSAH are rare and most likely related to the severity of early brain injury. Particularly, younger individuals are not only at higher risk for SAO, but are also prone to poor outcome in case of aSAH accompanied with SAO. TRIAL REGISTRATION NUMBER: German clinical trial registry (DRKS, unique identifier: DRKS00008749, 06/09/2015).

HER2 Receptor Conversion Is a strong Survival Predictor in Patients with Breast Cancer Brain Metastases.

BACKGROUND: Hormone and human epidermal growth factor receptor 2 (HER2/neu) receptor status is prognostic and predictive in breast cancer (BC) and guides the choice of therapy. However, owing to receptor conversion, the receptor status can differ in metastases compared with that of the primary tumor. The aim of the present study was to analyze the prognostic value of receptor status, receptor conversion, and clinical parameters in patients with resected BC brain metastases (BMs). METHODS: Patients with BCBMs treated at our institution from July 2007 to December 2019 were eligible for the present study. The receptor status of the BC and corresponding BMs and the occurrence of receptor conversion were separately recorded for 3 common receptors: HER2/neu, estrogen receptor, and progesterone receptor. The association between the receptor status or receptor conversion and clinical parameters was adjusted for outcome-relevant patient and tumor characteristics. RESULTS: The final analysis included 78 patients. HER2/neu receptor status in BMs was associated with overall survival (P = 0.033). Receptor conversion was identified in 39 patients (50.0%): HER2/neu, n = 9 (11.5%); estrogen receptor, n = 22 (28.2%); and progesterone receptor, n = 25 (32.1%). In the final multivariate Cox regression analysis, HER2/neu receptor conversion (adjusted hazard ratio [aHR], 3.58; P = 0.006), Karnofsky performance status score <70% (aHR, 3.11; P = 0.048), infratentorial BM location (aHR, 2.49; P = 0.007), and age ≥55 years at BM diagnosis (aHR, 2.20; P = 0.046) were independently associated with poorer survival. CONCLUSIONS: Of the 3 common BC receptors, only HER2/neu receptor conversion was strongly associated with the prognosis of patients with surgically treated BCBMs. The clinical relevance of the reevaluation of receptor status in BMs favors surgical treatment of patients with noneloquent BCBMs.

Microenvironmentally-driven Plasticity of CD44 isoform expression determines Engraftment and Stem-like Phenotype in CRC cell lines.

Theranostic biomarkers for putative cancer stem-like cells (CSC) in colorectal cancer (CRC) are of particular interest in translational research to develop patient-individualized treatment strategies. Surface proteins still under debate are CD44 and CD133. The structural and functional diversity of these antigens, as well as their plasticity, has only just begun to be understood. Our study aimed to gain novel insight into the plasticity of CD133/CD44, thereby proving the hypothesis of marker-associated tumorigenic and non-tumorigenic phenotypes to be environmentally driven. Methods: CD133/CD44 profiles of 20 CRC cell lines were monitored; three models with distinct surface patterns in vitro were systematically examined. CD133/CD44 subpopulations were isolated by FACS and analyzed upon in vitro growth and/or in limiting dilution engraftment studies. The experimental setup included biomarker analyses on the protein (flow cytometry, Western blotting, immunofluorescence) and mRNA levels (RT-/qPCR) as well as CD44 gene sequencing. Results: In general, we found that (i) the in vitro CD133/CD44 pattern never determined engraftment and (ii) the CD133/CD44 population distributions harmonized under in vivo conditions. The LS1034 cell line appeared as a unique model due to its de novo in vivo presentation of CD44. CD44v8-10 was identified as main transcript, which was stronger expressed in primary human CRC than in normal colon tissues. Biomarker pattern of LS1034 cells in vivo reflected secondary engraftment: the tumorigenic potential was highest in CD133+/CD44+, intermediate in CD133+/CD44- and entirely lost in CD133-/CD44- subfractions. Both CD44+ and CD44- LS1034 cells gave rise to tumorigenic and non-tumorigenic progeny and were convertible - but only as long as they expressed CD133 in vivo. The highly tumorigenic CD133+/CD44(v8-10)+ LS1034 cells were localized in well-oxygenated perivascular but not hypoxic regions. From a multitude of putative modulators, only the direct interaction with stromal fibroblasts triggered an essential, in vivo-like enhancement of CD44v8-10 presentation in vitro. Conclusion: Environmental conditions modulate CD133/CD44 phenotypes and tumorigenic potential of CRC subpopulations. The identification of fibroblasts as drivers of cancer-specific CD44 expression profile and plasticity sheds light on the limitation of per se dynamic surface antigens as biomarkers. It can also explain the location of putative CD133/CD44-positive CRC CSC in the perivascular niche, which is likely to comprise cancer-associated fibroblasts. The LS1034 in vitro/in vivo model is a valuable tool to unravel the mechanism of stromal-induced CD44v8-10 expression and identify further therapeutically relevant, mutual interrelations between microenvironment and tumorigenic phenotype.

Intracranial Aneurysms in Sickle Cell Disease.

BACKGROUND: The exact causes of intracranial aneurysms (IAs) are still unknown. However, certain diseases are known to be associated with IAs. OBJECTIVE: To analyze the differences in IA characteristics in the general population and in individuals with sickle-cell disease (SCD). METHODS: We systematically searched PubMed, Scopus, Web of Science, and Cochrane Library for Data on SCD patients with IAs. We compared IA characteristics of SCD patients with those from 2451 healthy IA carriers from our observational cohort. RESULTS: 129 SCD patients with IAs were identified in 42 studies. The SCD patient cohort was characterized by younger age (mean 27.1 vs 54.9 years, p<0.0001) and lower female prevalence (57.7% vs 68.4%, p=0.0177). The prevalence (47% vs 34.5%, p=0.004) and the number (3.02 vs 2.56 IAs/patient, p=0.004) of multiple IAs were also higher in the SCD cohort. Unruptured IAs (3.27 vs 6.16 mm, p<0.0001), but not ruptured IAs (7.8 vs 7.34 mm, p=0.9086) were significantly smaller in the SCD cohort. In addition, IAs were more frequently located in the internal carotid artery (45% vs 29%, p<0.0001) or posterior circulation (43% vs 20%, p<0.0001). Higher age (≥30 years, p=0.007), IA size ≥7 mm (p=0.008), and location in posterior circulation (p=0.01) were independently associated with subarachnoid hemorrhage in SCD. CONCLUSION: There is a distinct demographic and radiographic pattern of IA in SCD. Risk factors for IA rupture in SCD are mostly congruent with those in healthy individuals.