Time interval between the diagnosis of breast cancer and brain metastases impacts prognosis after metastasis surgery.

PURPOSE: Breast cancer (BC) is the most frequently diagnosed tumor entity in women. Occurring at different time intervals (TI) after BC diagnosis, brain metastases (BM) are associated with poor prognosis. We aimed to identify the risk factors related to and the clinical impact of timing on overall survival (OS) after BM surgery. METHODS: We included 93 female patients who underwent BC BM surgery in our institution (2008-2019). Various clinical, radiographic, and histopathologic markers were analyzed with respect to TI and OS. RESULTS: The median TI was 45.0 months (range: 9-334.0 months). Fifteen individuals (16.1%) showed late occurrence of BM (TI ≥ 10 years), which was independently related to invasive lobular BC [adjusted odds ratio (aOR) 9.49, 95% confidence interval (CI) 1.47-61.39, p = 0.018] and adjuvant breast radiation (aOR 0.12, 95% CI 0.02-0.67, p = 0.016). Shorter TI (< 5 years, aOR 4.28, 95% CI 1.46-12.53, p = 0.008) was independently associated with postoperative survival and independently associated with the Union for International Cancer Control stage (UICC) III-IV of BC (aOR 4.82, 95% CI 1.10-21.17, p = 0.037), midline brain shift in preoperative imaging (aOR10.35, 95% CI 1.09-98.33, p = 0.042) and identic estrogen receptor status in BM (aOR 4.56, 95% CI 1.35-15.40, p = 0.015). CONCLUSIONS: Several factors seem to influence the period between BC and BM. Occurrence of BM within five years is independently associated with poorer prognosis after BM surgery. Patients with invasive lobular BC and without adjuvant breast radiation are more likely to develop BM after a long progression-free survival necessitating more prolonged cancer aftercare of these individuals.

Radiographic markers of breast cancer brain metastases: relation to clinical characteristics and postoperative outcome.

OBJECTIVE: Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Magnetic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy. The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other patients' characteristics and overall survival (OS). METHODS: We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and multivariable analyses were performed. RESULTS: The median OS was 17 months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis was independently associated with OS (14.5 vs 22.5 months, p = 0.027). In turn, intra-tumoral necrosis was more often in individuals with shorter time interval between BC and BM diagnosis (< 3 years, p = 0.035) and preoperative leukocytosis (p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024). CONCLUSION: Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC. The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients.

Machine learning-based differentiation between multiple sclerosis and glioma WHO II°-IV° using O-(2-[18F] fluoroethyl)-L-tyrosine positron emission tomography.

INTRODUCTION: This study aimed to test the diagnostic significance of FET-PET imaging combined with machine learning for the differentiation between multiple sclerosis (MS) and glioma II°-IV°. METHODS: Our database was screened for patients in whom FET-PET imaging was performed for the diagnostic workup of newly diagnosed lesions evident on MRI and suggestive of glioma. Among those, we identified patients with histologically confirmed glioma II°-IV°, and those who later turned out to have MS. For each group, tumor-to-brain ratio (TBR) derived features of FET were determined. A support vector machine (SVM) based machine learning algorithm was constructed to enhance classification ability, and Receiver Operating Characteristic (ROC) analysis with area under the curve (AUC) metric served to ascertain model performance. RESULTS: A total of 41 patients met selection criteria, including seven patients with MS and 34 patients with glioma. TBR values were significantly higher in the glioma group (TBRmax glioma vs. MS: p = 0.002; TBRmean glioma vs. MS: p = 0.014). In a subgroup analysis, TBR values significantly differentiated between MS and glioblastoma (TBRmax glioblastoma vs. MS: p = 0.0003, TBRmean glioblastoma vs. MS: p = 0.0003) and between MS and oligodendroglioma (ODG) (TBRmax ODG vs. MS: p = 0.003; TBRmean ODG vs. MS: p = 0.01). The ability to differentiate between MS and glioma II°-IV° increased from 0.79 using standard TBR analysis to 0.94 using a SVM based machine learning algorithm. CONCLUSIONS: FET-PET imaging may help differentiate MS from glioma II°-IV° and SVM based machine learning approaches can enhance classification performance.

Size does matter: The role of decompressive craniectomy extent for outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: In previous studies in patients with traumatic brain injury and ischemic stroke, the size of decompressive craniectomy (DC) was reported to be paramount with regard to patient outcomes. We aimed to identify the impact of DC size on treatment results in individuals with aneurysmal subarachnoid hemorrhage (SAH). METHODS: The extent of DC in 232 patients with SAH who underwent bifrontal or hemicraniectomy between January 2003 and December 2015 was analyzed using semi-automated surface measurements. The study endpoints were course of intracranial pressure (ICP) treatment after DC, occurrence of cerebral infarcts, in-hospital mortality, and unfavorable outcome at 6 months (defined as modified Rankin scale score >3). The associations of DC size with the study endpoints were adjusted for DC timing, patient age, clinical and radiographic severity of SAH, aneurysm location, and treatment modality. RESULTS: The mean DC surface area was 100.9 (±45.8) cm2 . In multivariate analysis, a large DC (>105 cm2 ) was independently associated with a lower risk of cerebral infarcts (adjusted odds ratio [aOR] 0.30, 95% confidence interval [CI] 0.16-0.56), in-hospital mortality (aOR 0.28, 95% CI 0.14-0.56) and unfavorable outcome (aOR 0.51, 95% CI 0.27-0.98). Moreover, SAH patients with a small DC size (<75 cm2 ) were more likely to require prolonged (>3 days, aOR 3.60, 95% CI 1.37-9.42) and enhanced (aOR 2.31, 95% CI 1.12-4.74) postoperative ICP treatment. CONCLUSION: This is the first study showing the impact of DC size on postoperative ICP control and patient outcome in the context of SAH; specifically, a large craniectomy flap (>105 cm2 ) might lead to better outcomes in SAH patients requiring decompressive surgery.

Electrolyte and renal disorders in patients with newly diagnosed glioblastoma.

Purpose: Disturbances of electrolytes and renal function have been linked to the prognosis of critically ill patients and recently also of cancer patients. This study aimed to assess electrolyte and renal disorders in glioblastoma patients and evaluate their prognostic effect. Methods: Medical records of patients with newly diagnosed glioblastoma between 2005 and 2018 were retrospectively reviewed for electrolyte and renal function parameters and for demographic, clinical and outcome parameters. Results: Electrolyte and renal function disorders were associated with poorer survival in univariate and Kaplan-Meier analysis. Multivariate analysis revealed hypochloremia as an independent prognostic factor for overall and 1-year survival. Conclusion: Only hypochloremia showed an association with glioblastoma prognosis, independent of other known prognostic factors, as age or molecular status.

Dosimetric impact of the positioning variation of tumor treating field electrodes in the PriCoTTF-phase I/II trial.

PURPOSE: The aim of the present study based on the PriCoTTF-phase I/II trial is the quantification of skin-normal tissue complication probabilities of patients with newly diagnosed glioblastoma multiforme treated with Tumor Treating Field (TTField) electrodes, concurrent radiotherapy, and temozolomide. Furthermore, the skin-sparing effect by the clinically applied strategy of repetitive transducer array fixation around their center position shall be examined. MATERIAL AND METHODS: Low-dose cone-beam computed tomography (CBCT) scans of all fractions of the first seven patients of the PriCoTTF-phase I/II trial, used for image guidance, were applied for the dosimetric analysis, for precise TTField transducer array positioning and contour delineation. Within this trial, array positioning was varied from fixation-to-fixation period with a standard deviation of 1.1 cm in the direction of the largest variation of positioning and 0.7 cm in the perpendicular direction. Physical TTField electrode composition was examined and a respective Hounsfield Unit attributed to the TTField electrodes. Dose distributions in the planning CT with TTField electrodes in place, as derived from prefraction CBCTs, were calculated and accumulated with the algorithm Acuros XB. Dose-volume histograms were obtained for the first and second 2 mm scalp layer with and without migrating electrodes and compared with those with fixed electrodes in an average position. Skin toxicity was quantified according to Lyman's model. Minimum doses in hot-spots of 0.05 cm2 and 25 cm2 ( Δ D0.05cm 2 , Δ D25cm 2 ) size in the superficial skin layers were analyzed. RESULTS: Normal tissue complication probabilities (NTCPs) for skin necrosis ranged from 0.005% to 1.474% (median 0.111%) for the different patients without electrodes. NTCP logarithms were significantly dependent on patient (P < 0.0001) and scenario (P < 0.0001) as classification variables. Fixed positioning of TTField arrays increased skin-NTCP by a factor of 5.50 (95%, CI: 3.66-8.27). The variation of array positioning increased skin-NTCP by a factor of only 3.54 (95%, CI: 2.36-5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes). NTCP showed a significant rank correlation with D25cm2 over all patients and scenarios (rs  = 0.76; P < 0.0001). CONCLUSION: Skin-NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high- and low-risk groups of skin toxicity. Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.

Pathophysiology of Intracranial Aneurysms: COX-2 Expression, Iron Deposition in Aneurysm Wall, and Correlation With Magnetic Resonance Imaging.

BACKGROUND AND PURPOSE: The pathophysiology of development, growth, and rupture of intracranial aneurysms (IAs) is only partly understood. Cyclooxygenase 2 (COX-2) converts arachidonic acid to prostaglandin H2, which, in turn, is isomerized to prostaglandin E2. In the human body, COX-2 plays an essential role in inflammatory pathways. This explorative study aimed to investigate COX-2 expression in the wall of IAs and its correlation to image features in clinical (1.0T, 1.5T, and 3.0T) magnetic resonance imaging (MRI) and ultra-high-field 7T MRI. METHODS: The study group comprised 40 patients with partly thrombosed saccular IAs. The cohort included 17 ruptured- and 24 unruptured IAs, which had all been treated microsurgically. Formaldehyde-fixed paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 (Dako, Santa Clara, CA; Clone: CX-294). We correlated Perls Prussian blue staining, MRI, and clinical data with immunohistochemistry, analyzed using the Trainable Weka Segmentation algorithm. RESULTS: Aneurysm dome size ranged between 2 and 67 mm. The proportion of COX-2 positive cells ranged between 3.54% to 85.09%. An upregulated COX-2 expression correlated with increasing IA dome size (P=0.047). Furthermore, there was a tendency of higher COX-2 expression in most ruptured IAs (P=0.064). At all field strengths, MRI shows wall hypointensities due to iron deposition correlating with COX-2 expression (P=0.022). CONCLUSIONS: Iron deposition and COX-2 expression in IAs walls correlate with signal hypointensity in MRI, which might, therefore, serve as a biomarker for IA instability. Furthermore, as COX-2 was also expressed in small unruptured IAs, it could be a potential target for specific medical treatment.

The predominant expression of cancer stem cell marker ALDH1A3 in tumor infiltrative area is associated with shorter overall survival of human glioblastoma.

BACKGROUND: ALDH1A3 is a cancer stem cell marker in neoplasms including glioblastoma (GBM). However, the comprehensive role of ALDH1A3 in GBM remains unclear. This study attempted to investigate the expression of ALDH1A3 in human GBM tissues and its association with clinical parameters. METHODS: Thirty primary GBM and 9 control were enrolled in this study. ALDH1A3 mRNA and protein expression levels were detected by RT2-PCR and western blot, respectively. Immunohistochemistry and immunofluorescence staining were performed to evaluate the regional and cellular expression manner of ALDH1A3. The association of ALDH1A3 expression with multiple clinical parameters was analyzed. RESULTS: ALDH1A3 protein level, but not mRNA level, in a subgroup of GBM was significantly higher than that in the control group. ALDH1A3 immunoreactivity was detected heterogeneously in individual GBMs. Fifteen of 30 cases showed a positive of ALDH1A3 immunoreactivity which was predominantly observed in the tumor infiltrative area (TI). Double immunofluorescence staining revealed a co-localization of ALDH1A3 with GFAP in glial-shaped cells and in tumor cells. ALDH1A3 immunoreactivity was often merged with CD44, but not with CD68. Moreover, ALDH1A3 expression was positively associated with the tumor edema grade and inversely with overall survival (OS) (median OS: 16 months vs 10 months), but with neither MGMT promoter methylation status nor Ki67 index in GBM. An upregulation of ALDH1A3 was accompanied by a reduced expression of STAT3ß and p-STAT3ß. CONCLUSIONS: Inter- and intra-tumoral heterogeneous expression of ALDH1A3 was exhibited in GBMs. A high immunoreactivity of ALDH1A3 in tumor infiltrative area was associated with shorter OS, especially in patients with MGMT promoter methylation. Our findings propose ALDH1A3 not only as a predictive biomarker but also as a potential target for personalized therapy of GBM.

TET2 promotor methylation and TET2 protein expression in pediatric posterior fossa ependymoma.

Pediatric posterior fossa ependymoma (PF) is one of the most common brain tumors in children. Recently, two subtypes of PF were identified. PF-A has a dismal prognosis and shows a hypermethylation phenotype, whereas PF-B shows a great genomic instability. The ten-eleven translocation methylcytosine dioxygenase 2 (TET2) gene (TET2) has been linked to the regulation of DNA methylation. We analyzed TET2 promotor methylation and protein expression to assess the role of TET2 in PF. Medical records of all PF cases treated in our institution between 1993 and 2015 were evaluated regarding tumor histology, grade, tumor location, gender, age, tumor recurrence, distant metastasis, survival and time to progression. Subsequently, we analyzed TET2 promotor methylation using methylation-specific polymerase chain reaction. TET2 protein expression was assessed using immunohistochemistry. Low TET2 expression was detected in seven of 17 cases. There was an association between low TET2 expression and tumor recurrence (P = 0.049). A TET2 promotor methylation was detected in five of 10 cases. There was no association between the TET2 promotor methylation with recurrence, tumor grade or gender. TET2 promotor methylation and low TET2 expression was detected in a subgroup of PF. Our data show an association between low TET2 expression and tumor recurrence in PF.

Laboratory biomarkers of delayed cerebral ischemia after subarachnoid hemorrhage: a systematic review.

Delayed cerebral ischemia (DCI) is a severe complication of subarachnoid hemorrhage (SAH). Clinical and radiographic features of SAH may be helpful in identification of individuals prone to DCI. The aim of this systematic review was to analyze the present evidence on predictive value of blood and cerebrospinal fluid (CSF) biomarkers of DCI after SAH. We systematically searched in PubMed, Scopus, Web of Science, and Cochrane Library databases for publications before July 15, 2018, reporting correlations between blood/CSF biomarkers and occurrence of DCI and/or vasospasm in SAH patients. Included studies underwent quality assessment according to QUIPS and STARD guidelines. Level of evidence (I-IV) for each of tested biomarkers was assessed according to GRADE guidelines. Of 2181 unique records identified in four databases, 270 original articles and 5 meta-analyses were included to this review. Of 257 blood and CSF parameters analyzed in 16.914 SAH patients, there was no biomarker with positive association with DCI/vasospasm showing level I evidence. Twenty-one biomarkers achieved level II evidence and could be confirmed as predictive biomarkers. In this review, six single nucleotide polymorphisms (for EET metabolic pathways, COMT, HMGB1, ACE, PAI-1 promoter, and Hp genes) and 15 non-genetic biomarkers (pNF-H, ADAMTS13, NPY, Copeptin, HMGB1, GFAP, periostin, Tau, BNP, NT pro-BNP, hs-TnT, PA-TEGMA, MPV:PLT, NLR, and PLR) were selected as predictive DCI biomarkers. We propose that a panel analysis of the selected genetic and protein biomarker candidates would be needed for further validation in a large SAH cohort.

Simultaneous primary cancer occurrence of melanoma and pulmonary adenocarcinoma in leptomeningeal metastases: a case report.

BACKGROUND: Leptomeningeal metastasis (LM) is a predominantly late stage, devastating complication of a variety of malignant solid tumors. Diagnosis relies predominantly on neurological, radiographic, and cerebrospinal fluid (CSF) assessments. Recently, liquid biopsy tests derived from CSF has shown to be a feasible, noninvasive promising approach to tumor molecular profiling for proper brain cancer diagnostic treatment, thereby providing an opportunity for CSF-based personalized medicine. However, LM is typically misleadingly assumed to originate from only one primary tumor type. CASE PRESENTATION: In this case report, we provide first evidence of the co-occurrence of LM originating from more than one primary tumor types. DISCUSSION AND CONCLUSIONS: Based on this patient case profile, the co-occurrence of LM from two or more primary tumor types should be accounted for when deriving diagnostic conclusions from liquid biopsy tests.

A rare case of a completely thrombosed bilobed giant intracranial aneurysm of the anterior cerebral artery with spontaneous parent vessel thrombosis: case report.

BACKGROUND: A huge spherical intracranial mass can sometimes be misdiagnosed, due to the lack of typical radiographic features. Thrombosed giant intracranial aneurysms (GIAs) are an uncommon but still a possible differential diagnosis that must be kept in mind to guarantee the best surgical approach and resection of the lesion. We describe an extremely rare case of a huge bifrontal mass mimicking a cystic echinococcosis, in which the surgery unveiled a completely thrombosed GIA of the left anterior cerebral artery (ACA). CASE PRESENTATION: A 61-year-old patient complained about intermittent weakness of the right leg, mild holocephalic headache, beginning cognitive deficits and lethargy. Magnetic resonance imaging (MRI) showed a huge partially calcified and bilobed frontal mass with peripheral edema. Based on a time-resolved angiography with interleaved Stochastic trajectories MRI (TWIST-MRI), a vascular origin of the lesion was considered unlikely. Therefore, the surgery was performed under the suspicion of a cystic echinococcosis but revealed a bilobed GIA of the left ACA with a parent vessel thrombosis. Although only a limited left frontal craniotomy was performed, a proximal control of the parent vessel could be ensured, and the aneurysm was successfully clipped. The patient showed postoperatively no new neurological deficits. CONCLUSIONS: Completely thrombosed GIAs with parent vessel thrombosis are rare lesions that might be misdiagnosed if typical radiographic features are missing. Thus, in case of an intracranial spherical mass with signs of intralesional hemorrhage and mural calcifications, presence of a completely thrombosed GIA should be considered as a possible differential diagnosis.

Risk Factors for and Clinical Consequences of Multiple Intracranial Aneurysms: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Multiple intracranial aneurysms (MIAs) are common findings of cerebral angiographies; however, MIA prevalence varies in different patient cohorts. We sought to elucidate risk factors influencing MIA prevalence and the clinical consequences. METHODS: We systematically searched PubMed, Scopus, Embase, and Cochrane Library databases for publications before January 15, 2017, reporting MIA prevalence and risk factors. We used random-effects meta-analysis and multivariate regression analysis to assess the impacts of individual, study, and population characteristics. RESULTS: We included 174 studies reporting on MIA (mean overall prevalence, 20.1%; range, 2%-44.9%) in 134 study populations with 86 989 intracranial aneurysm (IA) patients enrolled between 1950 and 2015. Studies from Europe and North America (P<0.001) and more recent enrolment years (P=0.046) were independently associated with higher MIA prevalence. In meta-analysis, MIA correlated with female sex (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.4-1.8), higher patient age (>40 years; OR, 1.6; 95% CI, 1.14-2.25), arterial hypertension (OR, 1.51; 95% CI, 1.17-1.94), smoking (OR, 1.89; 95% CI, 1.37-2.6) and familial IA (OR, 2.02; 95% CI, 1.47-2.77), and formation of de novo (OR, 3.92; 95% CI, 1.95-7.87) and growth of initial IA (OR, 3.47; 95% CI, 1.87-6.45). Risk of subarachnoid hemorrhage in MIA patients was higher only in longitudinal studies from Japan and Korea (OR, 2.08; 95% CI, 1.46-2.96). CONCLUSIONS: Female sex, higher age, arterial hypertension, smoking, and familial IA are major risk factors for MIA. In addition, MIA patients are at risk for enhanced IA formation. Further studies are needed to evaluate rupture risk and the role of ethnicity, especially in the context of increased MIA identification with improved neurovascular imaging.

Vasospasm-related complications after subarachnoid hemorrhage: the role of patients' age and sex.

BACKGROUND: Outcome of aneurysmal subarachnoid hemorrhage (SAH) depends strongly on occurrence of symptomatic vasospasm (SV) leading to delayed cerebral ischemia (DCI). Various demographic, radiographic, and clinical predictors of SV have been reported so far, partially with conflicting results. The aim of this study was to analyze the role of patients' age and sex on SV/DCI risk, especially to identify age and sex-specific risk groups. METHODS: All patients admitted with acute SAH during a 14-year-period ending in 2016 were eligible for this study. The study endpoints were the following: SV requiring spasmolysis, occurrence of DCI in follow-up computed tomography scans and unfavorable outcome at 6 months (modified Rankin scale > 2). RESULTS: Nine hundred ninety-four patients were included in this study. The majority was female (666; 67%). SV, DCI, and unfavorable outcomes were observed in 21.5, 21.8, and 43.6% of the patients, respectively. Younger age (p < 0.001; OR = 1.03 per year decrease) and female sex (p = 0.025; OR = 1.510) were confirmed as independent predictors of SV. Regarding the sex differences, there were three age groups for SV/DCI risk ≤ 54, 55-74, and ≥ 75 years. Male patients showed earlier decrease in SV risk (at ≥ 55 vs. ≥ 75 years in females). Therefore, SAH females aged between 55 and 74 years were at the highest risk for DCI and unfavorable outcome, as compared to younger/older females (p = 0.001, OR = 1.77/p = 0.001, OR = 1.80). In contrast, their male counterparts did not show these risk alterations (p = 0.445/p = 0.822). CONCLUSION: After acute SAH, female and male patients seem to show different age patterns for the risk of SV and DCI. Females aged between 55 and 74 years are at particular risk of vasospasm-related SAH complications, possibly due to onset of menopause. CLINICAL TRIAL REGISTRATION NUMBER: DRKS, Unique identifier: DRKS00008749.

Study of angiogenic signaling pathways in hemangioblastoma.

Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper-vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT2 -PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4-Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core-components of Dll4-Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti-angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor.

The Role of Fibroblast Activation Protein in Glioblastoma and Gliosarcoma: A Comparison of Tissue, 68Ga-FAPI-46 PET Data, and Survival Data.

Despite their unique histologic features, gliosarcomas belong to the group of glioblastomas and are treated according to the same standards. Fibroblast activation protein (FAP) is a component of a tumor-specific subpopulation of fibroblasts that plays a critical role in tumor growth and invasion. Some case studies suggest an elevated expression of FAP in glioblastoma and a particularly strong expression in gliosarcoma attributed to traits of predominant mesenchymal differentiation. However, the prognostic impact of FAP and its diagnostic and therapeutic potential remain unclear. Here, we investigate the clinical relevance of FAP expression in gliosarcoma and glioblastoma and how it correlates with 68Ga-FAP inhibitor (FAPI)-46 PET uptake. Methods: Patients diagnosed with gliosarcoma or glioblastoma without sarcomatous differentiation with an overall survival of less than 2.5 y were enrolled. Histologic examination included immunohistochemistry and semiquantitative scoring of FAP (0-3, with higher values indicating stronger expression). Additionally, 68Ga-FAPI-46 PET scans were performed in a subset of glioblastomas without sarcomatous differentiation patients. The clinical SUVs were correlated with FAP expression levels in surgically derived tumor tissue and relevant prognostic factors. Results: Of the 61 patients who were enrolled, 13 of them had gliosarcoma. Immunohistochemistry revealed significantly more FAP in gliosarcomas than in glioblastomas without sarcomatous differentiation of tumor tissue (P < 0.0001). In the latter, FAP expression was confined to the perivascular space, whereas neoplastic cells additionally expressed FAP in gliosarcoma. A significant correlation of immunohistochemical FAP with SUVmean and SUVpeak of 68Ga-FAPI-46 PET indicates that clinical tracer uptake represents FAP expression of the tumor. Although gliosarcomas express higher levels of FAP than do glioblastomas without sarcomatous differentiation, overall survival does not significantly differ between the groups. Conclusion: The analysis reveals a significant correlation between SUVmean and SUVpeak in 68Ga-FAPI-46 PET and immunohistochemical FAP expression. This study indicates that FAP expression is much more abundant in the gliosarcoma subgroup of glioblastomas. This could open not only a diagnostic but also a therapeutic gap, since FAP could be explored as a theranostic target to enhance survival in a distinct subgroup of high-risk brain tumor patients with poor survival prognosis.

Preoperative cervical traction with Gardner-Wells tongs: who profits most?

BACKGROUND: Preoperative traction with the Gardner-Wells tongs (PTGWT) is a valuable option for cervical spine injuries with malalignment. The aim of this study was to analyze the factors related to the treatment success of PTGWT. METHODS: All consecutive cases with PTGWT due to cervical spine injury with malalignment treated between 01/2010 and 09/2020 were included. Patients' records were reviewed for demographic and clinical characteristics. Treatment success was evaluated upon the angle correction in the sagittal plane using the computed tomography scans before and after the treatment. RESULTS: Of 20 patients in the final analysis (median age: 77.5 years; 12 females [60%]), 14 individuals were treated for the type-II odontoid fracture, and six cases presented with subluxation fractures between C3 and C7. After PTGWT and subsequent intraoperative reposition, there was an improvement of the median deviation angle from initial 32° to 5.5°. PTGWT resulted in a significant improvement of the median deviation angle for the odontoid (17°, P<0.0001), but not for the subluxation (4°, P=0.10) fractures. The time interval between trauma and PTGWT was associated with the treatment success of subluxation (P=0.051) but not of odontoid (P=0.87) fractures. Older individuals aged ≥51 years showed better reposition results with PTGWT (17° vs. 7.5°, P=0.02). There were no PTGWT-related complications in the cohort. CONCLUSIONS: PTGWT is an effective and safe treatment for cervical spine injuries with malalignment. The patients with odontoid fractures might particularly profit from the PTGWT. Treatment delay seems more relevant for PTGWT success in subluxation than in odontoid fractures.

Precision neuro-oncology: a pilot analysis of personalized treatment in recurrent glioma.

PURPOSE: When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. METHODS: We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. RESULTS: The investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357). CONCLUSION: These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.

A New Subform? Fast-Progressing, Severe Neurological Deterioration Caused by Spinal Epidural Lipomatosis.

Spinal epidural lipomatosis (SEL) is a rare condition caused by hypertrophic growth of epidural fat. The prevalence of SEL in the Western world is approximately 1 in 40 patients and is likely to increase due to current medical and socio-economic developments. Rarely, SEL can lead to rapid severe neurological deterioration. The pathophysiology, optimal treatment, and outcome of these patients remain unclear. This study aims to widen current knowledge about this "SEL subform" and to improve its clinical management. A systematic literature review according to the PRISMA guidelines using PubMed, Scopus, Web of Science, and Cochrane Library was used to identify publications before 7 November 2021 reporting on acute/rapidly progressing, severe SEL. The final analysis comprised 12 patients with acute, severe SEL. The majority of the patients were male (9/12) and multimorbid (10/12). SEL mainly affected the thoracic part of the spinal cord (11/12), extending a median number of 7 spinal levels (range: 4-19). Surgery was the only chosen therapy (11/12), except for one critically ill patient. Regarding the outcome, half of the patients regained independence (6/11; = modified McCormick Scale ≤ II). Acute, severe SEL is a rare condition, mainly affecting multimorbid patients. The prognosis is poor in nearly 50% of the patients, even with maximum therapy. Further research is needed to stratify patients for conservative or surgical treatment.

Prediction of Short and Long Survival after Surgery for Breast Cancer Brain Metastases.

Background: Brain metastases requiring surgical treatment determine the prognosis of patients with breast cancer. We aimed to develop the scores for the prediction of short (<6 months) and long (≥3 years) survival after BCBM surgery. Methods: Female patients with BCBM surgery between 2008 and 2019 were included. The new scores were constructed upon independent predictors for short and long postoperative survival. Results: In the final cohort (n = 95), 18 (18.9%) and 22 (23.2%) patients experienced short and long postoperative survival, respectively. Breast-preserving surgery, presence of multiple brain metastases and age ≥ 65 years at breast cancer diagnosis were identified as independent predictors of short postoperative survival. In turn, positive HER2 receptor status in brain metastases, time interval ≥ 3 years between breast cancer and brain metastases diagnosis and KPS ≥ 90% independently predicted long survival. The appropriate short and long survival scores showed higher diagnostic accuracy for the prediction of short (AUC = 0.773) and long (AUC = 0.775) survival than the breast Graded Prognostic Assessment score (AUC = 0.498/0.615). A cumulative survival score (total score) showed significant association with overall survival (p = 0.001). Conclusion: We identified predictors independently impacting the prognosis after BCBM surgery. After external validation, the presented scores might become useful tools for the selection of proper candidates for BCBM surgery.