Deep Proteome Analysis of Cerebrospinal Fluid from Pediatric Patients with Central Nervous System Cancer.

The cerebrospinal fluid (CSF) is a key matrix for discovery of biomarkers relevant for prognosis and the development of therapeutic targets in pediatric central nervous system malignancies. However, the wide range of protein concentrations and age-related differences in children makes such discoveries challenging. In addition, pediatric CSF samples are often sparse and first prioritized for clinical purposes. The present work focused on optimizing each step of the proteome analysis workflow to extract the most detailed proteome information possible from the limited CSF resources available for research purposes. The strategy included applying sequential ultracentrifugation to enrich for extracellular vesicles (EV) in addition to analysis of a small volume of raw CSF, which allowed quantification of 1351 proteins (+55% relative to raw CSF) from 400 µL CSF. When including a spectral library, a total of 2103 proteins (+240%) could be quantified. The workflow was optimized for CSF input volume, tryptic digestion method, gradient length, mass spectrometry data acquisition method and database search strategy to quantify as many proteins a possible. The fully optimized workflow included protein aggregation capture (PAC) digestion, paired with data-independent acquisition (DIA, 21 min gradient) and allowed 2989 unique proteins to be quantified from only 400 µL CSF, which is a 340% increase in proteins compared to analysis of a tryptic digest of raw CSF.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Implementation of TERT promoter mutations improve prognostication of the WHO classification in meningioma.

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas.

Adjuvant radiotherapy and stereotactic radiosurgery in grade 3 meningiomas - a systematic review and meta-analysis.

Malignant meningioma is a rare, aggressive form of meningioma. Radiation is commonly included in treatment guidelines either as adjuvant radiotherapy (RT) or stereotactic radiosurgery (SRS). Nevertheless, the treatment recommendations are not supported by prospective comparative trials and systematical, critical evaluation of supportive evidence is lacking. For this systematic review, studies analyzing the effectiveness of adjuvant RT and SRS in grade 3 (gr. 3) meningioma were reviewed. Thirty studies met the inclusion criteria for qualitative synthesis, and 6 studies were assessed in quantitative analysis. In quantitative analysis, the weighted average of hazard ratios for adjuvant RT in univariate analyses of overall survival (OS) was 0.55 (CI: 0.41; 0.69). The median 5-year OS after adjuvant RT in gr. 3 meningiomas was 56.3%, and the median OS ranged from 24 to 80 months for patients treated with adjuvant RT versus 13 to 41.2 months in patients not treated. For SRS, the 3-year progression free survival was 0% in one study and 57% in another. The 2-year OS ranged from 25 to 75% in 2 studies. The quality of evidence was rated as "very low" in 14 studies analyzed, and considerable allocation bias was detected. Treatment toxicity was reported in 47% of the studies. The severity, according to the CTCAE, ranged from grades I-V and 5.3 to 100% of patients experienced complications. Adjuvant RT is usually considered standard of care for WHO grade 3 meningiomas, although supporting evidence was of low quality. Better evidence from registries and prospective trials can improve the evidence base for adjuvant fractionated RT in malignant meningiomas.

Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.

Proposal of a new grading system for meningioma resection: the Copenhagen Protocol.

INTRODUCTION: The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between "gross total removal" and "subtotal removal," while the latter comprises a five-tiered differentiation of the surgeon's impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas. OBJECTIVE: To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68Ga DOTATOC PET, we propose "Copenhagen Grading" for meningiomas. RESULTS: Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen. CONCLUSION: Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation.

Impact of time to treatment initiation for patients with oral cavity squamous cell carcinoma: a population-based, retrospective study.

BACKGROUND: The increasing incidence of oral cavity squamous cell carcinoma (OSCC) is challenging the capacity to treat patients efficiently. The aim of this study was to evaluate the impact of time to treatment initiation (TTI) on overall survival (OS) and recurrence free survival (RFS) for patients with primary OSCC. MATERIAL AND METHODS: All patients with primary OSCC treated with curative intent at Rigshospitalet in the period 2000-2014 with known date of diagnosis and treatment initiation were included. Correlation analyses between TTI and Charlson comorbidity index (CCI), UICC stage, and year of diagnosis were performed in addition to uni- and multivariate Cox proportional hazard regression analyses. Further, interaction analysis of TTI and UICC stage were conducted. RESULTS: Eight hundred and sixty-two patients (64% men) with a median age at diagnosis of 62 years (range: 28-95 years) were included. The median TTI was 31 days (range: 2-137 days). Correlation analyses showed correlations between TTI and CCI, TTI and UICC stage, and TTI and year of diagnosis (rho = -0.10, p-value = <.01; rho = 0.16, p-value = <.001; rho = -0.47 p-value = <.001). Univariate analyses showed a statistically significant increase in hazard ratio for both OS and RFS with a five-day increase in TTI (HR = 1.05, 95%CI: 1.02-1.07 and HR = 1.04, 95%CI: 1.02-1.07). However, when adjusting for age, sex, smoking, UICC stage, tumor sublocation, CCI, and year of diagnosis in a multivariate analysis, the increase in HR with TTI was not statistically significant. There was no statistically significant interaction between TTI and UICC stage. CONCLUSION: Survival of OSCC patients decreased with increasing TTI, yet not statistically significant in multivariate analysis. There was no difference in the effect of TTI between patients diagnosed in low or advanced stages.

Expression of the stem cell marker CD133 in malignant meningioma.

The stem cell marker CD133 has been sporadically investigated in meningioma, but because of the rarity of malignant meningioma (WHO grade III), only 7 malignant meningioma specimens have been included in previous studies. We investigated CD133 expression using the AC133 antibody clone in a consecutive cohort of 38 malignant meningiomas. Our results showed few, small CD133-positive hot spots with a pattern dominated by membranous staining and capping of the proteins without any nuclear CD133 staining in 30 of the 38 tumors. We could not corroborate spatial co-expression of hot spots with the proliferative marker, Ki-67, and CD133 hot spots in adjacent slides, nor did we find differences between Ki-67 expression in CD133-negative and -positive tumor specimens (Fisher's exact test: p = 0.69). CD13-positive niches represented only 0 - 1% of meningioma cells in most of the malignant meningioma, while CD133-positive cells were undetectable in 21% of the whole-section tumor samples. We found stem cell niches in 79% of malignant meningioma specimens in our cohort.

Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis.

BACKGROUND: TERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought. METHODS: We applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs. RESULTS: TERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients. CONCLUSIONS: TERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification. TRIAL REGISTRATION NUMBER: PROSPERO: CRD42018110566.

Improved Survival of Children, Adolescents, and Young Adults With Head and Neck Soft Tissue Sarcomas in Denmark.

AIM: The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas. MATERIALS AND METHODS: The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk. RESULTS: We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%). CONCLUSION: Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.

Antiepileptic drugs as prophylaxis for de novo brain tumour-related epilepsy after craniotomy: a systematic review and meta-analysis of harm and benefits.

OBJECTIVES: To investigate potential harm and benefits of antiepileptic drugs (AED) given prophylactically to prevent de novo brain tumour-related epilepsy after craniotomy. METHODS: Randomised controlled trials (RCT) and retrospective studies published before 27 November 2018 were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied. Eligible patients were diagnosed with a brain tumour, were seizure naïve and underwent craniotomy. The random effects model was used for quantitative synthesis. The analysis was adjusted for the confounding effect of including patients with a history of seizure prior to study inclusion. RESULTS: A total of 454 patients received prophylactic AED whereas 333 were allocated to placebo or no treatment. Two RCTs and four retrospective studies were identified. The OR was 1.09 (95% CI 0.7 to 1.8, p=0.7, I2=5.6%, χ2 p=0.5), indicating study consistency and no significant differences. An additional two RCTs and one retrospective study combined craniotomy and diagnostic biopsy, and were subgroup analysed-which supported no difference in odds for epilepsy. CONCLUSIONS: A prophylactic effect of AED could not be demonstrated (nor rejected statistically). Levetiracetam was associated with less adverse effects than phenytoin. The potential harm of AED was not balanced by the potential prophylactic benefit. This study suggests that prophylactic AED should not be administered to prevent brain tumour-related epilepsy after craniotomy.

Incidence of head and neck cancer in children: A Danish nationwide study from 1978 to 2014.

BACKGROUND: Pediatric head and neck malignancies are rare and only a few descriptive epidemiological studies have been published. Using unique nationwide registries, we report age-specific incidence rates of head and neck cancer (HNC) among children during four decades. METHODS: Data were obtained from the Danish Cancer Registry. We included children aged 0-14 years diagnosed between January 1, 1978 and December 31, 2014 with extra-orbital, nonskin and nonbone HNC. Patients were divided into nine groups in regard to tumor location: oral cavity, oropharynx, nasopharynx, hypopharynx, thyroid, major salivary glands, larynx, and middle ear. Based on the World Health Organization standard population and Danish age-specific population counts, age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) were calculated and examined for trends. RESULTS: In total, 169 children (55.6% females) were registered with a malignant tumor in the head and neck region. The AAIR increased with an AAPC of 2.2% (95% CI, 0.8-3.7%). Females showed an AAIR of 0.54 per 100,000 person years compared to that of males, with 0.41 per 100,000 person years (P < 0.01). The AAIR was higher among children aged 10-14 years compared to 0-9-year-old children (P < 0.01). Based on morphology, a significant increase in AAIR was observed for sarcomas, with an increase of 0.16-0.27 per 100,000 person years (P < 0.05). CONCLUSIONS: The incidence rate of pediatric HNC was higher among females and evidence of increasing rates was observed during 1978-2014, explained by an increase mainly in sarcomas.

Mass spectrometry-based proteomics of cerebrospinal fluid in pediatric central nervous system malignancies: a systematic review with meta-analysis of individual patient data.

BACKGROUND: The cerebrospinal fluid (CSF) proteome could offer important insights into central nervous system (CNS) malignancies. To advance proteomic research in pediatric CNS cancer, the current study aims to (1) evaluate past mass spectrometry-based workflows and (2) synthesize previous CSF proteomic data, focusing on both qualitative summaries and quantitative re-analysis. MAIN: In our analysis of 11 studies investigating the CSF proteome in pediatric patients with acute lymphoblastic leukemia (ALL) or primary brain tumors, we observed significant methodological variability. This variability negatively affects comparative analysis of the included studies, as per GRADE criteria for quality of evidence. The qualitative summaries covered 161 patients and 134 non-tumor controls, while the application of validation cohort varied among the studies. The quantitative re-analysis comprised 15 B-ALL vs 6 "healthy" controls and 15 medulloblastoma patients vs 22 non-tumor controls. Certain CSF proteins were identified as potential indicators of specific malignancies or stages of neurotoxicity during chemotherapy, yet definitive conclusions were impeded by inconsistent data. There were no proteins with statistically significant differences when comparing cases versus controls that were corroborated across studies where quantitative reanalysis was feasible. From a gene ontology enrichment, we observed that age disparities between unmatched case and controls may mislead to protein correlations more indicative of age-related CNS developmental stages rather than neuro-oncological disease. Despite efforts to batch correct (HarmonizR) and impute missing values, merging of dataset proved unfeasible and thereby limited meaningful data integration across different studies. CONCLUSION: Infrequent publications on rare pediatric cancer entities, which often involve small sample sizes, are inherently prone to result in heterogeneous studies-particularly when conducted within a rapidly evolving field like proteomics. As a result, obtaining clear evidence, such as CSF proteome biomarkers for CNS dissemination or early-stage neurotoxicity, is currently impractical. Our general recommendations comprise the need for standardized methodologies, collaborative efforts, and improved data sharing in pediatric CNS malignancy research. We specifically emphasize the possible importance of considering natural age-related variations in CSF due to different CNS development stages when matching cases and controls in future studies.

Translocator protein (TSPO) expression in neoplastic cells and tumor-associated macrophages in meningiomas.

Meningiomas are the most common primary intracranial tumors and show extensive infiltration of macrophages. The mitochondrial membrane protein translocator protein (TSPO) has been used as an in vivo marker of microglia and macrophage activation to visualize neuroinflammation. However, it is unknown which cell types express TSPO in meningiomas. Immunohistochemistry of 38 WHO grade 1-3 meningiomas was subjected to segmentation and deep learning classification of TSPO expression to either Iba1-positive tumor-associated macrophages (TAMs) or all other (mainly neoplastic) cells. A possible association between clinical data and TSPO expression intensities was also investigated. TAMs accounted for 15.9%-26% of all cells in the meningioma tissue. Mean fluorescence intensity of TSPO was significantly higher in TAMs (p < 0.0001), but the mass of neoplastic cells in the tumors exceeded that of TAMs. Thus, the summed fluorescence intensity of TSPO in meningioma cells was 64.1% higher than in TAMs (p = 0.0003). We observed no correlation between TSPO expression intensity and WHO grade. These results indicate that both macrophage-lineage and neoplastic cells in meningiomas express TSPO and that the SPECT-TSPO signal in meningiomas mainly reflects the latter; TSPO is expressed equally in parenchymal activated and resting macrophage/microglia lineage cells.

Gene expression analysis during progression of malignant meningioma compared to benign meningioma.

OBJECTIVE: Meningioma is the most common primary intracranial neoplasm. Only 1%-3% of meningiomas are malignant according to the 2016 WHO criteria (WHO grade III). High-grade meningiomas present specific gene expression signatures indicating aggressive growth or recurrence. However, changes in gene expression and in neuroinflammatory gene expression signatures in WHO grade III meningiomas and during progression from WHO grade I or II to grade III are unknown. METHODS: The authors used a NanoString targeted gene expression panel with focus on 787 genes relevant in meningioma pathology and neuroinflammatory pathways to investigate patients with grade III meningiomas treated at Rigshospitalet from 2000 to 2020 (n = 51). A temporal dimension was added to the investigation by including samples from patients' earlier grade I and II meningiomas and grade III recurrences (n = 139 meningiomas). The authors investigated changes in neuroinflammatory gene expression signatures in 1) grade I meningiomas that later transformed into grade III meningiomas, and 2) grade III meningiomas compared with nonrecurrent grade I meningiomas. RESULTS: The authors' data indicate that FOXM1, TOP2A, BIRC5, and MYBL2 were enriched and the HOTAIR regulatory pathway was enriched in grade III meningiomas compared with nonrecurrent grade I meningiomas. They discovered a separation of malignant and benign meningiomas based only on genes involved in microglia regulation with enrichment of P2RY12 in grade I compared with grade III meningiomas. Interestingly, FOXM1 was upregulated in premalignant grade I meningioma years before the grade III transformation. CONCLUSIONS: The authors found gene expression changes in low-grade meningiomas that predated histological transformation to grade III meningiomas. Neuroinflammation genes distinguished grade III from grade I meningiomas.

Limits and potential implementation of the present pN classification for oral squamous cell carcinoma.

PURPOSE OF REVIEW: The purpose of this review is to highlight the most important changes in the eighth TNM classification system for oral squamous cell carcinomas compared with the seventh edition with focus on lymph node staging (pN). Nodal involvement is crucial when addressing prediction of survival, and staging must mirror the disease extension. pN classification will be evaluated with respect to lymph node yield (LNY), lymph node density (LND), and a recently proposed classification: pN-N+ reflecting positive regional lymph nodes (metastatic burden) and extra nodal extension. RECENT FINDINGS: TNM8 was introduced in 2018, and the most noteworthy changes were depth of invasion (DOI) and extranodal extension (ENE). Recent studies indicate, that TNM8-related pN is not superior to TNM7 with respect to predicting survival. LNY and LND are biased with ecological interference fallacy, and currently not recommended in future iterations of TNM. In contrast, the pN-N+ classification has demonstrated improved survival prediction compared with TNM8. SUMMARY: The recent findings support the inclusion of pN-N+, that is, metastatic burden and extranodal extension in future iterations of TNM.

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions.

Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2-3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear - we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.

Intratympanic corticosteroid as salvage therapy in treatment of idiopathic sudden sensorineural hearing loss: A systematic review and meta-analysis.

BACKGROUND: The standard treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) constitutes of systemic oral corticosteroid. Although oral corticosteroid might revert the acute deafness, some patients with ISSNHL display a more treatment refractory course. For these patients, corticosteroid installed directly into the middle ear has become a more frequent treatment, due to the potential benefits of a high, local concentration compared to a systemic administration. As such, for patients being refractory to standard treatment, intratympanic injection of a high dosage of corticosteroid as salvage therapy may be beneficial. OBJECTIVES: To evaluate the efficacy of intratympanic corticosteroid (ITC) as a salvage treatment of ISSNHL. METHODS: A systematic literature search was performed in relevant databases. Both randomized trials and observational studies were considered for inclusion. The risk of bias was evaluated using the Cochrane risk of bias tool (randomized trials) or ROBINS-I tool (observational studies). Meta-analysis was performed to investigate the improvement of PTA (dB) and number of patients displaying recovery following salvage ITC injections. Occurrence of serious side effects was investigated. Finally, the certainty of the evidence was evaluated using the GRADE approach. RESULTS: Eleven relevant studies were identified (4 randomized trials and 7 observational studies). Both observational and randomized trials showed that salvage ITC significantly increased the number of patients displaying recovery. No serious adverse events were identified in any of the included studies. The certainty of evidence ranged from moderate to very low, due to risk of bias, imprecision, and heterogeneity. CONCLUSION: Collectively, our findings indicate that salvage ITC treatment may be a beneficial and safe treatment for patients with sudden hearing loss, who otherwise are refractory to standard treatment approaches. However, the evidence level indicates need for a cautious interpretation of especially the magnitude of effect and thus the extrapolation on how much the individual may improve from this treatment. Furthermore, it remains to be investigated whether treatment outcomes may vary across different patient groups presenting with ISSNHL. This potential variation in treatment response should be kept in mind, when counselling the patient. TRIAL REGISTRATION NUMBER: The protocol is registered in PROSPERO. Registration number: CRD42019130586.

Loss of H3K27me3 in WHO grade 3 meningioma.

Immunohistochemical quantification of H3K27me3 was reported to distinguish meningioma patients with an unfavorable prognosis but is not yet established as a prognostic biomarker within WHO grade 3 meningiomas. We studied H3K27me3 loss in a series of biopsies from primary and secondary malignant meningioma to validate its prognostic performance and describe if loss of H3K27me3 occurs during malignant transformation. Two observers quantified H3K27me3 status as "complete loss", < 50% and > 50% stained cells in 110 tumor samples from a population-based consecutive cohort of 40 WHO grade 3 meningioma patients. We found no difference in overall survival (OS) in patients with > 50% H3K27me3 retention compared to < 50% in the cohort of patients with WHO grade 3 meningioma (Wald test p = 0.5). H3K27me3 staining showed heterogeneity in full section tumor slides while staining of the Barr body and peri-necrotic cells complicated quantification further. H3K27me3 expression differed without a discernible pattern between biopsies from repeated surgeries of meningioma recurrences. In conclusion, our results were not compatible with a systematic pattern of immunohistochemical H3K27me3 loss being associated with OS or malignant transformation of meningiomas and did not support H3K27me3 loss as a useful immunohistochemical biomarker within grade 3 meningiomas due to staining-specific challenges in quantification.