The T1/T2 Ratio is Associated With Resectability in Patients With Isocitrate Dehydrogenase-Mutant Astrocytomas Central Nervous System World Health Organization Grades 2 and 3.

BACKGROUND AND OBJECTIVES: Isocitrate dehydrogenase (IDH)-mutant astrocytomas central nervous system World Health Organization grade 2 and 3 show heterogeneous appearance on MRI. In the premolecular era, the discrepancy between T1 hypointense and T2 hyperintense tumor volume in absolute values has been proposed as a marker for diffuse tumor growth. We set out to investigate if a ratio of T1 to T2 tumor volume (T1/T2 ratio) is associated with resectability and overall survival (OS) in patients with IDH-mutant astrocytomas. METHODS: Patient data from 2 centers (Sahlgrenska University Hospital, Center A; LMU University Hospital, Center B) were collected retrospectively. Inclusion criteria were as follows: pre and postoperative MRI scans available for volumetric analysis (I), diagnosis of an IDH-mutant astrocytoma between 2003 and 2021 (II), and tumor resection at initial diagnosis (III). Tumor volumes were manually segmented. The T1/T2 ratio was calculated and correlated with extent of resection, residual T2 tumor volume, and OS. RESULTS: The study comprised 134 patients with 65 patients included from Center A and 69 patients from Center B. The median OS was 134 months and did not differ between the cohorts (P = .29). Overall, the median T1/T2 ratio was 0.79 (range 0.15-1.0). Tumors displaying a T1/T2 ratio of 0.33 or lower showed significantly larger residual tumor volumes postoperatively (median 17.9 cm3 vs 4.6 cm3, P = .03). The median extent of resection in these patients was 65% vs 90% (P = .03). The ratio itself did not correlate with OS. In multivariable analyses, larger postoperative tumor volumes were associated with shorter survival times (hazard ratio 1.02, 95% CI 1.01-1.03, P < .01). CONCLUSION: The T1/T2 ratio might be a good indicator for diffuse tumor growth on MRI and is associated with resectability in patients with IDH-mutant astrocytoma. This ratio might aid to identify patients in which an oncologically relevant tumor volume reduction cannot be safely achieved.

Refinement of prognostication for IDH-mutant astrocytomas using DNA methylation-based classification.

The 2021 World Health Organization (WHO) grading system of isocitrate dehydrogenase (IDH)-mutant astrocytomas relies on histological features and the presence of homozygous deletion of the cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A/B). DNA methylation profiling has become highly relevant in the diagnosis of central nervous system (CNS) tumors including gliomas, and it has been incorporated into routine clinical diagnostics in some countries. In this study, we, therefore, examined the value of DNA methylation-based classification for prognostication of patients with IDH-mutant astrocytomas. We analyzed histopathological diagnoses, genome-wide DNA methylation array data, and chromosomal copy number alteration profiles from a cohort of 385 adult-type IDH-mutant astrocytomas, including a local cohort of 127 cases and 258 cases from public repositories. Prognosis based on WHO 2021 CNS criteria (histological grade and CDKN2A/B homozygous deletion status), other relevant chromosomal/gene alterations in IDH-mutant astrocytomas and DNA methylation-based subclassification according to the molecular neuropathology classifier were assessed. We demonstrate that DNA methylation-based classification of IDH-mutant astrocytomas can be used to predict outcome of the patients equally well as WHO 2021 CNS criteria. In addition, methylation-based subclassification enabled the identification of IDH-mutant astrocytoma patients with poor survival among patients with grade 3 tumors and patients with grade 4 tumors with a more favorable outcome. In conclusion, DNA methylation-based subclassification adds prognostic information for IDH-mutant astrocytomas that can further refine the current WHO 2021 grading scheme for these patients.

The clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas.

OBJECTIVES: Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria. METHODS: Using a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time. RESULTS: In total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347). CONCLUSION: Subtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in glioblastoma, did not affect survival. Group sizes were, however, too small to draw any firm conclusions.

Meningioma classification by immunohistochemistry: A replicability study.

Introduction: Meningiomas account for nearly 40% of intracranial tumors. Recently, the immunohistochemistry (IHC) markers S100B, SCGN, ACADL and MCM2 have been shown to be associated with underlying biological subtypes of meningioma (MG1-MG4). We aimed to evaluate these IHC markers in a clinical setting. Research question: Are the new proposed IHC markers clinically useful? Methods: In total, 244 patients with meningiomas with tissue in TMAs were included and the IHC markers S100B, SCGN, ACADL and MCM2 were analyzed. Two sets of analyses were performed; the first included all samples with any staining considered positive, the second only samples with >10% immunopositivity. PFS and OS were analyzed in correlation to immunopositivity in the second analysis set. Results: In the first set of analyses only 26.2% of samples could be to allocate to one group. No further analyses were performed with this selection. In the second set of analyses 52.0% could be allocated to a group. There was an enrichment of WHO grade 2 and 3 tumors in MG3 and MG4 as compared to MG1 (24.1% and 25.7% vs. 12.1%). Both the molecular group (p â€‹= â€‹0.032) and WHO grade (p â€‹= â€‹0.005) had significant impact on PFS, but only WHO grade predicted OS (p â€‹= â€‹0.033). Conclusion: We studied the proposed new method of classifying meningiomas into groups MG1, MG2, MG3 and MG4 using IHC markers, but found difficulties applying the classification system in our material mainly due to lack of exclusivity of markers. Thus, in its present form the classification method lacks clinical applicability.

Taxonomic notes and key to the West Palearctic Antocha (Antocha) Osten Sacken, 1860 (Diptera, Limoniidae) with description of a new species from Morocco.

Background: The Mediterranean Region of the West Palearctic is one of the most species-rich biomes in the world, hosting a high level of endemism and relict species with important conservation value. The North Africa Atlas Mountains (spanning Morocco, Algeria and Tunisia) belong to a poorly-investigated region of the Mediterranean area, with overlooked aquatic biodiversity; hence, a number of species still remain to be discovered. New information: The subgenus Antocha (Antocha) Osten Sacken, 1860 is recorded for the first time from Africa, with a description of A. (A.) staryi Keresztes & Mabrouki sp. nov. from hilly regions of the Middle Atlas region, Morocco. The unique design of the male terminalia differentiates well the newly-discovered species from its closely-related and range-restricted A. (A.) phoenicia Thomas and Dia, 1982. This is in contrast with the high intraspecific and geographically poorly-defined variability of the widespread A. (A.) vitripennis (Meigen, 1830), for which morphological variability of male genital structures is discussed.Illustrations of male genital parts, distribution data and key to the species from the West Palearctic area are also provided.

Changes in clinical management of diffuse IDH-mutated lower-grade gliomas: patterns of care in a 15-year period.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutated diffuse lower-grade gliomas (dLGG) are infiltrating brain tumors and increasing evidence is in favor of early multimodal treatment. In a Scandinavian population-based setting, we wanted to study treatment patterns over the last 15 years, focusing on the short-term postoperative course to better understand the potential negative consequences of treatment. METHODS: Patients ≥ 18 years with primary IDH-mutated dLGG grade 2 and 3, operated between January 2007-June 2021 were identified. Patients were divided into subgroups (2007-2011, 2012-2016, and 2017-2021) and comparisons regarding tumor- and disease characteristics, treatment, and postoperative outcome were performed. RESULTS: We identified 202 patients (n = 61, 2007-2011; n = 72, 2012-2016; n = 69, 2017-2021), where of 193 underwent resection without change in proportion of resections over time. More patients underwent complete resections in recent times (6.1%; 15.7%; 26.1%, respectively; p = 0.016). Forty-two patients had any neurological deficit postoperatively (14.8%; 23.6%; 23.2%; p = 0.379), mostly minor and transient. Differences in oncological therapy were seen between the investigated subgroups. Early radiotherapy alone (32.8%; 7%; 2.9%; p < 0.001), concomitant chemoradiotherapy (23%; 37.5%; 17.4%; p = 0.022), sequential chemoradiotherapy (0%; 18%; 49.3%; p < 0.001), and no adjuvant treatment (42.6%; 23.6%; 18.8%; p = 0.009) shifted during the studied period. Increasingly more patients received proton radiotherapy compared to photon radiotherapy during the later time periods (p < 0.001). CONCLUSION: Complete resections were performed more often in later time periods without an apparent increase in surgical morbidity. Early adjuvant oncological treatment shifted towards providing chemotherapy and combined chemoradiotherapy more often in later time periods. Protons replaced photons as the radiation modality of choice.

Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study.

Background: The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied. Methods: We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grades 2-3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results: Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42). Conclusions: We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.

WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas.

BACKGROUND: While molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting. MATERIAL AND METHODS: A total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed. RESULTS: There was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01-1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00-1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00-1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01-1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08). CONCLUSION: Our findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

The proportion of diploid 46,XX cells increases with time in women with Turner syndrome--a 10-year follow-up study.

In the normal population, loss of one of the sex chromosomes leading to monosomy (45,X) is a part of the aging process. In Turner syndrome (TS), the classic karyotype 45,X is found in up to 50% at birth, and others have a second cell line; mosaicism. The aim was to study if the chromosomal pattern in TS women changes over time. Fluorescence in situ hybridization was performed on buccal smear cells obtained twice, 10 years apart, from 42 women with TS aged 26-66 years (mean±standard deviation: 42.0±11.6). DNA probes specific for chromosomes X (DXZ1) and Y (DYZ3) were used and >100 cells were analyzed/patient. Nineteen women had monosomy (45,X) (<10% 46,XX), nine had 45,X/46,XX mosaicism, and 14 had iso, ring, or a marker chromosome at baseline. At 10 years, the percentage of diploid cells had increased in 29 of 42 women (69%), with an average increase of 5.7±13.0%. There was a positive correlation between age and % change in diploid 46,XX or 46,XY cells (r=0.38, p=0.023). This new finding might have relevance for the life expectancy in TS.