MET fusions and splicing variants in glioma: a landscape integrating clinical, pathological, and survival features.

BackgroundDiffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA).MethodsHematoxylin–eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data. Six G34-DHG patients from another organization were used as external validation.ResultsWES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months.ConclusionsOur results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs.

BACKGROUND Glioblastoma diagnostic criteria have been redefined with the 5th edition of WHO classification of tumors of the central nervous system. Glioblastomas are defined as IDH wildtype diffuse astrocytic glioma tumors with one of the following features: microvascular proliferation, or necrosis, or TERT promoter mutation, or EGFR gene amplification, or +7/-10 chromosome copy number changes. The aim of this study is to establish the impact of extent of resection in overall survival (OS) and progression free survival (PFS) in glioblastoma, IDH-wildtype (WT), WHO grade 4 (WHO 2021). METHODS Systematic literature search was performed using the following databases: PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and ClinicalTrials.gov to identify studies comparing OS and PFS after gross total resection (GTR) vs subtotal resection (STR) or biopsy for glioblastoma IDH-WT. Prognostic hazard ratios (HR) for OS and PFS were analyzed using a random-effects model. RESULTS We identified 1439 publications. Nine studies met inclusion/exclusion criteria. 788 patients underwent GTR out of 1818. The meta-analysis showed a significant increase in OS and PFS duration when undergoing GTR for glioblastoma IDH-WT with a median OS of 20 months 95% CI (17-25) compared to 12 months 95% CI (9-15) for STR or biopsy and a median PFS of 11 months 95% CI (9-12) for GTR compared to 7 months 95% CI (5-7) for STR or biopsy respectively. GTR showed a 49% significant reduction of mortality risk HR=0.51 95%CI (0.42-0.59) and a 44% significant reduction of progression risk HR=0.56 95%CI (0.41-0.71) compared to STR or biopsy. CONCLUSIONS This systematic review indicates that GTR may be associated with improved OS and PFS compared to STR or biopsy for Glioblastoma, IDH-WT, WHO grade 4 (WHO 2021). However, this is limited by variable study design and significant clinical and methodological heterogeneity among studies.

Astrocytoma cells characteristically possess high invasion potentials. Recent studies have revealed that knockdown of signal transducers and activators of transcription 3 (STAT3) expression by RNAi induces apoptosis in astrocytoma cell. Nevertheless, the distinct roles of STAT3 in astrocytoma’s invasion and recurrence have not been elucidated. In this study, we silenced STAT3 using Small interfering RNAs in two human glioblastoma multiforme (GBM) cell lines (U251 and U87), and investigated the effect on GBM cell adhesion and invasion. Our results demonstrate that disruption of STAT3 inhibits GBM cell’s adhesion and invasion. Knockdown of STAT3 significantly increased E-cadherin but decreased N-cadherin, vascular endothelial growth factor, matrix metalloproteinase 2 and matrix metalloproteinase 9. Additionally, expression of pSTAT3Tyr705 correlates with astrocytoma WHO classification, Karnofsky performance status scale score, tumor recurrence and survival. Furthmore, pSTAT3Tyr705 is a significant prognostic factor in astrocytoma. In conclusion, STAT3 may affect astrocytoma invasion, expression of pSTAT3Tyr705 is a significant prognostic factor in tumor recurrence and overall survival in astrocytoma patients. Therefore, STAT3 may provide a potential target for molecular therapy in human astrocytoma, and pSTAT3Tyr705could be an important biomarker for astrocytoma prognosis.

PURPOSE: Since its introduction, the RANO criteria have not been validated using outcome data from prospective trials. We examined the radiologic data of patients with recurrent glioblastoma treated with bevacizumab from the randomized phase II BRAIN trial (AVF3708g) to determine the effect of including T2/FLAIR evaluation in the RANO criteria on measurements of objective response rates (ORR) and progression free survival (PFS). METHODS: The imaging data of 163 patients with recurrent glioblastoma from the BRAIN trial were evaluated by 6 readers blinded to clinical information. The ORR and median PFS were determined using the RANO criteria and compared to those obtained using the Macdonald criteria. Landmark analyses were performed at 2, 4 and 6 months, and Cox proportional hazard models were used to determine the associations between OR and progression with subsequent survival. RESULTS: The ORRs were 0.331 (95% CI: 0.260 - 0.409) and 0.393 (95% CI: 0.317 - 0.472) by RANO and Macdonald criteria, respectively (p < 0.0001). The median PFS was 4.6 months (95% CI: 4.1-5.5) using RANO criteria, compared to 6.4 months (95% CI: 5.5-7.1) as determined by Macdonald criteria (p = 0.01). At 2-, 4-, and 6-month landmarks, both OR status and PFS determined by RANO criteria were predictive of overall survival (OS) (hazard ratios for 4-month landmark; OR HR= 1.93, p = 0.0012, PFS HR = 4.23, p < 0.0001). CONCLUSION: The inclusion of T2/FLAIR assessment in the RANO criteria results in moderate and statistically significant differences in median PFS and ORR. OR and PFS determined by RANO correlated with OS.

BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C&gt;T and c.818 G&gt;A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p&lt;0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p&lt;0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p&lt;0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

BACKGROUND: Infiltrating WHO grade II and III gliomas are devastating and difficult to treat neoplasms classified as astrocytoma (A2), oligodendroglioma (O2), oligoastrocytoma (OA2), or anaplastic astrocytoma (A3), oligodendroglioma (O3), and oligoastrocytoma (OA3). Anaplastic grade is critically dependent on the presence of mitoses (astrocytomas) or high mitotic activity (oligodendroglial tumors), with CDKN2A deletion considered the most common mechanism for associated cell cycle dysregulation. We therefore sought to determine if p16 loss by immunohistochemistry (IHC) or CDKN2A gene by fluorescence in situ hybridization (FISH) are associated with patient survival across histologic groupings after controlling for age, grade, and other molecular markers. METHODS: Adults (18 years of age) with infiltrating gliomas (grades II or III) were selected from the UCSF Adult Glioma Study (N = 157). The population consisted of 90 males (average age = 43.2) and 67 females (average age = 40.7). Isocitrate dehydrogenase (IDH) status (IDH1 and IDH2) was known for all cases. Histology and grade were as follows: 53 O2, 33 A2, 29 OA2, 20 O3, 15 A3, 7 OA3. CDKN2A FISH was performed using commercial probes and immunostains for p16 and MIB1 (Ki-67) were similarly performed using commercial antibodies. The end point for the analysis was overall survival, analyzed using Cox proportional hazards, stratified by tumor histology and with adjustment for sex, age, grade, and various tumor markers. A total of 61 events (deaths) were observed, and median follow-up time across all subjects was 6.4 years. RESULTS: After controlling for age, sex, and grade, CDKN2A deletion was associated with decreased survival in astrocytoma patients (P = 0.045; HR = 3.1; 95%CI = 1.03-9.2) but not in oligodendroglioma or oligoastrocytoma patients (P = 0.57 and P = 0.67, respectively). A strong inverse association between IDH mutation and CDKN2A deletion was observed in astrocytomas, and the association of CDKN2A deletion with survival was attenuated after controlling for IDH status (P = 0.34). Interestingly, CDKN2A loss was observed in 83% of IDH wild-type versus 33% of IDH-mutant astrocytomas (P = 0.029). CDKN2A loss was only weakly associated with decreased p16 expression (p = 0.09), and the p16 labeling index (LI) was not associated with outcome. There was also no clear association between CDKN2A deletion and MIB1 LI (P = 0.92). CONCLUSIONS: CDKN2A deletion by FISH is associated with shortened survival in astrocytoma patients, but not in patients with oligodendroglial tumors. The strong inverse association between IDH mutation and CDKN2A deletion suggests that CDKN2A status may have prognostic value in the clinical work-up of grade II and III astrocytoma patients. SECONDARY CATEGORY: n/a.

Introduction to 2021 WHO Classification of Thoracic Tumors

The authors aimed to explore the clinical outcomes and risk factors related to recurrence of and survival from solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) that were reclassified according to the 2021 WHO classification of central nervous system (CNS) tumors. The authors retrospectively collected and analyzed the clinical and pathological data of SFTs and HPCs recorded from January 2007 to December 2021. Two neuropathologists reassessed pathological slides and regraded specimens on the basis of the 2021 WHO classification. The prognostic factors related to progression-free survival (PFS) and overall survival (OS) were statistically assessed with univariate and multivariate Cox regression analyses. A total of 146 patients (74 men and 72 women, mean ± SD [range] age 46.1 ± 14.3 [3-78] years) were reviewed, and 86, 35, and 25 patients were reclassified as having grade 1, 2, and 3 SFTs on the basis of the 2021 WHO classification, respectively. The median PFS and OS of the patients with WHO grade 1 SFT were 105 months and 199 months after initial diagnosis; for patients with WHO grade 2 SFT, 77 months and 145 months; and for patients with WHO grade 3 SFT, 44 months and 112 months, respectively. Of the entire cohort, 61 patients experienced local recurrence and 31 died, of whom 27 (87.1%) died of SFT and relevant complications. Ten patients had extracranial metastasis. In multivariate Cox regression analysis, subtotal resection (STR) (HR 4.648, 95% CI 2.601-8.304, p < 0.001), tumor located in the parasagittal or parafalx region (HR 2.105, 95% CI 1.099-4.033, p = 0.025), tumor in the vertebrae (HR 3.352, 95% CI 1.228-9.148, p = 0.018), WHO grade 2 SFT (HR 2.579, 95% CI 1.343-4.953, p = 0.004), and WHO grade 3 SFT (HR 5.814, 95% CI 2.887-11.712, p < 0.001) were significantly associated with shortened PFS, whereas STR (HR 3.217, 95% CI 1.435-7.210, p = 0.005) and WHO grade 3 SFT (HR 3.433, 95% CI 1.324-8.901, p = 0.011) were significantly associated with shortened OS. In univariate analyses, patients who received adjuvant radiotherapy (RT) after STR had longer PFS than patients who did not receive RT. The 2021 WHO classification of CNS tumors better predicted malignancy with different pathological grades, and in particular WHO grade 3 SFT had worse prognosis. Gross-total resection (GTR) can significantly prolong PFS and OS and should serve as the most important treatment method. Adjuvant RT was helpful for patients who underwent STR but not for patients who underwent GTR.

Objective: To compare the prognostic impact of different extents of resection among patients with molecularly defined glioma subtypes. Methods: This retrospective cohort study included 1 191 glioma patients who underwent surgical treatment at Beijing Tiantan Hospital, Capital Medical University, between January 2011 and January 2021. The cohort comprised 692 males and 499 females, with an age of (44.5±11.9) years (range: 18 to 75 years). Tumors were classified according to the 2021 WHO Classification of Tumors of the Central Nervous System (5th edition), and the extent of resection was assessed using postoperative MRI. Kaplan-Meier survival analyses and log-rank tests were used to evaluate the effects of resection extent on progression-free survival (PFS) and overall survival (OS) within each molecular subtype. Cox proportional hazards models were applied to identify independent prognostic factors for PFS and OS. Follow-up was completed in January 2024. Results: Among the 1 191 patients, 291 cases (24.43%) had isocitrate dehydrogenase(IDH)-mutant and 1p/19q-codeleted oligodendroglioma (OG), 338 cases (28.38%) had IDH-mutant astrocytoma, and 562 cases (47.19%) had IDH-wild-type glioblastoma (GBM). Patients with IDH-mutant and 1p/19q-codeleted OG had the best prognosis, with median PFS time and median OS time not reached. In IDH-wild type GBM, the median PFS time and median OS time were 12.0 and 24.0 months, respectively; in IDH-mutant astrocytoma, the median PFS time and median OS time were 61.0 and 102.0 months. Differences in PFS and OS among the three groups were statistically significant (both P<0.01). In patients with IDH-wild type GBM, supratotal resection yielded better PFS and OS than gross total resection (both P<0.05). In IDH-mutant astrocytoma, PFS and OS did not differ between supratotal and gross total resection (both P>0.05), while gross total resection was superior to subtotal resection (both P<0.05). In IDH-mutant, 1p/19q-codeleted OG, PFS and OS did not differ significantly across resection categories (both P>0.05). Multivariate analyses identified age, Karnofsky performance status, extent of resection, tumor grade, and O6-methylguanine-DNA methyltransferase promoter methylation status as independent predictors of both PFS and OS (both P<0.05). Conclusions: For IDH-wild type GBM, maximal efforts should be made to achieve supratotal resection. For IDH-mutant astrocytoma, maximal safe resection is recommended with preservation of neurological function. For IDH-mutant, 1p/19q-codeleted oligodendroglioma, a relatively conservative approach may be appropriate to protect neurological function.

Reduced Plasmacytoid Dendritic Cell Output Is Associated With High Risk in Low-grade Myelodysplastic Syndrome.

OBJECTIVE Malignant meningioma is rare and classified as Grade III in the WHO classification of CNS tumors. However, the presence of estrogen receptor (ER) in WHO Grade III meningiomas and its correlation with patients' outcomes are still unclear. In this single-center cohort study, the authors analyzed clinical features, treatment, and prognosis of these malignant tumors in patients with long-term follow-up. METHODS A total of 87 patients who were pathologically diagnosed with WHO Grade III meningiomas between 2003 and 2008 were enrolled in this study and followed for at least 7 years. Clinical information was collected to analyze the factors determining the prognosis. RESULTS Twelve patients with rhabdoid, 12 with papillary, and 63 with anaplastic meningioma were included. The mean progression-free survival (PFS) and overall survival (OS) were 56.2 ± 49.8 months and 68.7 ± 47.4 months, respectively. No significant differences were observed among the 3 histological subtypes in either PFS (p = 0.929) or OS (p = 0.688). Patients who received gross-total resection had a longer PFS (p = 0.001) and OS (p = 0.027) than those who received subtotal resection. Adjuvant radiotherapy was associated with OS (p = 0.034) but not PFS (p = 0.433). Compared with primary meningiomas, patients with recurrent disease had worse PFS (p < 0.001). For patients who had malignant transformations, the prognosis was poorer than for patients without malignant transformations for both PFS (p = 0.002) and OS (p = 0.019). ER-positive patients had a significantly worse prognosis than ER-negative patients regarding both PFS (p = 0.003) and OS (p < 0.001), whereas no association between progesterone receptor and patients' outcomes was observed. Multivariate analysis demonstrated that ER expression was an independent prognostic factor for both PFS (p = 0.008) and OS (p < 0.001). CONCLUSIONS This retrospective study showed that patients with meningioma with ER-positive expression had a much worse prognosis than those with ER weak-positive or ER-negative status. The results demonstrated that ER is an independent prognostic factor for both PFS and OS of patients with WHO Grade III meningioma. The authors also found that more radical resection of the tumor, as well as postoperative radiotherapy, may prolong patients' survival time.

The purpose of this study was to analyze the clinical outcomes and malignant progression of tumors in patients who underwent reoperation for recurrent solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs). We identified 48 patients who underwent reoperation because of tumor recurrence at Tangdu Hospital between January 2010 and December 2021 and analyzed the clinical outcomes, namely, the rate of gross total resection (GTR), progression-free survival (PFS), overall survival (OS), malignant progression of tumors and radiotherapy. The survival curves for each group were plotted using the Kaplan‒Meier method and compared using log-rank tests. Of the 48 patients (25 men and 23 women, mean age 49.5 ± 14.3 years), 25 experienced a second recurrence or metastasis, 15 of whom underwent a third surgery, and the remaining 10 patients who did not undergo surgery ultimately died after tumor progression. The median time (95% CI) to tumor recurrence was 40.0 (32.3-47.7) months after reoperation, with 3-, 5- and 10-year PFS rates of 54.6%, 29.5% and 14.8%, respectively. The median (95% CI) survival time was 70.0 (46.6-93.4) months, with 3-, 5- and 10-year survival rates of 67.9%, 55.1% and 36.7%, respectively. Among the 48 patients who underwent reoperation, 27 (56.3%) achieved GTR, and 21 (43.8%) achieved STR. Twelve patients in the GTR group (12/27, 44.4%) received radiotherapy after surgery, and 18 patients in the STR group (18/21, 85.7%) received radiotherapy. Of the 48 recurrent SFTs, 24 were classified as WHO grade 1, 14 were classified as WHO grade 2, and 10 were classified as WHO grade 3 based on 2021 WHO classification after the primary operation. After reoperation, 9 tumors developed malignant progression, including 4 WHO grade 1 tumors progressing to WHO grade 2 tumors, 1 WHO grade 1 tumor progressing to a WHO grade 3 tumor and 4 WHO grade 2 tumors progressing to WHO grade 3 tumors. GTR after reoperation was associated with better PFS and OS compared to STR. However, the PFS after the third surgery was significantly shorter than that after the second surgery, and the rate of GTR also decreased. Malignant progression may occur after second or third tumor recurrence. Furthermore, compared with WHO grade 1 SFTs, WHO grade 2 and grade 3 SFTs significantly decreased PFS, but OS did not differ among the three groups. Radiotherapy did not prolong PFS or OS in patients who underwent reoperation.

Treatment Outcomes in the Management of Lymphoblastic Lymphoma (LBL) in Adults: An Institutional Review

Rituximab Added to CODOX-M/IVAC has No Clear Benefit Compared to CODOX-M/IVAC alone in Adult Patients with Burkitt Lymphoma.

2028 Background: Salvage treatment with bevacizumab (BEV) has been increasingly used in grade III AG, but limited data are available, with conflicting results reported. Because of differences in molecular characteristics, angiogenesis mechanisms, growth rate and chemosensitivity, results observed in glioblastoma (GBM) treated with BEV may not apply to AG, and may differ between anaplastic astrocytomas (AA) and oligodendrogliomas (AO). Methods: IRB approved retrospective review of all pts with recurrent WHO grade III AG treated with BEV at MSKCC. Response and progression were determined by RANO criteria. Results: BEV was given to 39 pts with recurrent grade III AG (AA: 26; AO: 10; anaplastic oligoastrocytoma [AOA]: 3); median (med) age: 49 (range 20-75); med KPS: 80 (60-100). MGMT promoter methylation was determined in 17 pts (methylated 8, unmethylated 9). Amongst AO/AOA, 1p/19q co-deletion was present in 6 and absent in 5. IDH1/ IDH2 mutations were present in 3/5 tested tumors. Med time from diagnosis of AG to BEV treatment was 11.5m (3 – 112.5). The med number of previous recurrences was 1 (range 1-4). BEV was given as single agent to 16 pts and combined with a cytotoxic agent in 23. Objective response rate (ORR) was 41% (complete response: 5; partial: 11). The med progression-free survival (PFS) was 4.8m (6-m PFS: 35% [95% CI 20-50]). The med overall survival (OS) was 11.5 m (1y-OS: 45% [95% CI 29-61]). In pts achieving ORR, med OS was 13 m vs 4 m in pts with stable/progressive disease (P=0.02). Pts at first recurrence fared better than pts with more than one recurrence (med PFS: 6 vs 3.4 months, P=0.04). AO/AOA tended to fare worse than AA (med PFS 3 vs 5.5 m, P=0.07). There were no differences in PFS (P=0.8) or OS (P=0.4) between single agent vs BEV + cytotoxic agent. Toxicity included one grade 4 brain hemorrhage. Conclusions: In this relatively large series, BEV was associated with higher ORR and PFS as compared to historical controls, although improvements in those endpoints were of a lower magnitude than in GBM. While ORR predicted OS, improvements in OS were not apparent; results in AO were particularly disappointing. The use of BEV in this population requires reappraisal in a randomized study with adequate stratification for histology and number of previous recurrences.