Radiotherapy for Recurrent Medulloblastoma in Children and Adolescents: Survival after Re-Irradiation and First-Time Irradiation.

BACKGROUND: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. METHODS: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. RESULTS: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7-28.7) vs. 12.0 (CI: 8.1-21.0) months] and OS [31.5 (CI: 27.6-64.8) vs. 20.0 (CI: 14.0-36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4-45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7-41.5) vs. 8.0 (CI: 6.6-12.2)/OS: 31.5 (CI: 27.6-NA) vs. 13.3 (CI: 8.1-20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8-60.6) vs. 6.6 (CI: 1.5-NA) months] and OS [40.2 (CI: 18.7-NA) vs. 12.4 (CI: 4.4-NA) months]. CONCLUSIONS: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival.

Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa - Results of the HIT 2000 trial.

BACKGROUND: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization and biology in pediatric survivors of a posterior fossa tumor. METHODS: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic (NBD) tool based on Cattell-Horn-Carroll's model for intelligence were analyzed. RESULTS: Cognitive performance 5.14 years (mean; range=1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had strong impact on most subtests. pCMS was associated with psychomotor abilities (ß=-0.25 to -0.16) and processing speed (ß=-0.32). Postoperative hydrocephalus correlated with crystallized intelligence (ß=-0.20) and short-term memory (ß=-0.15), age with crystallized intelligence (ß=0.15) and psychomotor abilities (ß=-0.16 and ß=-0.17). Scores for fluid intelligence (ß=-0.23), short-term memory (ß=-0.17) and visual processing (ß=-0.25) declined, and scores for selective attention improved (ß=0.29) with time after diagnosis. CONCLUSION: Dose of CSI was strongly associated with neurocognitive outcome. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI-dose and toxicity caused by other treatment modalities.

Adaption of neurosurgical resection patterns for pediatric low-grade glioma spanning two decades-Report from the German LGG-studies 1996-2018.

INTRODUCTION: Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. PATIENTS AND METHODS: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age. RESULTS: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. CONCLUSIONS: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

Imaging in malignant germ cell tumors involving the hypothalamo-neurohypophyseal axis: the evaluation of the posterior pituitary bright spot is essential.

PURPOSE: Malignant intracranial germ cell tumors (GCTs) are rare diseases in Western countries. They arise in midline structures and diagnosis is often delayed. We evaluated imaging characteristics and early tumor signs of suprasellar and bifocal GCT on MRI. METHODS: Patients with the diagnosis of a germinoma or non-germinomatous GCT (NGGCT) who received non-contrast sagittal T1WI on MRI pre-therapy were included. Loss of the posterior pituitary bright spot (PPBS), the expansion and size of the tumor, and the expansion and infiltration of surrounding structures were evaluated. Group comparison for histologies and localizations was performed. RESULTS: A total of 102 GCT patients (median age at diagnosis 12.3 years, range 4.4-33.8; 57 males; 67 in suprasellar localization) were enrolled in the study. In the suprasellar cohort, NGGCTs (n = 20) were noticeably larger than germinomas (n = 47; p < .001). Each tumor showed involvement of the posterior lobe or pituitary stalk. A PPBS loss (total n = 98) was observed for each localization and entity in more than 90% and was related to diabetes insipidus. Osseous infiltration was observed exclusively in suprasellar GCT (significantly more frequent in NGGCT; p = .004). Time between the first MRI and therapy start was significantly longer in the suprasellar cohort (p = .005), with an even greater delay in germinoma compared to NGGCT (p = .002). The longest interval to treatment had circumscribed suprasellar germinomas (median 312 days). CONCLUSION: A loss of the PPBS is a hint of tumor origin revealing small tumors in the neurohypophysis. Using this sign in children with diabetes insipidus avoids a delay in diagnosis.

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.

PURPOSE: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). METHODS: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. RESULTS: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. CONCLUSION: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.

Medulloblastoma in children with Fanconi anemia: Association with FA-D1/FA-N, SHH type and poor survival independent of treatment strategies.

BACKGROUND: Outcome of children with medulloblastoma (MB) and Fanconi Anemia (FA), an inherited DNA repair deficiency, has not been described systematically. Treatment is complicated by high vulnerability to treatment-associated side effects, yet structured data are lacking. This study aims at giving a comprehensive overview about clinical and molecular characteristics of pediatric FA MB patients. METHODS: Clinical data including detailed information on treatment and toxicities of six previously unreported FA MB patients were supplemented with data of 16 published cases. RESULTS: We identified 22 cases of children with FA and MB with clinical data available. All MBs with subgroup reporting were SHH-activated (n=9), confirmed by methylation profiling in five patients. FA MB patients exclusively belonged to complementation groups FA-D1 (n=16) or FA-N (n=3). Patients were treated with postoperative chemotherapy only (50%) or radiotherapy (RT)±chemotherapy (27%). 23% did not receive adjuvant therapy. Excessive treatment-related toxicities were frequent. Severe hematological toxicity occurred in 91% of patients treated with alkylating chemotherapy, while non-alkylating agents and RT were less toxic. Median overall survival (OS) was 1 year (95%CI 0.3-1.8). 1-year-progression-free-survival (PFS) was 26.3±10.1% and 1-year-OS was 42.1±11.3%. Adjuvant therapy prolonged survival (1y-OS/1y-PFS 0%/0% without adjuvant therapy vs. 53.3±12.9%/33.3±12.2% with adjuvant therapy, p=0.006/p=0.086). CONCLUSIONS: MB in FA patients is strongly associated with SHH activation and FA-D1/FA-N. Despite the dismal prognosis, adjuvant therapy may prolong survival. Non-alkylating chemotherapy and RT are feasible in selected patients with careful monitoring of toxicities and dose adjustments. Curative therapy for FA MB-SHH remains an unmet medical need.

L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial.

The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.

BACKGROUND: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS. CONCLUSION: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.

Methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" was recently defined based on methylation profiling and tSNE analysis of a series of 21 neuroepithelial tumors with predominant presence of a BCOR fusion and/or characteristic CNV breakpoints at chromosome 22q12.31 and chromosome Xp11.4. Clear diagnostic criteria are still missing for this tumor type, specially that BCOR/BCOR(L1)-fusion is not a consistent finding in these tumors despite being frequent and that none of the Heidelberger classifier versions is able to clearly identify these cases, in particular tumors with alternative fusions other than those involving BCOR, BCORL1, EP300 and CREBBP. In this study, we introduce a BCOR::CREBBP fusion in an adult patient with a right temporomediobasal tumor, for the first time in association with methylation class "CNS tumor with BCOR/BCOR(L1)-fusion" in addition to 35 cases of CNS neuroepithelial tumors with molecular and histopathological characteristics compatible with "CNS tumor with BCOR/BCOR(L1)-fusion" based on a comprehensive literature review and data mining in the repository of 23 published studies on neuroepithelial brain Tumors including 7207 samples of 6761 patients. Based on our index case and the 35 cases found in the literature, we suggest the archetypical histological and molecular features of "CNS tumor with BCOR/BCOR(L1)-fusion". We also present four adult diffuse glioma cases including GBM, IDH-Wildtype and Astrocytoma, IDH-Mutant with CREBBP fusions and describe the necessity of complementary molecular analysis in "CNS tumor with BCOR/BCOR(L1)-alterations for securing a final diagnosis.

Modulated critical currents of spin-transfer torque-induced resistance changes in NiCu/Cu multilayered nanowires.

We present a novel method combining anodic aluminum oxide template synthesis and nanolithography to selectively deposit vertically patterned magnetic nanowires on a Si substrate. With this approach we fabricated three-dimensional nanowire-based spin valve devices without the need of complex etching processes or additional spacer coating. Through this method, we successfully obtained NiCu/Cu multilayered nanowire arrays with a controlled sequence along the long axis of the nanowires. Both magnetic switching and excitation phenomena driven by spin-polarized currents were clearly demonstrated in our NiCu/Cu multilayered nanowires. Moreover, the critical currents for switching and excitation were observed to be modulated in an oscillatory manner by the magnetic field in the nanowire-based devices. We present a toy model to qualitatively explain these observations.

Treatment response as surrogate to predict risk for disease progression in pediatric medulloblastoma with persistent MRI lesions after first-line treatment.

BACKGROUND: This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma. METHODS: Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed MRI at the end of first-line therapy were analyzed. RESULTS: Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥25% reduction, MR/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5±7.0%[MR/PR] vs. 35.9±12.8%[SD], p=0.03; pptOS: 79.7±5.9[MR/PR] vs. 55.5±13.9[SD], p=0.04). Further, R+/M+ was associated with a higher risk for progression (5-year pptPFS: 22.9±17.9%[R+,M+] vs. 72.4±12.0%[R+,M0]; p=0.03). Watch-and-wait was pursued in 58 patients, while n=26 received additional treatments (chemotherapy only, n=19; surgery only, n=2; combined, n=3; valproic acid, n=2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5±7.7% vs. 51.6±10.7% p=0.71; 5-year pptOS: 76.3±6.9% vs. 69.8±9.7%, p=0.74). For the whole cohort, five-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0±35.4%, Group-4, 52.5±10.5, Group-3 54.2±13.8%; (p=0.08). CONCLUSION: Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in case of solitary persistent medulloblastoma MRI lesion, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information needs consideration for indication of additional treatments for persisting lesions.

Ependymoma from Benign to Highly Aggressive Diseases: A Review.

Ependymomas comprise biologically distinct tumor types with respect to age distribution, (epi)genetics, localization, and prognosis. Multimodal risk-stratification, including histopathological and molecular features, is essential in these biologically defined tumor types. Gross total resection (GTR), achieved with intraoperative monitoring and neuronavigation, and if necessary, second-look surgery, is the most effective treatment. Adjuvant radiation therapy is mandatory in high-risk tumors and in case of residual tumor. There is yet growing evidence that some ependymal tumors may be cured by surgery alone. To date, the role of chemotherapy is unclear and subject of current studies.Even though standard therapy can achieve reasonable survival rates for the majority of ependymoma patients, long-term follow-up still reveals a high probability of relapse in certain biological entities.With increasing knowledge of biologically distinct tumor types, risk-adapted adjuvant therapy gains importance. Beyond initial tumor control, and avoidance of therapy-induced morbidity for low-risk patients, intensified treatment for high-risk patients comprises another challenge. With identification of specific risk features regarding molecular alterations, targeted therapy may represent an option for individualized treatment modalities in the future.

Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma.

Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in patients with IDH-mutant astrocytomas confirmed by central pathology review. Patients were identified in the German Glioma Network cohort study; additional cohorts of patients with CNS WHO grade 4 tumors were identified retrospectively at two sites. In total, 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) were studied. The median age at diagnosis was similar for all grades. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p < 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was not reached for grade 2 (median follow-up 10.4 years), 8.1 years (95% CI 5.4-10.8) for grade 3, and 4.7 years (95% CI 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% CI 4.3-6.7) without (n = 58) versus 1.8 years (95% CI 0-4.1) with (n = 12) homozygous CDKN2A deletion. Lower levels of global DNA methylation as detected by LINE-1 methylation analysis were strongly associated with CNS WHO grade 4 (p < 0.001) and poor outcome. MGMT promoter methylation status was not prognostic for overall survival. Histomolecular stratification based on CNS WHO grade, LINE-1 methylation level, and CDKN2A status revealed four subgroups of patients with significantly different outcomes. In conclusion, CNS WHO grade, global DNA methylation status, and CDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors.

Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology.

Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically, cell density was associated with poor progression-free and overall survival (pPFS = 0.0026, pOS < 0.01). Molecularly, tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors and were significantly enriched in cell-dense tumor areas as shown by single-cell RNA (scRNA)-sequencing as well as copy number profiling and fluorescence in situ hybridization (FISH) analyses of different tumor areas. Finally, spatial transcriptomics revealed cell-dense areas of different tumors to be more similar than various different areas of the same tumor. High-density areas distinctly overexpressed genes encoding histone proteins, WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher proportion of cell-dense areas (p = 0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors. Our data suggest that PF-EPN-A ependymomas habor a previously unrecognized intratumoral heterogeneity with clinical implications, which has to be accounted for when selecting diagnostic material, inter alia, by histological evaluation of the proportion of cell-dense areas.

Radiation Therapy Plays an Important Role in the Treatment of Atypical Teratoid/Rhabdoid Tumors: Analysis of the EU-RHAB Cohorts and Their Precursors.

PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignancy of the central nervous system in young children with a dismal prognosis. Prognostic markers have been extensively investigated but have not been validated. The role of radiation therapy (RT) remains controversial. We evaluated the impact of RT as part of multimodality treatment by analyzing data of a European AT/RT cohort. METHODS AND MATERIALS: We retrospectively analyzed data of the European Registry for Rhabdoid Tumors and its precursors. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Potential impact of prognostic factors was analyzed using univariable and multivariable Cox regression analyses with RT as a time-dependent factor. RESULTS: Data of 186 children (118 male, 68 female) treated from 1990 to 2016 were evaluable. The median age at diagnosis was 1.57 years (range, 0.01-26.70 years); 47% (87/186) of the patients were under the age of 18 months. Sixty-nine percent (128/186) received RT (focal RT, n = 93; craniospinal treatment with local boost, n = 34; spinal irradiation, n = 1). The median follow-up duration of the entire cohort was 1.73 years (range, 0.06-20.11 years). The estimated PFS and OS rates were 48% (95% CI, 41%-55%) and 72% (95% CI, 65%-78%) at 1 year and 33% (95% CI, 26%-40%) and 49% (95% CI, 41%-56%) at 2 years, respectively. On multivariable analysis, RT was an independent significant prognostic factor for PFS (hazard ratio, 0.45; 95% CI, 0.27-0.75; P = .002) and OS (hazard ratio, 0.54; 95% CI, 0.32-0.93; P = .025). CONCLUSIONS: This analysis confirms the relevance of local therapies. RT was an independent prognostic factor for outcomes in children experiencing AT/RT. However, long-term sequelae have to be carefully evaluated and considered given the young age at time of RT.

Pineal anlage tumor: clinical and diagnostic features, and rationales for treatment.

PURPOSE: To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT). METHODS: Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases. RESULTS: Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports). Age at diagnosis ranged from 0.3 to 35.0 (median: 3.2 ± 7.8) years. All but three cases were diagnosed before the age of three years. For three cases, metastatic disease at initial staging was described. All patients underwent tumor surgery (gross-total resection: 9, subtotal resection/biopsy: 9, extent of resection unknown: 2). 15/20 patients were alive at last follow-up. Median follow-up for 10/15 surviving patients with available follow-up and treatment data was 2.4 years (0.3-6.5). Relapse was reported for 3 patients within 0.8 years after diagnosis. Five patients died, 3 after relapse and 2 from early postoperative complications. Two-year-progression-free- and -overall survival were 65.2 ± 12.7% and 49.2 ± 18.2%, respectively. All 4 patients who received intensive chemotherapy including high-dose chemotherapy combined with radiotherapy (2 focal, 2 craniospinal [CSI]) had no recurrence. Focal radiotherapy- and CSI-free survival rates in 13 evaluable patients were 46.2% (6/13) and 61.5% (8/13), respectively. CONCLUSION: PAT is an aggressive disease mostly affecting young children. Therefore, adjuvant therapy using intensive chemotherapy and considering radiotherapy appears to comprise an appropriate treatment strategy. Reporting further cases is crucial to evaluate distinct treatment strategies.

p16 Immunohistochemistry as a Screening Tool for Homozygous CDKN2A Deletions in CNS Tumors.

The 2021 World Health Organization classification of tumors of the central nervous system emphasizes the significance of molecular parameters for an integrated diagnosis. Homozygous deletion of cyclin-dependent kinase inhibitor 2a (CDKN2A) has been associated with an adverse prognosis in IDH -mutant gliomas, supratentorial ependymomas, meningiomas, and MPNST. In this study, we examined the value of p16 protein immunohistochemistry as a rapid and cost-effective screening tool for a homozygous CDKN2A deletion. Genetic analyses for CDKN2A in 30 pleomorphic xanthoastrocytomas, 32 IDH -wild-type high-grade gliomas, 40 supratentorial ependymomas with ZFTA-RELA gene fusion, 21 IDH-mutant astrocytomas, and 24 meningiomas were performed mainly by a molecular inversion probe assay, a high-resolution, quantitative technology for the assessment of chromosomal copy number alterations. Immunohistochemistry for p16 proved to have a high positive predictive value (range 90% to 100%) and an overall low negative predictive value (range 22% to 93%) for a homozygous CDKN2A deletion. In a setting where molecular testing is limited for cost and time reasons, p16 immunohistochemistry serves as a useful and rapid screening tool for identifying cases that should be subjected to further molecular testing for CDKN2A deletions.