Astrocytoma with high-grade features and MYBL1-MMP16 fusion.

Background: Gliomas represent the most common primary intraparenchymal brain tumors in adult and pediatric patients. Neuropathological work-up of these gliomas typically entails the determination of isocitrate dehydrogenase (IDH) mutational status, presence or absence of 1p/19q co-deletion, and O6 methylguanine-DNA methyl-transferase (MGMT) promoter methylation status. Case Description: We present here an unusual case of a posterior fossa tumor in a 51-year-old female, which was initially diagnosed as astrocytoma with some high-grade features that recurred, displaying even more aggressive features such as infiltration and increased proliferative activity. Both the initially resected and recurrent tumor revealed MYBL1-MMP16 fusion, which is much more commonly found in pediatric low-grade gliomas and, to our knowledge has not been described in the context of an adult glioma. Conclusion: The significance of MYBL1-MMP16 fusion in adult gliomas in relation to survival and likelihood of recurrence is, therefore, unknown and requires more extensive research.

Obstructive Hydrocephalus Due to Aggressive Posterior Fossa Tumor Exhibiting Histological Characteristics of Pilocytic Astrocytoma in Two Adult Neurofibromatosis Type 1 (NF1) Cases.

Neurofibromatosis type 1 (NF1) is an autosomal dominant syndrome caused by germline alteration of the NF1gene. Among various NF1-related manifestations, obstructive hydrocephalus especially in adult NF1 cases is less frequently found. We report two adult NF1 cases exhibiting obstructive hydrocephalus due to an aggressive posterior fossa tumor exhibiting pathological characteristics of pilocytic astrocytoma as NF1-related manifestations. In these two cases, we performed endoscopic third ventriculostomy (ETV) and tumor biopsy as an initial treatment. The initial pathological diagnosis of the tumor is conventional pilocytic astrocytoma. After biopsy both cases revealed rapid tumor growth, therefore, we performed tumor removal, chemotherapy, and radiation therapy during an aggressive clinical course. However, both cases revealed dismal prognosis due to the progression of the tumor in spite of successful management of hydrocephalus by an initial ETV. DNA methylation analysis revealed that the tumor of one case matched high-grade astrocytoma with piloid features (HGAP). Most central nervous system tumors developed in NF1 are less aggressive such as pilocytic astrocytoma; however, recently a few studies revealed that HGAP, which has been a newly introduced malignant tumor in the World Health Organization Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS 5), rarely develops in NF1 cases. These findings suggested that HGAP might be one of the important causes of obstructive hydrocephalus in adult NF1 cases.

Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences.

Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.

Leptomeningeal metastases and dural spread in adult high-grade astrocytomas.

Leptomeningeal (LM) metastases or dural spread by adult high-grade astrocytomas are problematic; it is unclear which tumor types are predisposed to spread and at what time intervals from original diagnosis. We reviewed our recent experience with these tumor types with LM or dural spread, all of which had assessments that allowed CNS World Health Organization, 5th Edition classification. Following a database search, 2018-present, 10 patients were identified: 4 glioblastomas, IDH-wildtype, WHO grade 4; 4 astrocytomas, IDH-mutant, WHO grade 4; 1 high-grade astrocytoma with piloid features (HGAP) proven by DNA methylation, and 1 high-grade astrocytic tumor that fell closest to the HGAP category by DNA methylation. Most had LM dissemination; 2 had dural spread. Intervals from initial tumor diagnosis to LM spread for 4 astrocytomas, IDH-mutant were 1, 6, 7, and 14 years. Two glioblastomas, IDH-wildtype had dural spread at the time of diagnosis; 1 had a 6-year interval to metastasis; and 1 had a 3-month interval to LM spread. The definite HGAP showed an interval of 7 years to metastasis and the possible HGAP had LM spread recognized at the time of initial diagnosis. All adult high-grade astrocytic tumor types are capable of LM or dural spread, including HGAP.

Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

The utility of DNA methylation analysis in elderly patients with pilocytic astrocytoma morphology.

PURPOSE: Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, a subset of PA patients shows unfavorable outcomes. In this study, we retrospectively reviewed PA patients and performed further molecular analysis, such as DNA methylation profiling, to identify prognostic factors. METHODS: We analyzed 29 histologically-confirmed PA patients from a single center from 2002 to 2021 and conducted integrated molecular analyses among elderly PA patients since age was an independent prognostic factor for poor outcomes. RESULTS: The median age at diagnosis was 14 years (range 3-82 years) and 4 patients (14%) were elderly (patients ≥ 60 years old). Age over 60 was associated with poor progression-free survival and overall survival. We performed DNA methylation analysis on 2 of the 4 elderly patients. Both cases were histologically diagnosed as PA, but DNA methylation profiling revealed one as high-grade astrocytoma with piloid features (all methylation class scores were below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score was over 0.5 in both v11b4 and v12.5), using the German Cancer Research Center methylation profiling classifiers and t-SNE analysis. CONCLUSIONS: Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, further molecular analysis and DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.

Circular RNA Sequencing Reveals Serum Exosome Circular RNA Panel for High-Grade Astrocytoma Diagnosis.

BACKGROUND: Although major advances have been made in the histopathological diagnosis of high-grade astrocytoma (HGA), methods for effective and noninvasive diagnosis remain largely unknown. Exosomes can cross the blood-brain barrier and are readily accessible in human biofluids, making them promising biomarkers for HGA. Circular RNAs (circRNAs) have potential as tumor biomarkers owing to their stability, conservation, and tissue specificity. However, the landscape and characteristics of exosome circRNAs in HGA remain to be studied. METHODS: CircRNA deep sequencing and bioinformatics approaches were used to generate a circRNA profiling database and analyze the features of HGA cell circRNAs and HGA cell-derived exosome circRNAs. Exosome circRNA expression in the serum and tissues of healthy individuals and patients with HGA was detected using reverse transcription-quantitative PCR. Additionally, the receiver operating characteristic curve and overall survival curves were analyzed. RESULTS: By investigating the characteristics of HGA cell-derived exosome circRNAs and HGA cell circRNAs, we observed that exosomes were more likely to enrich short-exon and suppressor circRNAs than HGA cells. Moreover, a serum exosome circRNA panel including hsa_circ_0075828, hsa_circ_0003828, and hsa_circ_0002976 could be used to screen for HGA, whereas a good prognosis panel comprised high concentrations of hsa_circ_0005019, hsa_circ_0000880, hsa_circ_0051680, and hsa_circ_0006365. CONCLUSIONS: This study revealed a comprehensive circRNA landscape in HGA exosomes and cells. The serum exosome circexosome circRNA panel and tissue circRNAs are potentially useful for HGA liquid biopsy and prognosis monitoring. Exosome circRNAs as novel targets should facilitate further biomarker discovery and aid in HGA diagnosis and therapy monitoring.

High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity.

PURPOSE: High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. METHODS: During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. RESULTS: Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. CONCLUSIONS: Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy.

＜Editors' Choice＞ Impact of maintenance of postoperative performance status on survival in elderly patients over 70 with high-grade astrocytoma.

This study aimed to identify the elderly generation with the worst prognoses for high-grade astrocytoma and find independent predictors of good outcomes. We conducted a retrospective analysis of 91 patients, ≥65 years old, with anaplastic astrocytoma or glioblastoma. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using log-rank test or multivariate Cox regression analysis. We included 21 (23%) and 70 (77%) patients aged 65-69 years and ≥70 years. In the two generations, significant differences were found in the Charlson comorbidity index, extent of resection, chemoradiotherapy (CRT) as adjuvant therapy, and radiation dose (all P < 0.05). The median PFS was 9.9 and 6.9 months in patients aged 65-69 and ≥70 years (P = 0.10). The median OS was 22.8 and 11.6 months in patients aged 65-69 and ≥70 years (P = 0.009). In the multivariate analyzes in patients ≥70 years, only postoperative Karnofsky performance status (KPS) scores ≥70 were significantly related to prolonged PFS (hazard ratio [HR]: 0.48, P = 0.04), and postoperative KPS, CRT as adjuvant therapy, and salvage therapy were significantly related to prolonged OS (HR: 0.45, P = 0.03, HR: 0.38, P = 0.002, and HR: 0.43, P = 0.01, respectively). In conclusion, in patients ≥70 with high-grade astrocytoma, OS was significantly shorter compared to those aged 65-69. Postoperative KPS score was significantly related to prolonged PFS and OS. Postoperative CRT and salvage therapy at recurrence may be effective in the selected elderly.

Clinicopathological characteristics of circumscribed high-grade astrocytomas with an unusual combination of BRAF V600E, ATRX, and CDKN2A/B alternations.

We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3-46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

Usefulness of [11C] Methionine PET in the Differentiation of Tumefactive Multiple Sclerosis from High Grade Astrocytoma.

Tumefactive multiple sclerosis (tumefactive MS) is an atypical variant of MS characterized by a large isolated demyelinating lesion. Because tumefactive MS mimics high grade astrocytoma clinically and radiologically, it is difficult to distinguish between the two using only traditional diagnostic modalities, such as routine magnetic resonance imaging. [11C] methionine positron emission tomography (MET PET) has been known as a useful diagnostic tool for glioma. However, it has not been established as a diagnostic tool for tumefactive MS yet. Therefore, the objective of this study was to evaluate the performance of MET PET in differentiating tumefactive MS from high grade astrocytoma. We studied patients with tumefactive MS [six patients (three men, three women), 7 lesions] and 77 patients with astrocytoma (World Health Organization grade II: 13 patients, grade III: 28 patients, and grade IV: 36 patients), and we compared MET uptake of tumefactive demyelinating lesions and astrocytoma. For MET PET analysis, Lesion/Normal region ratios (L/N ratios) were calculated and compared between tumefactive demyelinating lesions and astrocytoma. On MET PET, the L mean/N ratio of tumefactive MS was 1.18 ± 0.50, which was significantly lower than that of high-grade glioma (astrocytoma grade III: 1.95 ± 0.62, P = 0.006; grade IV: 2.35 ± 0.54, P <0.0001). The L maximum (L max)/N ratio of tumefactive demyelinating lesion was also significantly lower than that of high grade astrocytoma (tumefactive MS: 1.89 ± 0.55; astrocytoma grade III: 3.37 ± 1.36, P = 0.0232; astrocytoma grade IV: 4.35 ± 1.30, P <0.0001). In conclusion, MET PET can help differentiate tumefactive MS from high grade astrocytoma.

Supratentorial high-grade astrocytoma with leptomeningeal spread to the fourth ventricle: a lethal dissemination with dismal prognosis.

PURPOSE: Leptomeningeal spread to the fourth ventricle (LSFV) from supratentorial high-grade astrocytoma (HGA) is rarely investigated. The incidence and prognostic merit of LSFV were analyzed in this study. METHODS: A consecutive cohort of 175 patients with pathologically diagnosed HGA according to the 2016 WHO classification of brain tumors was enrolled. LSFV was defined as radiological occupation in the fourth ventricle at the moment of initial progression. Clinical, radiological, and pathological data were analyzed to explore the difference between HGA patients with and without LSFV. RESULTS: There were 18 of 175 (10.3%) HGAs confirmed with LSFV. The difference of survival rate between patients with LSFV or not was significant in both overall survival (OS) (14.5 vs. 24 months, P = 0.0007) and post progression survival (PPS) (6.0 vs. 11.5 months, P = 0.0004), while no significant difference was observed in time to progression (TTP) (8.5 months vs. 9.5 months P = 0.6795). In the Cox multivariate analysis, LSFV was confirmed as an independent prognostic risk factor for OS (HR 2.06, P = 0.010). LSFV was correlated with younger age (P = 0.044), ventricle infringement of primary tumor (P < 0.001) and higher Ki-67 index (P = 0.013) in further analysis, and the latter two have been validated in the Logistic regression analysis (OR 18.16, P = 0.006; OR 4.04, P = 0.012, respectively). CONCLUSION: LSFV was indicative of end-stage for supratentorial HGA patients, which shortened patients' PPS and OS instead of TTP. It's never too cautious to alert this lethal event when tumor harbored ventricle infringement and higher Ki-67 index in routine clinical course.

Evaluation of high-grade astrocytoma recurrence patterns after radiotherapy in the era of temozolomide: A single institution experience.

AIM: Evaluating the recurrence patterns of high-grade astrocytomas in patients who were treated with radiotherapy (RT) plus temozolomide (TMZ). BACKGROUND: The current literature suggests that reducing the margins added to the CTV does not significantly change the risk of recurrence and overall survival; thus, we decided to analyze our data and to examine the possibility of changing the adopted margins. MATERIALS AND METHODS: From February 2008 till September 2013, 55 patients were treated for high-grade astrocytomas, 20 patients who had been confirmed to have recurrence were selected for the present study. Post-operative MRI was superimposed on the planning CT images in order to correlate the anatomical structures with the treatment targets. Recurrences were defined according to the Response Assessment Criteria for Glioblastoma. The mean margins of the PTVinitial and PTVboost were 1.2 cm and 1.4 cm, respectively. The analysis of the percentage of the recurrence volume (Volrec) within the 100% isodose surface was based on the following criteria: (I) Central: >95% of the Volrec; (II) In-field: 81-95% of the Volrec; (III) Marginal: 20-80% of the Volrec; and (IV) Outside: <20% of the Volrec. RESULTS: Of the 20 patients, 13 presented with central recurrences, 3 with in-field recurrences, 2 with marginal recurrences and 2 with outside recurrences. Therefore, the lower Volrec within 100% of the prescribed dose was considered in the classification. CONCLUSIONS: Of the selected patients, 80% had ≥81-95% of the Volrec within 100% of the prescribed dose and predominantly had central or in-field recurrences. These results are comparable with those from the literature.

Gene expression microarray analysis reveals prognostic markers of survival in high grade astrocytomas.

OBJECTIVE: High grade astrocytoma (HGA) as an aggressive brain tumor, is always correlated with poor prognosis. In this paper, we aimed to explore the genetic prognostic biomarkers for HGA. METHODS: The genome-wide expression profile of 26 brain tumor samples obtained from 26 patients with HGA was downloaded from Gene Expression Omnibus. The risk genes for prognosis of HGA were identified and verified by the data in TCGA database. Protein-protein interaction (PPI) network of risk factor genes was constructed and significant module was screened. Function and pathway annotations were performed for risk genes and drug target genes were further analyzed. RESULTS: A total of 598 genes were identified as significant risk genes for prognosis, such as checkpoint kinase 1, potassium inwardly-rectifying channel, subfamily J, member 6, leukocyte receptor tyrosine kinase and uncharacterized LOC283887. All risk genes for prognosis of HGA were significantly enriched in cell cycle, mitotic as well as mitotic anaphase. While the genes in the network module mainly participated in functions such as cell cycle, mitotic cell cycle and cell cycle process. Moreover, the genes in the network module mainly participated in the pathways such as cell cycle and cell cycle, mitotic. Drug target analysis showed that seven genes were recorded in Drugbank database, and there were as many as 32 drug records of CHEK1. CONCLUSION: The prognostic effect of CHEK1 was validated based on the expression profile data of 615 low-grade glioma and glioblastoma samples. We proposed CHEK1 as prognostic biomarker for HGA. Our work might provide the candidate target for HGA therapy.

Cerebellar high-grade astrocytoma with IDH mutations in the elderly: A report of two cases.

Cerebellar high-grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH-mutated cerebellar high-grade glioma with unusual histological features and uncommon patient ages. One case was an 83-year-old man, whose tumor was predominantly composed of densely packed round-to-polygonal epithelioid cells. The other was a 75-year-old woman's high-grade astrocytoma characterized by cord-like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH-mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2-mutation. Although the number is limited, IDH-mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.

Vessel Morphologies of the Brain in Cytological Squash Preparations Are Useful for Intraoperative Diagnosis of High-Grade Astrocytomas.

OBJECTIVE: The aim of this study was to determine whether intraoperative cytological evaluation of squash preparations is of benefit for differentiating high-grade from low-grade astrocytomas. METHODS: Squash preparations of 42 astrocytomas were classified histologically according to the World Health Organization (WHO) 2007 classification system as grade II (n = 12), grade III (n = 11), and grade IV (n = 19) and were divided into 2 groups, namely a low-grade group (grade II) and a high-grade group (grades III and IV). The focus was on morphological cell and vessel characteristics, namely nuclear atypia, chromatin pattern, nuclear enlargement, variation in nuclear size, the presence of nucleoli, mitosis, tumor necrosis, cell density, multibranched vessels, and vascular dilatation, and these characteristics were compared between the low- and high-grade groups. RESULTS: Nuclear atypia, the presence of coarse chromatin, variations in nuclear size, and cell density ≥200 per high-power field were significantly more prevalent in high- than in low-grade astrocytomas (p = 0.0407, p < 0.01, p < 0.01, and p < 0.01, respectively). Vessels with > 3 branches and a mean vessel diameter ≥20 µm were more prevalent in high- than in low-grade astrocytomas (p < 0.01). CONCLUSION: Squash preparation cytology provides added benefit for the intraoperative identification of high-grade astrocytoma.

Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma.

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas.

Serial changes in lymphocyte subsets in patients with newly diagnosed high grade astrocytomas treated with standard radiation and temozolomide.

The immune system plays a significant role in cancer prevention and outcome. In high grade astrocytomas (HGA), severe lymphopenia is associated with shortened survival due to tumor progression. This study was performed to quantify serial changes in lymphocyte subsets in HGA following standard radiation (RT) and temozolomide (TMZ). Adults (KPS >60, HIV negative) with newly diagnosed HGA scheduled to receive concurrent RT and TMZ and adjuvant TMZ were eligible. Blood was collected before beginning concurrent RT/TMZ and at weeks 6, 10, 18, and 26, and 3 months after completing adjuvant TMZ. Lymphocyte subsets were analyzed by flow cytometry. Twenty patients (70% glioblastoma, median age 53, 50% male, 80% Caucasian) who enrolled from January 2014 to August 2014 were followed until April 2016. Baseline dexamethasone dose was 0.5 mg/day and 15% had absolute lymphocyte counts (ALC) <1000 cells/mm3 before starting RT/TMZ. However, 75% developed lymphopenia with ALC <1000 cells/mm3 after completion of RT/TMZ. NK cells, B cells and all T lymphocytes subsets dropped significantly after concurrent RT/TMZ and remained depressed for the 48 weeks of observation. The CD4+/CD8+ ratio was not affected significantly during follow-up. Severe lymphopenia involving all subsets occurred early in treatment and remained present for nearly 1 year. To our knowledge, this is the first report of serial trends in lymphocyte subsets following standard RT and TMZ for HGA.

A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. METHODS: Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. RESULTS: Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. CONCLUSIONS: The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population.