High-grade Astrocytomas Research Articles

A 25-year-female with Diffuse Intrinsic Pontine Glioma Surviving for More than Nine Years Following Treatment with Antineoplastons

Rationale: Diffuse intrinsic pontine glioma (DIPG) is a lethal brain tumor and leading cause of brain tumor–related death in children. Over the past few decades, clinical trials have shown no improvement in outcome. Most DIPGs occur in the pediatric population. Adult brainstem gliomas are rare, constitute less than 2% of adult gliomas, and show a slight male predominance. The case of this 25-year-old female is presented to detail and discuss the use of Antineoplastons A10 (Atengenal) and AS2-1 (Astugenal) in the treatment of DIPG that persisted despite radiation therapy (RT) and temozolomide. Objectives: The patient described was treated at the Burzynski Clinic (BC), as a special exception, according to the phase II protocol, BT-09, which utilized Antineoplastons A10 and AS2-1 (ANP therapy) in the treatment of brain tumors. The delivery of ANP therapy was via a subclavian catheter and infusion pump. Tumor response to therapy was measured by sequential magnetic resonance imaging (MRI) of the brain. Overall Survival (OS) and Adverse Events (AES) were also documented. Findings: At her presentation to the BC, the patient complained of diplopia, left-sided weakness, and difficulty walking. On physical exam, she was alert and orientated. Her cranial nerves were intact. There was weakness of the left-sided extremities. Deep tendon reflexes were equal bilaterally with down-going toes bilaterally. Reports of the original brain MRIs in Argentina suggested a DIPG with extension to the medulla and cerebellum. In addition, tumor biopsy confirmed a grade 3 astrocytoma. Following radiation therapy (RT) and temozolomide in Argentina, the patient was treated at BC for persistent disease with ANP therapy. Sequential MRI imaging of the residual tumor, which was non-enhancing, showed no change in size during therapy. However, the patient did achieve resolution of her neurologic signs and symptoms and has survived more than nine years since first being seen at BC. Correspondence with the patient on September 9, 2021 indicated she was feeling fine, had a healthy child, and was enjoying life. Conclusions: We have presented here the case of an adult female with a DIPG who had resolution of signs and symptoms and survived more than nine years after ANP therapy. For patients with DIPG (or other high-grade astrocytoma), who do not qualify for/refuse RT or show persistent or progressive disease following RT and/or chemotherapy, ANP therapy is an effective therapeutic option. In collaboration with the FDA confirmatory Phase II and Phase III studies have been developed.

Spinal intramedullary tumors

Intramedullary spinal cord tumors constitute an uncommon group of central nervous system neoplasms which pose considerable diagnostic and management challenges. Often low grade, these tumors have an insidious onset and slow progression, which makes early diagnosis a challenge. Advances in magnetic resonance imaging technology have greatly aided the diagnosis and preoperative planning of intramedullary tumors. Yet, radiological diagnosis can be difficult in the presence of several tumor mimics. The introduction and advancement of microsurgical techniques have made surgery the preferred treatment modality. Timing of intervention, however, is contentious. Eloquence of the surrounding tissue and the unforgiving nature of the spinal cord adds to the surgical challenge. Their treatment and prognosis is largely dependent on tumor histology and patient functionality. Well-demarcated tumors like ependymomas and hemangioblastomas can be resected completely with good outcome. Infiltrative tumors such as high-grade astrocytomas are best managed with biopsies or limited resections. Postoperative deficits can be crippling and the use of intraoperative neurophysiologic monitoring and other adjuncts is mandatory. Subtotal resection carry a high risk of recurrence and gross total resection carries a high risk of operative morbidity. With the availability of newer imaging modalities and intraoperative adjuncts, the earlier pessimistic conservative approach has been replaced by an aggressive surgical approach. This review provides an overview on the entire spectra of spinal intramedullary tumors with particular focus on management strategies.

IDH-mutant astrocytoma with EGFR amplification-Genomic profiling in four cases and review of literature.

Abstract EGFR amplification is associated with aggressive glioma behavior and regarded as a molecular feature of glioblastoma. Although rare, IDH-mutant astrocytomas with EGFR amplification exist but remain poorly understood. We report the clinical and molecular profile of four grade 4 IDH-mutant astrocytomas with EGFR amplification, evaluated using histology, DNA sequencing, cytogenetics, and DNA methylation profiling. Other alterations included ATRX, TP53, and PIK3CA mutations; CDKN2A/B loss; PDGFRA+KIT amplifications; and MGMT methylation in two cases. None disclosed microsatellite instability. DNA methylation confidently classified all tumors as “IDH-mutant High-Grade Astrocytoma” (0.99 0.997, 0.98, and 0.99 scores), despite their EGFR-amplified status. Literature review indicated EGFR amplification occurs within 8-19% of IDH-mutant gliomas, with significantly lower overall survival only in the co-presence of CDKN2A/B loss and MET amplification. Our report suggests IDH-mutant astrocytomas with EGFR amplification are under-recognized and that EGFR amplification status alone does not carry diagnostic or prognostic significance in these tumors.

STMO-17 Treatment outcome of photodynamic therapy using talaporfin sodium for recurrent high-grade glioma

Objective: Photodynamic therapy (PDT) using Talaporfin Sodium (TS) is a novel therapeutic strategy to improve local tumor control in high-grade glioma. TS is a photosensitizer that accumulates in tumor cells and produces highly toxic free radicals by intraoperative irradiation of laser with a 664nm wavelength. However, little is known about the treatment outcomes of PDT in recurrent high-grade gliomas (rHGG). In this study, we investigated the treatment outcome of PDT in rHGG and evaluated the correlation between intratumoral TS accumulation and outcomes. Methods: We included 21 patients with rHGG and 22 tumors, who were treated by PDT between June 2016 and March 2021. TS was transvenously administered 22–26 hours before PDT. Intratumoral TS concentrations were measured by liquid chromatography using frozen tissue. Results: The rHGGs included 10 glioblastoma, IDH1/2-wildtype (GBM, IDH1/2-WT: 45.5%), 3 GBM, IDH1/2-mutant (GBM, IDH1/2-Mut: 13.6%), 7 anaplastic oligodendroglioma, IDH1/2-Mut/codel (AO, IDH1/2-Mut/codel: 31.8%), 1 anaplastic astrocytoma, IDH1/2-WT (AA, IDH1/2-WT: 4.5%), 1 high-grade astrocytoma, IDH1/2-WT (4.5%). The median local progression free survival (PFS) time after PDT was 3.6 months and the median survival time from PDT was 19.4 months. The intratumoral TS concentrations of 7 tumors (TS(-): 31.8%) were below the limit of quantification, and the intratumoral TS concentrations of the remaining 15 tumors (TS(+)) were 43.5 ng/mg-protein (14.7–132 ng/mg-protein). The intratumoral TS concentrations were not significantly associated with IDH1/2 mutation status, cellularity, tumor grade, and pattern of enhancement. The median PFS from PDT tended to be longer in TS(+) than in TS(-) (TS(+): 6.3 vs TS(-): 1.4 months, p = 0.054). Conclusions: We found that the intratumoral TS concentrations were heterogeneous and 31.8% were below the limit of quantification. TS(+) tended to have better local tumor control than TS(-), suggesting the intratumoral TS accumulation have an impact of treatment outcomes of PDT.

Automated Early Detection of Astrocytomas Tumor Based on Optimized Adaptive Cluster with Super Pixel Model

In the medical image-processing field brain tumor segmentation is aquintessential task. Thereby early diagnosis gives us a chance of increasing survival rate. It will be way much complex and time consuming when comes to processing large amount of MRI images manually, so for that we need an automatic way of brain tumor image segmentation process. This paper aims to gives a comparative study of brain tumor segmentation, which are MRI-based. So recent methods of automatic segmentation along with advanced techniques gives us an improved result and can solve issue better than any other methods. Therefore, this paper brings comparative analysis of three models such as Deformable model of Fuzzy C-Mean clustering (DMFCM), Adaptive Cluster with Super Pixel Segmentation (ACSP) and Grey Wolf Optimization based ACSP (GWO_ACSP) and these are tested on CANCER IMAGE ACHRCHIEVE which is a preparation information base containing High Grade and Low-Grade astrocytoma tumors. Here boundaries including Accuracy, Dice coefficient, Jaccard score and MCC are assessed and along these lines produce the outcomes. From this examination the test consequences of Grey Wolf Optimization based ACSP (GWO_ACSP) gives better answer for mind tumor division issue.

NCOG-46. WHITE MATTER TRACT INVOLVEMENT BY INTRA-AXIAL BRAIN TUMORS; DIAGNOSTIC & THERAPEUTIC IMPLICATIONS

Abstract Diffusion tensor imaging (DTI) is a relatively recent modality which aids in visualization of WMT and their relation to intracranial lesions. Despite almost two decades since the beginning of its use in tumor resection, there is still dearth of data on its diagnostic and prognostic value from low- and middle-income countries. We aimed to assess the pattern of involvement of white matter tracts (WMT) by intra-axial brain tumors on DTI. Secondary objectives were to evaluate implications of involvement of WMT on surgical resection, and post-operative functional outcome. This was a retrospective study of 77 consecutive patients, who underwent DTI guided surgery for brain tumors. The involvement of WMT by tumors on DTI was assessed by a radiologist (who was blind to the pathology) using the Witwer classification. The pathology was reported by histopathologists using WHO brain tumor classification. Karnofsky Performance Scale (KPS) was used for assessing patients’ neurological status at admission, and at follow-up. Forty-five (58.4%) out of 77 tumors reviewed, caused infiltration of WMT, whereas only 22 (28.6%) tumors caused displacement of WMT (p = 0.040). Among 32 cases of astrocytoma, involvement of WMTs was influenced by the grade of tumor (p = 0.012), as high-grade tumors caused infiltration (19; 59.4%), unlike low grade tumors which commonly caused displacement (2; 50%). Oligodendroglioma caused infiltration/disruption of WMTs in most cases, irrespective of the grade (19 out of 25 cases; 76%). At last follow-up, 27 (35.1%) patients showed improvement in KPS and 14 (18.2%) reported deterioration, while there was no change observed in 36 (46.8%) patients. Infiltration of WMTs was associated with poor functional outcome. We conclude that intra-axial brain tumors mostly cause infiltration of WMTs, particularly high-grade astrocytoma, and oligodendroglioma of any grade. Infiltration of WMTs is associated with poor functional outcome at follow-up.

NECESSITY FOR A CUSTOMIZED NGS PANEL FOR ACCURATE DIAGNOSIS AND TARGETED THERAPIES IN PEDIATRIC GLIAL TUMORS

Pediatric glial tumors comprise wide range pathologies which may mimic histomorphological features of each other's but generally have very diverse disease course. WHO Classification of Tumors of Central Nervous System (2016 and 2021) points to the necessity of investigating several molecular alterations for integrated pathological diagnosis of childhood CNS tumors. This makes customized next-generation sequencing (NGS) a powerful tool for the diagnosis of childhood CNS tumors. Acıbadem Molecular Pathology Brain Tumor NGS Panel was designed according to targeted deep RNA and DNA sequencing. RNA and DNA were isolated from paraffin blocks containing more than 50% tumor in 45 cases with childhood CNS tumors. Miniseq Sequencıng System, Illumına and Archer Analysıs Ver 6.0.3.2 platforms were used. Fusions (translocations), mutations, and DNA copy number changes in 81 genes were screened for the most common molecular alterations in CNS tumors. Fourty-five childhood CNS tumors were evaluated with NGS results. Among these there were 19 pilocytic astrocytomas, 1 case of high grade astrocytoma with piloid features, 4 diffuse leptomeningeal glioneuronal tumors, 1 pleomorphic xanthoastrocytoma, 4 pediatric diffuse glial tumors, 1 infantile hemispheric astrocytoma, 1 astroblastoma, 12 diffuse midline glioma. Sixteen of these tumors were able to be diagnosed based on these molecular findings. Thirty-four cases received targeted therapies. The customized NGS panel, as a single molecular workflow is very helpful and supportive in diagnosis for CNS childhood tumors. Since the number of driver mutations are few in childhood tumors, detection of the driver molecular alteration is guiding the medical treatment startegy in terms of targeted regimens.

Second Cancer Risk in Childhood Cancer Survivors Treated with Intensity-Modulated Radiation Therapy (IMRT): An Updated Analysis of More Than 10 Years of Follow-Up

It is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in pediatric patients. A preliminary report from our institution published in 2015 by Casey et al. demonstrated a 10-year cumulative incidence (CI) of 3.3%, which we sought to update with now a median follow-up of over 10 years.Pediatric patients < = 21 years of age treated with IMRT at our institution between December 1998 and February 2009 and who survived with follow-up data > = 5 years after IMRT were included. The total dose of IMRT to any field was calculated and adjusted for contribution of conventional radiotherapy. Exposure to chemotherapy was recorded and noted if exposed to alkylating agents, anthracyclines, and/or epidodophyllotoxins. Treatment plans were evaluated to assess whether SMNs occurred within the treatment field. CI estimates of all SMN and second solid malignancies were calculated using the CI method of competing risks with death considered a competing event.A total of 326 patients were included with a median follow-up of 11 years from IMRT initiation (IQR, 8.6-14.0). The most common primary diagnosis was soft tissue sarcoma (n = 109, 33.4%) followed by neuroblastoma (n = 64, 19.6%). Most (n = 282, 86.5%) received chemotherapy. Most (n = 200, 61.3%) patients had > 10 years of follow-up and 285 (87.4%) patients were alive at the time of this analysis. At a median time of 8.2 years from IMRT (range, 3.2-19.2), 17 developed SMNs (11 solid, 6 hematologic) with a 10-year and 15-year CI of 1.8% (95% confidence interval [CI] 0.8-4.3) and 3.6% (95% CI 1.5-8.3), respectively. Six of these patients (35.3%) are still alive. Of the 11 solid SMNs, most (7, 63.6%) had received IMRT to the head and neck, 3 to the CNS, and 1 to the abdomen/pelvis. The mean and median doses to the IMRT field were 5360cGy (standard deviation, 2433) and 5580cGy (range, 2100-9640), respectively. Median time to solid SMN was 11.0 years (range, 6.8-19.2) and cancers included 2 colon adenocarcinomas, 3 osteosarcomas, 1 high grade astrocytoma, 2 glioblastomas, 1 papillary thyroid cancer, 1 widely metastatic cancer of unknown primary, and 1 presumed soft tissue sarcoma. 2 patients with SMNs had hereditary retinoblastoma. 5 solid SMNs developed within the 100% isodose line (IDL) of the IMRT field, 1 within 80% IDL, 1 within 50% IDL, and 1 within 40% IDL. A colon cancer is estimated to have developed within the 70-80% IDL of the conventional posteroanterior field as part of craniospinal irradiation. The papillary thyroid carcinoma was out of the IMRT field. The metastatic cancer of unknown primary could not be categorized or attributable to IMRT.With a median follow-up of 11 years, there was an increased CI of solid SMNs after IMRT in childhood cancer survivors. SMNs developed both in and out of the high dose region. These data serve as a foundation for comparison with other modalities of radiation treatment, namely proton therapy.

Incidence and survival for childhood central nervous system tumours in Australia, 1983-2016.

To investigate incidence and survival of childhood tumours of the central nervous system (CNS) by histological subtype, tumour behaviour and tumour grade. National, population-based data on all children under 15years old diagnosed with a CNS tumour between 1983 and 2016 were sourced from the Australian Childhood Cancer Registry. Incidence rate trends were calculated using Joinpoint regression. Relative survival was calculated using the cohort method, with changes in survival over time by cancer type and tumour grade assessed by multivariable flexible parametric survival modelling. The study cohort included 4914 patients, with astrocytoma (n = 2181, 44%) and embryonal tumours (n = 931, 19%) the most common diagnostic subgroups. Almost half (n = 2181, 44%) of all tumours were classified as high grade (III or IV). Incidence rates increased by 29% between 1983 and 2016, with high grade tumours rising by an annual average of + 1.1% (95% CI = + 0.7%, + 1.5%, p < 0.001). 5-year survival for all patients combined was 72% (95% CI = 71-74%), ranging from 50% (46-54%) for those with other gliomas to 81% (79-83%) for astrocytoma (p < 0.001). Survival improved over time for grade II and III ependymomas but not for patients with astrocytoma irrespective of grade. Improvements in diagnostic technology leading to more precise tumour classification are likely to explain some of the differences in incidence rate trends by histological type and grade. While improvements in survival over time were noted for some tumours, outcomes remained poor among patients with high-grade astrocytoma.

P14.11 Severe treatment-induced myelosuppression is more frequent in female malignant glioma patients and associated with reduced overall survival

Abstract BACKGROUND An association of treatment-related myelotoxicity with female gender has been previously suggested. However, a systematic analysis of the prognostic relevance of radiochemotherapy-related cytopenia involving the different blood cell lineages is lacking. MATERIAL AND METHODS We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy (RCT) in 493 glioma patients. Histological grading, molecular pathology, surgical procedures and median overall survival (OS) were recorded. The extent of cytopenia was correlated with gender and outcome. RESULTS Treatment-induced severe cytopenia (leuko-, lympho-, neutro- and thrombocytopenia) occurred much more often in female than in male glioma patients (40.8 vs. 13.9%, p-value &amp;lt;0.0001). In female patients with IDH-wildtype high-grade astrocytomas there was a negative correlation of severe leuko-, lympho- and thrombocytopenia during temozolomide RCT with OS (36 vs. 54, 37 vs. 54 and 36 vs. 57 weeks, respectively; all p-values &amp;lt;0.05). In male patients there was also a trend for this unfavorable effect. Additionally, severe cytopenia correlated with reduced temozolomide dose exposure during RCT (all p-values &amp;lt;0.05 in total cohort) and reduced dose exposure was independently associated with worse OS (p-values &amp;lt;0.05 in the total and female cohort). CONCLUSION Our data confirm that women are at higher risk for treatment-induced cytopenia during RCT which is associated with a significant decrease in OS. From our data, it appears plausible that reduced temozolomide dose exposure during RCT is at least in part responsible for this finding. Immunosuppression of patients with severe cytopenia may be an independent contributor to adverse outcome.

Characterization and oncogenic role of the somatostatin receptor splicing variant SST5TMD4 in human high-grade astrocytomas

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Anaplastic gangliogliomas of the spinal cord: a scoping review of the literature.

Gangliogliomas (GGs) are rare, usually low-grade tumors that account for 1-2% of all central nervous system (CNS) neoplasms. Spinal GGs are exceedingly rare (1% of all spinal tumors) and the presentation of anaplastic features in them is even rarer. According to the last World Health Organization (WHO) classification of CNS neoplasms, anaplastic GG (AGG) is classified as a malignant neoplasm (grade III). We performed a scoping review of the literature to elucidate the epidemiology, clinical features, histopathology, treatment, and outcome of primary spinal AGGs, which, to the best of our knowledge, is the first such review. Relevant studies were identified by a search of the MEDLINE and SCOPUS databases, using the following combination of search strings: (anaplastic ganglioglioma or malignant ganglioglioma or high grade ganglioglioma) AND (spine or spinal or spinal cord). We included studies related to primary or recurrent AGGs and malignant transformation of low-grade GGs. The search produced 15 eligible studies, plus two studies from the references, all of which were case reports of patients with spinal AGGs (17 studies with 22 patients). The mean age of the patients was 21.4years and the sex ratio was 1:1, with male predominance. Motor impairment was the most common presentation, followed by sensory impairment, gait problems, urinary disturbances, and back pain. The thoracic spine was the most frequently involved area (14/22) followed by the cervical (6/22) and lumbar (5/22) spine. In terms of histology, the anaplastic features were usually predominant in the glial element, resembling high-grade astrocytomas, while the neuronal element was composed of the so-called dysplastic ganglion (neuronal) synaptophysin-positive cells, without mitotic figures. Complete surgical resection of the tumor without neurological compromise, plus adjuvant chemotherapy and radiotherapy, was the treatment protocol implemented in the two patients with the best outcome. Primary spinal AGG is an exceedingly rare entity, with only 22 cases being retrieved after an extensive literature search. They appear to affect children and young adults and tend to manifest aggressive behavior. Most studies report that only the glial component of AGGs presents high-grade malignant features, with low mitotic activity in the neuronal component. We therefore suggest that, pending novel targeted therapy, AGGs should be treated as high-grade gliomas, with an aggressive treatment protocol consisting of maximal safe resection and adjuvant chemotherapy and radiotherapy.

Evaluation of progesterone receptor expression in low- and high-grade astrocytomas.

Gliomas are tumors originating from glial cells. Gliomas are the most common primary neoplasms of the central nervous system, with astrocytomas being the most prevalent glioma subtype. Progesterone regulates several reproductive processes, such as ovulation and sexual behavior, and influences neuronal excitability, learning, and the neoplastic proliferation of glial cells. Progesterone functions mainly by interacting with intracellular progesterone receptors to modify the expression of the genes involved in cell proliferation, angiogenesis, and epidermal growth factor production. As not many studies on the hormone receptors in glial tumors have been reported, the objective of this study was to evaluate the expression of these proteins in astrocytomas and to determine whether their expression levels vary according to the tumor grade. This was a retrospective study using glial tumor paraffin blocks obtained from the São Marcos Hospital Pathology Department archives. Forty cases were divided equally into two groups, based on histological types and the World Health Organization criteria (low- and high-grade tumors). Progesterone receptor expression was analyzed by immunohistochemistry. The data were statistically analyzed using the Mann-Whitney U test and Spearman's correlation coefficient; results with p<0.05 were considered statistically significant. There were no statistically significant differences between the mean nuclear progesterone receptor expression of low-grade (0.1495) and high-grade (0.0937) astrocytomas (p=0.2). Progesterone receptors are present in both low- and high-grade gliomas; however, there is no significant difference in the levels of progesterone receptor expression between the tumor grades.

Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas

Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.

Selected Articles from This Issue

Zotiraciclib, a cyclin-dependent kinase 9 (CDK9) inhibitor, was previously shown to synergize with temozolomide (TMZ) in preclinical studies. To translate this finding to the clinic, Wu and colleagues performed a clinical trial of zotiraciclib plus TMZ in recurrent high-grade astrocytoma. This two-stage phase I trial simultaneously optimized the dosing and schedule of the combination of zotiraciclib and temozolomide using a BOIN dose-finding design. In addition to establishing the optimal dosing schedule for zotiraciclib and temozolomide, in-depth analyses of zotiraciclib-induced neutropenia, PK/p. and longitudinal symptom burden analysis were performed. The comprehensive information from this multifaceted early-stage investigation supports further clinical trials of this agent.Nuclear exporter protein exportin1/XPO1 overexpression in hematological malignancies leads to cytoplasmic mislocalization and functional inactivation of tumor suppressors. Specific inhibitor of nuclear export (SINE) compounds block XPO1-mediated protein transport, retaining tumor suppressors in the nucleus. Seymour and colleagues demonstrate preclinical efficacy and clinical validation of XPO1 inhibitor selinexor in non-Hodgkin lymphoma with a phase I study of R-CHOP plus weekly selinexor as frontline treatment of NHL. This combination was well tolerated, and an MTD was not reached. An ORR of 100% and a CR rate of 90% were observed. Further study of this combination in lymphoma is warranted.While neoadjuvant chemoradiation (nCRT) has improved the survival of patients with resectable esophageal adenocarcinoma (rEAC), nearly half of patients succumb to their disease within 5 years. To assess improving this treatment strategy, van den Ende and colleagues assessed the combination of nCRT with PD-L1 inhibition in patients with rEAC. The pathological complete response rate was 25%, but there was no significant improvement in survival compared with nCRT alone. However, potential biomarkers of response were identified. An IFNy signature was associated with response, while low levels of cytotoxic lymphocytes or the presence of checkpoint inhibition correlated with lack of response. Further study is necessary to clarify the therapeutic potential of this combination in rEAC.IL-15 is an important cytokine for the function of NK cells, and IL-15 activation has been proposed as a strategy for immunotherapy. Foltz and colleagues conducted a clinical trial of N-803, an IL-15 receptor superagonist complex, with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma. This combination was well tolerated and led to prolonged responses in a subset of patients. N-803 treatment led to the activation of NK cells, CD8+ T cells, and monocytes. Further clinical study of N-803 is needed to identify patient populations for whom this agent will be beneficial, as well as appropriate combination treatments.

Overcoming the Challenges in the Treatment of Glioblastoma via Nanocarrier- based Drug Delivery Approach.

Glioblastoma multiforme is the most malignant form of high-grade astrocytoma. Clinically it is characterized as 4th grade of astrocytoma having necrotic tissue and hyperplastic blood vessel. It is observed to be the most frequent adult brain tumor representing an overall 15.4% of all brain tumors and about 60-75% of the entire astrocytoma. There are limited therapies available, and the most widely used therapy includes surgical intrusion followed by radiotherapy plus chemotherapy (paclitaxel, temozolomide, docetaxel, etc.), with an overall patient survival rate from 6-14 months. Various studies have proved that nanoformulations offer considerable advantages like enhanced drug solubility, targeted activity, and attenuated side effects. The key objective of this review article is to exemplify numerous studies carried out using nanocarriers for overcoming the challenges associated with the treatment of glioblastoma. It also describes the pathways associated with the induction, initiation, and progression of glioblastoma. Research articles that focused on the use of nanocarrier-based drug delivery approach for the treatment of various glioblastoma were collected from different search engines such as Google Scholar, Science Direct, and PubMed using keywords like glioblastoma, nanocarriers, brain delivery, etc. Results: Nanocarriers have shown enormous potential in overcoming the challenges associated with the treatment of glioblastoma. Broad research is essential so that these nanocarriers can be used clinically for the welfare of mankind, in the management of glioblastoma, in the near future.

LGG-06. COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1

BackgroundLow-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs. MethodsNF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects. ResultsMost LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class. ConclusionsGiven the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.

Accuracy of Machine Learning Algorithms for the Classification of Molecular Features of Gliomas on MRI: A Systematic Literature Review and Meta-Analysis.

Simple SummaryGlioma prognosis and treatment are based on histopathological characteristics and molecular profile. Following the World Health Organization (WHO) guidelines (2016), the most important molecular diagnostic markers include IDH1/2-genotype and 1p/19q codeletion status, although more recent publications also include ARTX genotype and TERT- and MGMT promoter methylation. Machine learning algorithms (MLAs), however, were described to successfully determine these molecular characteristics non-invasively by using magnetic resonance imaging (MRI) data. The aim of this review and meta-analysis was to define the diagnostic accuracy of MLAs with regard to these different molecular markers. We found high accuracies of MLAs to predict each individual molecular marker, with IDH1/2-genotype being the most investigated and the most accurate. Radiogenomics could therefore be a promising tool for discriminating genetically determined gliomas in a non-invasive fashion. Although encouraging results are presented here, large-scale, prospective trials with external validation groups are warranted.Treatment planning and prognosis in glioma treatment are based on the classification into low- and high-grade oligodendroglioma or astrocytoma, which is mainly based on molecular characteristics (IDH1/2- and 1p/19q codeletion status). It would be of great value if this classification could be made reliably before surgery, without biopsy. Machine learning algorithms (MLAs) could play a role in achieving this by enabling glioma characterization on magnetic resonance imaging (MRI) data without invasive tissue sampling. The aim of this study is to provide a performance evaluation and meta-analysis of various MLAs for glioma characterization. Systematic literature search and meta-analysis were performed on the aggregated data, after which subgroup analyses for several target conditions were conducted. This study is registered with PROSPERO, CRD42020191033. We identified 724 studies; 60 and 17 studies were eligible to be included in the systematic review and meta-analysis, respectively. Meta-analysis showed excellent accuracy for all subgroups, with the classification of 1p/19q codeletion status scoring significantly poorer than other subgroups (AUC: 0.748, p = 0.132). There was considerable heterogeneity among some of the included studies. Although promising results were found with regard to the ability of MLA-tools to be used for the non-invasive classification of gliomas, large-scale, prospective trials with external validation are warranted in the future.

Presence and pathophysiological role of sst5TMD4, an aberrant spliced variant of the somatostatin receptor subtype 5, in human high-grade astrocytomas

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Metformin and simvastatin in combination: drugs repositioning to impair high-grade astrocytomas progression

Metformin and simvastatin in combination: drugs repositioning to impair high-grade astrocytomas progression