P11.75.B Survival benefit of radiotherapy and surgery in patients with lung cancer brain metastases with poor prognosis factors

alexandrossfakianakis shared this article with you from Inoreader P11.75.B Survival benefit of radiotherapy and surgery in patients with lung cancer brain metastases with poor prognosis factors via # Neuro-Oncology Current Issue Abstract Background Radiotherapy and surgery are the standard treatments for lung cancer brain metastases (BMs). However, limitted studies focused on the treatments for patients with lung cancer BMs with poor prognosis factors. The purpose of this study was to investigate the effects of radiotherapy and surgery in patients with lung cancer BMs with poor prognosis factors, providing reference for clinical strategies. Material and Methods We analyzed retrospectively 714 patients with lung cancer BMs. A 1:1 propensity score matching (PSM) was performed to balance potential confounders. Analyses of overall survival (OS) and risk factors for OS were assessed by log-rank test and Cox proportional hazard model. Results Age ≥65 years, Karnofsky Performance Scale (KPS) score ≤70, anaplastic large-cell lymphoma kinase (ALK)/epidermal growth factor receptor (EGFR) wild type, extracranial metastases, non-surgery and non-radiotherapy le d to poor prognosis. Patients were stratified according to these factors. Radiotherapy and surgery showed no survival benefit in patients with aged ≥65 years or pretreatment KPS score ≤70 before and after PSM. Before PSM, whole brain radiotherapy (WBRT) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or extracranial metastases. WBRT also predicted good prognosis in patients with non-surgery. Stereotactic radiosurgery (SRS) improved the OS and predicted good prognosis in patients with ALK/EGFR wild type or non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with extracranial metastases or non-surgery. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS and predicted good prognosis in patients with non-radiotherapy. After PSM, SRS improved the OS and predicted good prognosis in patients with non-surgery. WBRT plus SRS improved the OS and predicted good prognosis in patients with non-surgery or extracranial metastases. WBRT plus SRS also predicted good prognosis in patients with ALK/EGFR wild type. Surgery improved the OS of patients with non-radiotherapy. We defined that the treatment would provide significant survival benefit if it both prolonged the OS and predicted good prognosis. Meanwhile, the results after PSM were more convincing than the results before PSM. Conclusion Radiotherapy has significant survival benefit in patients with lung cancer BMs with poor prognosis factors, including patients with ALK/EGFR wild type or extracranial metastases or non-surgery. Surgery only has significant survival benefit in patients with non-radiotherapy. View on Web

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P02.01.B The telomere maintenance mechanism spectrum and its dynamics in gliomas

alexandrossfakianakis shared this article with you from Inoreader P02.01.B The telomere maintenance mechanism spectrum and its dynamics in gliomas via # Neuro-Oncology Current Issue Abstract The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation indicates alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues. Here, we show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined in the dichotomy of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation and ATRX mutation. Moreover, we observed that a considerable proportion of gli omas lack both telomerase activity and ALT (Neither group). And this Neither group exhibited evidence of slow growth potential. From a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed but changes with glioma progression. Collectively, these results suggest that the TMM is a dynamic entity and that reflects the plasticity of the oncogenic biological status of tumor cells and that the TMM should be defined by the direct measurement of telomerase enzyme activity and evidence of ALT. View on Web

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P11.74.A Plexiform Neurofibromas prevalence and treatment modalities in a referral comprehensive cancer center

alexandrossfakianakis shared this article with you from Inoreader P11.74.A Plexiform Neurofibromas prevalence and treatment modalities in a referral comprehensive cancer center via # Neuro-Oncology Current Issue Abstract Background Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, with an incidence of 1/3500. Plexiform neurofibromas (PN) are benign tumors that can occur along the nerve sheath throughout the body, with unpredictable growth and with risk of malignant transformation. Symptoms will depend on their size and location, and include pain, deformity and functional impairment. There is a great variability in the PN severity and impact on quality-of-life (QOL). An unknown percentage of NF1 patients may need treatment, either medical and/or surgical. Objectives To assess the frequency of PN in a NF1 population followed in a comprehensive cancer center. Material and Methods Retrospective study. All patients with NF1 and PN followed in our center, between 31/12/2000 and 31/12/2021. Results Of 438 NF1 patients, 185 had PN (42%). 52 NF1 patients with PN were children (≤ 18). The most common sym ptoms were pain in 71 people (38,4%), deformity in 70 (37,8%) and functional impairment in 69 (37,3%). Several patients had a combination of these symptoms. Different treatment modalities were used for PN: medical, surgical or both. In this study, 54 patients (29,1%) were treated with MEK inhibitors (selumetinib), 74 patients (40%) were treated surgically and 12,4% (23) needed a combined approach (medical and surgical treatment). Conclusion PN are frequent in NF1 patients. A significant percentage is symptomatic and will require treatment, surgical, medical or both. There is no standard of care for PN NF1. The timing and sequence of medical and surgical treatment is yet to be defined. View on Web

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P02.10.A CRISPR/Cas9 deletion of SOX2 Regulatory Region 2 (SRR2) decreases SOX2 malignant activity in glioblastoma

alexandrossfakianakis shared this article with you from Inoreader P02.10.A CRISPR/Cas9 deletion of SOX2 Regulatory Region 2 (SRR2) decreases SOX2 malignant activity in glioblastoma via # Neuro-Oncology Current Issue Abstract Background SOX2 is a transcription factor associated with stem cell activity in several tissues. SOX2 expression is elevated in a large proportion of cancers, such as glioblastoma (GB), the most common malignant primary brain tumor in adults. SOX2 acts as a relevant driver of GB progression and high levels are associated with the population of tumor initiating cells and poor patient outcome. Transcriptional regulation of SOX2 is complex and not fully understood. The SOX2 regulatory region 2 (SRR2) is located downstream of the SOX2 coding region and mediates SOX2 expression by the association of p21CIP1 and p27KIP1 to SRR2. In this study we dissected the role of SRR2 on SOX2 activity in GB. Material and Methods We deleted SRR2 (SRR2del) by CRISPR/Cas9 technology in U373 GB cells. We analyzed the expression of SOX2 and performed in vitro functional experiments. We accomplished rescue experiments overexpressing SOX2 in SRR2del cells and we studied the link between SOX2, p21CIP1 and p27KIP1. Finally, we carried out an in vivo carcinogenesis assay by the injection of SRR2del cells in immunodeficient mice. Results We report that the deletion of SRR2 in GB cells leads to a reduction of SOX2 expression, which was accompanied with an impairment of cell growth and proliferation as well as with a reduction of self-renewal capacity in vitro. These data reveal that SRR2 is required for SOX2 expression and that its deletion results in impaired tumorigenic capacity of GB cells. These effects correlated with an increased expression of p21CIP1 and p27KIP1 together with high levels of p53 in SRR2del cells. On the contrary, SRR2del cells presented decreased levels of stem cell markers, supporting the idea that SRR2 is necessary for the SOX2-mediated regulation of stemness pathways. Furthermore, ectopic overexpression of SOX2 in SRR2del cells restored SOX2 expression as well as proliferation and stem cell properties, indicating that the expression and the oncogenic activity of SOX2 is regulated by SRR2. Additionally, our xenograft models re vealed that the lack of SRR2 impairs tumor initiation and growth in vivo. Tumors derived from SRR2del cells were significantly smaller compared to controls and exhibit low levels of SOX2, Ki67 and BMI1 but high levels of p21CIP1 and p27KIP1. Conclusion Our data confirm that the SRR2 regulates SOX2 expression and reveal that SRR2 deletion reduces SOX2 levels and halts malignant activity driven by SOX2 in GB. View on Web

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P11.71.B Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) in a patient with blastic plasmacytoid dendritic cell neoplasm: a rare neurologic manifestation in a rare disease

alexandrossfakianakis shared this article with you from Inoreader P11.71.B Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) in a patient with blastic plasmacytoid dendritic cell neoplasm: a rare neurologic manifestation in a rare disease via # Neuro-Oncology Current Issue Abstract Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid hematological malignancy. Skin lesions, bone marrow, lymph nodes or visceral organs can be involved. 30% of patients will have infiltration to the nervous system,occult asymptomatic infiltration is frequent. Immunophenotype express CD4, CD56, and CD123, and flow cytometry is essential. Material and Methods 70-yo Hispanic male with a 1-month history of multiple violaceous cutaneous nodules and adenopathies.Neurological complaints included diplopia, hypoesthesia in the left face, dysphagia, gait difficulties, and generalized weakness with distal hypoesthesia. Examination revealed multiple cranial neuropathy (bilateral VI and VII nerve palsies, left V3 and VIII palsies and IX, X involvement), global areflexia, length-dependent weakness, ataxic gait and cerebellar syndrome. An inguinal ganglionar biopsy retrieved cells positive for CD4, TCL 1, CD68 and CD123, whereas CD3, CD20, CD7, CD8, CD30 and myeloperoxidase were negative. PET/CT showed multiple supra and infradiaphragmatic adenopathies, bilateral pleural, pericardial and abdominal implants. Bone marrow biopsy was negative. Brain MRI showed contrast enhancement in the cerebellar folia and in the roots of the cranial nerves clinically involved. Multiple CSFs demonstrated high protein count (281- 310mg/dl), normal glucose and cell count; CSF flow cytometry and cytology reported no blastic infiltration (negative CD4, CD56 and CD123), CSF onconeuronal antibodies were negative. Nerve conduction studies fulfilled definite electrodiagnostic EFNS criteria for CIDP. Sural nerve biopsy reported inflammatory demyelination without infiltration. Systemic chemotherapy (Cyclophosphamide/Vincristine) with intrathecal cytarbine/methotrexate was administered. Results Favorable initial, but brief response was noticed for the cranial nerves and gait. He had neurological relap se with gait impossibility. Neuraxis MRI showed no contrast enhancement in the brain but new contrast enhancement of lumbosacral roots. Nerve conduction studies reported severe worsening criteria of CIDP. The PET/CT demonstrated complete response. Five days of methylprednisolone (1gr IV) followed by oral prednisone were prescribed (50 mg qd). However, two weeks later he suffered clinical neurological worsening with respiratory failure. IVIg was started (.4g/kg/day for 5 days) with no improvement; palliative care decision was consented. Conclusion We report the case of an adult male with multiple cranial nerve palsy, cerebellar syndrome and refractory rapidly progressive asymmetric polyneuropathy with BPDCN. CIDP in the absence of multiple attempts to demonstrate nervous system infiltration led us to consider this as a paraneoplastic phenomenon refractory to treatment. To our knowledge no CIDP has been reported in this rare disease View on Web

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OS08.7.A Lomustine and the immunocytokine L19TNF are a promising treatment combination for recurrent glioblastoma

alexandrossfakianakis shared this article with you from Inoreader OS08.7.A Lomustine and the immunocytokine L19TNF are a promising treatment combination for recurrent glioblastoma via # Neuro-Oncology Current Issue Abstract Background Treatment options for recurrent glioblastoma are limited and with the possible exception of regorafenib, no agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigated different treatment combinations based on the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and translated the most effective treatment combination to patients with recurrent glioblastoma. Material and Methods Orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity of L19TNF in combination with anti-PD1, bevacizumab or lomustine. Tumor growth was monitored by MRI. Flow cytometry and microscopy were used to characterize tumor-infiltrating-immune cells. MHC immunoaffinity purification and mass spectrometry were used to characterize the MHC immunopeptidome. Genetic mouse models were used to study immune-dependent effects. Subsequently, we translated the most efficient treatment combination to patients with recurrent glioblastoma within a phase I/II clinical trial (NCT04573192). Results The combination of L19TNF and lomustine demonstrated strong synergistic anti-tumor activity in two immunocompetent orthotopic glioma models and cured a majority of tumor-bearing mice. In contrast, combinations with anti-PD-1 or bevacizumab had only limited anti-glioma activity. Furthermore, compared to the monotherapies, the combination of L19TNF and lomustine led to the strongest increase in tumor-infiltrating lymphoid cells as demonstrated by flow cytometry and microsopy and to the highest number of peptides presented in the context of MHC-I. The treatment effect was abrograted in different genetic immunodeficient mouse models. The treatment combination of L19TNF and lomustine was well tolerated in the first patients treated within a phase I/I I clinical trial and we observed partial tumor responses also in patients with an unmethylated MGMT promoter. Conclusion The combination of L19TNF and lomustine demonstrated promising anti-glioma activity and patients are currently recruited within a phase I/II clinical trial for patients with recurrent glioblastoma. View on Web

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KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

alexandrossfakianakis shared this article with you from Inoreader KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients via # Neuro-Oncology Current Issue Abstract Background In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types' impact on the local white matter fiber architecture and clinical outcome. Patients and Methods This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber densi ty was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group. Results The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p<0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a c omparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score). Conclusions Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients' performance due to the larger volume affected. Funding Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation. View on Web

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