Αρχειοθήκη ιστολογίου

Δευτέρα 5 Σεπτεμβρίου 2022

P03.05.A Radiation-induced leukoencephalopathy (RIL) in glioma: unique injury dynamics following proton vs photon beam radiotherapy

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Abstract
Background
White matter injury after brain-directed radiotherapy (RT), aka radiation-induced leukoencephalopathy (RIL), is common in brain tumor patients. Differentiation from progressive disease can be challenging. Dosimetric advantages of protons (PRT) over photons (XRT) minimize radiation to healthy brain tissue, potentially limiting radiotoxic sequelae including RIL. We characterized RIL during periods of progression-free survival (PFS) in glioma patients irradiated with either PRT or XRT, hypothesizing that PRT would result in reduced RIL outside of the target field.
Material and Methods
34 patients (19 male; mean age = 40.10y) with grade 2/3 gliomas and a history of partial cranial RT were stratified by RT modality [XRT (n=17) vs PRT (n=17)] and matched on 11 criteria [age, sex, tumor type/location/laterality, mutational status (IDH; 1p19q deletion), concurrent/adjuvant chemotherapy, radiation dose/fractions] for retrospe ctive analysis. RIL development was characterized longitudinally for up to 3 years post-RT via analysis of serial MRI T2/FLAIR sequences. A novel RIL scoring system with embedded Fazekas scale was designed to quantify injury severity at both global (whole brain) and hemispheric levels.
Results
Matched groups did not differ significantly on any demographic or clinical characteristics. Median PFS post-RT was 4.7 (XRT) and 5.1 (PRT) years. The novel RIL scoring system was reliable (intraclass correlation coefficient >0.9). There was a significant increase in global RIL in both XRT [F(3, 57)=8.63, p< .001] and PRT [F(3, 61)=4.69, p< .005] groups over time, relative to baseline (1-month post-RT). A majority [62% (XRT) and 72% (PRT)] developed moderate or severe RIL within 3 years, with the ipsilesional hemisphere more severely affected. Analysis of RIL injury dynamics (i.e., average % change between 1 and 3 years post-RT) at hemispheric level identified radiation modality-specific differences: XRT resulted in greater contralesional hemispheric injury than PRT [F(1, 31)=4.32, p<.05]. This effect was not observed in ipsilesional hemispheres.
Conclusion
RIL is common in glioma patients and quantifiable by characteristic imaging features, including early onset post-RT, greater ipsilesional injury burden, and progression over time. RIL injury dynamics appear to be radiation modality-specific, whereby XRT causes greater delayed injury in the remote, contralesional hemisphere. These findings may reflect dosimetric differences between protons and photons. The impact of such sequelae on cognitive function is subject of current investigation.
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P12.13.B Investigating the tumor - immune cell crosstalk inex vivo glioblastoma models

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Immunotherapy is a promising therapeutic approach to fight cancer by activating the immune system. Multiple immune-based strategies are under development that aim at recruiting or re-activating cellular components of the immune system. While immunotherapies have recently revolutionized cancer therapy, they have shown so far little therapeutic success in glioblastoma patients. To enhance the efficacy of novel strategies, we need to better understand the immunogenic status of glioblastoma cells and their cross-talk with immune cells in different microenvironmental niches.
Material and Methods
We assessed expression of molecules related to antigen processing and presentation as well as immune checkpoints in patient tumor databases as well as in a series of glioblastoma patient-derived organoids, 3D stem-like cultures and adherent cell lines under varying microenvironmental conditions (varying oxygen levels, inflammation ). We further established an allogenic co-culture protocol for glioblastoma organoids with immune cells isolated from HLA matched donor blood, allowing for the functional assessment of the crosstalk between tumor and immune cells.
Results
Analysis of a large cohort of patient tumors and patient-derived glioblastoma preclinical models shows inter-patient heterogeneity at the level of components of major histocompatibility complex (MHC)-MHC-II, immune checkpoints. Glioblastoma cells in general express MHC-I machinery, albeit at different levels. MHC-II and immune checkpoints are variably expressed across glioblastoma cells. Different tumor microenvironment conditions, including hypoxia and interferon-γ, impact the expression of immune-related molecules. Upon co-culture, HLA-matched donor-derived T cells integrate well into the core of glioblastoma tumor organoids and display reciprocal crosstalk with tumor cells.
Conclusion
Assessing antigen presentation and immune cell responses at the functional level are key to improve patient-specific responses to immunotherapies. Advanced glioblastoma organoids incorporating the immune compartment appear as clinically-relevant models for ex vivo efficacy studies.
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P12.09.B Extracellular vesicle derived-miR-146a increases melanoma brain metastasis progression via Notch signalling pathway dysregulation

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Abstract
Background
Melanoma has the highest tropism of any cancer to metastasize to the brain, and 40% of late-stage patients develop brain metastasis. Invasion, survival, and progression of tumors is dependent on the support of the surrounding microenvironment; therefore, modulation of neighboring cells is a key factor in metastasis. Extracellular vesicles (EVs) are important in cell-to-cell signalling, shuttling proteins, RNA and DNA to alter the surroundings into a favorable tumor microenvironment. Our aims were to investigate the role of melanoma brain metastasis (MBM) derived EVs in MBM development to find possible contributing mechanisms to cancer progression for eventual therapeutic targeting.
Material and Methods
MBM-EVs isolated via sequential ultracentrifugation were injected into mice as a pre-treatment prior to intracardial injection of MBM cells. EVs were co-cultured with normal human astrocytes (NHA) to investigate phenot ypic changes. MiRNA sequencing was performed on EVs collected from MBM cells and compared to NHA and melanocytes to determine a candidate miRNA for targeting. In situ hybridization was utilized to evaluate the level of miRNA in clinical patient MBM samples. Functional in vivo validation was performed by injecting miRNA knockout MBM cells into mice. Sequencing of NHA in the presence or absence of target miRNA mimic was used to determine downstream targets.
Results
Mice primed with EVs had a significant increase in MBM tumor burden, compared to non-primed mice. Co-culture with MBM-EVs resulted in NHA activation in vitro, with increased proliferation, invasion, cytokine production, and upregulation of GFAP. MiR-146a was highly upregulated in MBM EVs, and miR-146a mimics activated NHA. Patient samples had a significant increase in miR-146a expression, compared to healthy brain controls. MiR-146a knockdown in MBM mice models reduced MBM burden and prolonged animal survival. Sequ encing of NHA determined NUMB, an inhibitor of the Notch signalling pathway, as a target of miR-146a. Numb and other downstream Notch proteins expression was significantly altered in NHA in the presence of both MBM-EVs and miR-146a.
Conclusion
In conclusion, EVs are important regulators of MBM and establish tumor-supporting reactive astrocytes by delivery of miR-146a. MiR-146a alters Notch signalling in astrocytes via inhibition of the tumor suppressor gene NUMB. Elevated miR-146a levels in patients suggests a potential clinical intervention is possible via miR-146a targeting.
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P11.61.B Capecitabine treatment of CNS metastases from breast cancer: intracranial response and survival

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
20-30% of breast cancer patients develop brain metastases (BM) and 5% leptomeningeal metastases (LM). Incidence of BM and/or LM is dependent on breast cancer subtype. Treatment of BM consists of local treatment (resection and/or radiotherapy) and if possible systemic therapy. LM can be treated with radiotherapy of the symptomatic location of the nervous system and/or systemic therapy. Capecitabin is effective for both systemic metastases and BM of HER2-positive breast cancer. The effect of capecitabine in the non-HER2-positive breast cancers and in the LM group is largely unknown. The goal of this study is to determine the intracranial response of capecitabine and survival in HM and/or LM of the various breast cancer subtypes.
Material and Methods
breast cancer patients with HM and/or LM treated with capecitabine were selected retrospectively from a breast cancer patient cohort treated at the Netherlands Cancer Inst itute - Antoni van Leeuwenhoek between 2005 and 2020. Follow-up MRI scans of the brains were performed in all patients. The primary endpoints were intracranial response, intracranial progression-free survival (PFS) and overall survival (OS). Subgroup analyses for breast cancer subtypes and BM and LM patient groups were done.
Results
93 of 381 patients treated for CNS metastases of breast cancer fulfilled the inclusion criteria. Sixty-one patients (66%) had HM only, 13 (14%) had LM only and 19 patients (20%) had both HM and LM. Forty-six percent of patients had HER2-positive breast cancer, 26% had hormone receptor-positive breast cancer and 28% of patients had a triple negative subtype. After three months of capecitabine treatment intracranial response was 53%. Median OS in the patient group with intracranial response was 16.5 months versus 4.5 months in the non-response group. The hazard ratio (HR) for the median OS, corrected for radiotherapy and concurrently administered , other systemic therapy was 0.33 (95% CI: 0.17-0.67). Median intracranial PFS was 7.3 months in the response group versus 1.4 months in the non-response group (p<0.001).The corrected HR for median intracranial PFS 0.13 (95% CI 0.06-0.27). The HER2-positive subtype group showed the longest median OS (22 months) as compared to the other subtypes (OS in hormone-receptor positive and triple negative subtype both 12 months)
Conclusion
Fifty-three percent of breast cancer patients with HM and/or LM treated with capecitabine demonstrate an intracranial response after three months of treatment. HER2+ breast cancer patients with HM and/or LM have a longer survival than patients with hormone receptor-positive or triple negative breast cancer subtypes.
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P11.31.B Pseudotumor Cerebri - a rare paraneoplastic manifestation

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Abstract
Background
Pseudotumor Cerebri (PC) is defined by an elevated intracranial pressure of unidentified cause, associated with normal cerebrospinal fluid (CSF) composition and no cause for hypertension on the neuroimaging evaluations. The symptoms described in association are headache, papilledema, changes in vision, and sometimes tinnitus. Its pathophysiology is far from being elucidated and the mechanisms proposed are multiple. There are some cases described in the literature in which PC is the first manifestation of a systemic neoplasm, most probably due to an abnormal response of the immune system to cancerous growth. We aim to emphasize a possible connection between adenocarcinoma of the lung and PC as the first paraneoplastic manifestation.
Material and Methods
We present the case of a 59-year-old patient, female, non-obese, who presented to the hospital for severe headache, blurred vision, tinnitus, and paresthesia on both h er upper limbs. On the first evaluation, the usual blood tests showed an increased creatinine level, and the subsequent abdominal echography and CT scan revealed bilateral ureter hydronephrosis, without an obvious obstacle, for which nephrostomies were implanted. On the ophthalmological evaluation bilateral papillary edema was described, although the cerebral CT with angiography and MRI showed no pathological modifications. A lumbar puncture with manometry was performed, that showed a CSF pressure of approximately 500 mmH2O.
Results
Following the clinical, imagistic, and biological manifestations, the diagnosis of PC was established. The decision to start the corticotherapy was made, followed by the addition of acetazolamide. Although the treatment tented was not efficient, the neurosurgery team decided that she is not a suitable candidate for a CSF shunting procedure and the ophthalmologist advised against an optic nerve sheath fenestration. The evolution was unfavorable, with the persistence of the symptoms. She underwent extensive investigations, the second cerebral MRI showing a slight dilation of the ventricles. On the thoracic-abdominal-pelvic CT, a pulmonary nodule with a malignant aspect was described, the histopathological results pleading for adenocarcinoma. The decision to excise the lesion was made, but after the surgery, the patient developed a cardiorespiratory arrest, without response to resuscitation.
Conclusion
Although there is scarce evidence of PC as a paraneoplastic syndrome, the evolution and investigations results support the possibility of a causal relationship. This is, to our knowledge, the second case of adenocarcinoma of the lung that primarily presents with PC. Further studies must be conducted to understand the underlying pathophysiology of this condition and to develop new treatment possibilities.
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P11.29.B Risk factors associated with the presence of brain metastasis at the moment of diagnosis in non-small cell lung cancer patients. Retrospective case series

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Lung cancer is the second most frequent neoplasm worldwide and the leading cause of cancer death in both sexes. Furthermore, it is the most common origin of brain metastases. The aim of this study is to identify clinical, histological, and molecular variables associated with a higher risk of presenting brain metastases at the moment of diagnosis in patients with lung cancer.
Material and Methods
A single-center retrospective case series analysis of patients with a new diagnosis of lung cancer (from January 2015 to December 2018) was performed. A total of 723 total patients with a new diagnosis of non-small cell lung cancer (NSCLC) were identified. Only patients with a brain imaging study at the time of diagnosis were included in the analysis. Non-parametric statistical tests were used to compare patients with or without metastases at the moment of diagnosis. A uni- and multivariate analysis were performed to identify risk factors associated with the presence of brain metastases at NSCLC diagnosis. Statistical significance was considered when p<0.05.
Results
We included 135 patients with a new diagnosis of lung cancer and with brain imaging study at the time of diagnosis (mean age at diagnosis of 64.69 years [SD= 10.34]; 71.9% men). The most common histology was adenocarcinoma (67.1%) followed by squamous carcinoma (25.2%). Brain metastases were present in 40% of patients at diagnosis. No significant differences in clinical, histological and molecular variables was identified between patients with or without brain metastases. In any case, as expected, the survival analysis showed that brain metastasis at diagnosis was associated with a worse overall survival (Log-Rank test, p<0.01).The univariate analysis showed that presenting neurological symptoms (OR=19.5, p<0.0001 CI [7.895-47.65]), histology of adenocarcinoma (OR= 2.113, p<0.014 CI [1.160-3.849]) and the presence of vis ceral metastases (OR= 14.444, p<0.0001 CI [6.161-33.86]) were associated to the presence of brain metastases at diagnosis. The presence of metastases limited to the thorax (OR= 0.019, p<0.001 CI [0.003-0.146] was associated to be free of brain metastasis at NSCLC diagnosis. However, only neurological symptoms (OR= 20.290, p<0.0001 CI [4.953-83.118]), presenting visceral metastases (OR= 4.451, p<0.010 CI [1.458-13.777]) and/or metastases limited to the thorax (OR= 0.066, p<0.024 CI [0.006-0.010]) reached statistical significance in the multivariate analysis.
Conclusion
Neurological symptoms and the presence of visceral metastases are independent predictors or presenting brain metastasis at the moment of diagnosis in lung cancer patients. On the other hand, the presence of lung cancer disease confined in the thoracic cavity is associated with a lower risk to present brain metastasis
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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
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.
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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
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.
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P11.73.B The diagnostic value of frame-based stereotactic biopsies in the age of precision oncology: A cross-sectional study

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
For non-resectable, eloquent, multifocal and deep-seated intracranial lesions, stereotactic frame-based biopsies can deliver a finite amount of tissue for neuropathology studies. With the increasing role of molecular genetics in the diagnostics of intracranial tumors, sufficient tissue for sequencing studies is of paramount importance. This study explored the rate of successful diagnosis after stereotactic frame-based biopsies of intracranial lesions in a high-throughput neurooncology center
Material and Methods
145 consecutive patients undergoing frame-based stereotactic biopsies in 2020 and 2021 at our neurosurgical department were included in this retrospective analysis. Aspects of histological and molecular (methylomics, panel-sequencing) neuropathology analysis in addition to clinical and radiological variables were analyzed. Cases were classified as conclusive, likely-conclusive (sufficient diagnosis with non-s atisfying sequencing information), and inconclusive neuropathological diagnosis.
Results
Of 145 cases analyzed, astrocytic tumors were suspected in n= 94 (67%) of patients. In n= 122 cases (84%), a conclusive diagnosis was possible. For 14 (11%) cases, a likely-conclusive diagnosis was established Diagnoses comprised mainly WHO 4 glioblastomas (56%), WHO 3 gliomas (2%) in addition to WHO 1 and 2 gliomas (n=7, 5%), CNS lymphomas (n=23, 16%), inflammatory diseases (n=10, 7%) and normal or reactive tissue (n=4, 3%). Methylomics were pivotal in providing an integrated diagnosis in 30% of the cases (panel sequencing in 14%). In n= 12 (8%) of the cases further testing was hindered by insufficient tissue sample DNA. Only in 3 out of 12 cases this resulted in a final inconclusive diagnosis.
Conclusion
Although stereotactic frame-based biopsies deliver a limited amount of tissue, they bear an excellent histopathological and molecular genetic diagnostic yield, with rare case s of missing molecular data or rarely insufficient diagnosis. Optimizing the number and representativeness of cell and DNA-rich stereotactic biopsy specimen might enhance the diagnostic and therapeutic potential of precision oncology even further.
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