bluuebunny/crossref_metadata_2025_split huggingface dataset:
P03.01.A “TO BE SMART” IN FOLLOW-UP AFTER CRANIAL RADIOTHERAPY: REPORT OF TWO CASES
Authors: KAMER S , Kitis O , Acarer A , Eraslan C , Calli C , Anacak Y 
Published: September 2023

Abstract

BACKGROUND
Stroke-like Migraine Attacks after Radiation Therapy Syndrome (SMART) is a rare, delayed complication of radiation therapy and its real incidence is unknown. In this study, clinical and treatment features of two cases with clinical and radiological diagnosis of SMART are presented.

METHODS
Case-1: 49 years old male was diagnosed with grade-3 Oligodendroglioma; after gross total surgery treated with 60 Gy local cranial radiotherapy and temozolomide. Patient presented with acute left-sided weakness and numbness, episodic myoclonic jerking of the left arm and leg, 6 years after treatment. Contrast-enhanced MRI and MR angiography revealed no sign of a recurrent tumor but contrast uptake at right parietooccipital cortical giriform in the lobe of the right temporal lobe on post-contrast images (FLAIR and T1) and an increase in cortical blood volume are observed in perfusion MRI (Figure A-B). The clinical and radiologic diagnosis was SMART syndrome. Pulse dose steroids was planned as the primary treatment, and neurological symptoms was completely disappeared. After 3.5 years of the primary episode, patient re-applied with acute headache, homonymous hemianopsia of the left eye and left sided hemiparesia. Cranial MRI revealed the similar features and after treatment with steroids for 7 days complete radiological and clinical regression was experienced. Case-2: 60 years old female with a right occipital grade-3 oligodendroglioma treated with resection followed by local cranial radiotherapy (60 Gy) and temozolomide chemotherapy. Ten years after the treatment she presented with severe headache, expressive aphasia and homonymous hemianopsia of the left eye. Contrast-enhanced MRI and MR angiography revealed no sign of a recurrent tumor but contrast uptake at right occipital cortical giriform on post-contrast images (FLAIR and T1) and an increase in cortical blood volume are observed in perfusion MRI (Figurec. The diagnosis was SMART syndrome. After one week of steroid treatment she completely recovered. Similar complaints recurred 9 months after the first episode and completely recovered with steroids in one week. Radiological finding disappeared in 2 months.

CONCLUSION
SMART syndrome represents an acute-onset rare condition which may result in serious consequences if not diagnosed and treated properly. It usualy appears years after cranial radiation therapy. Clinical signs and radiological findings may resemble tumor recurrence and distinction from real tumor progression is essential. Treatment is symptomatic, most patients recover with steroids and radiological signs disappear completely, however SMART episodes may recur during the follow-up which can be treated similarly.
P03.06.A FRAMELESS FRACTIONATED STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: AN INSTITUTIONAL SERIES OF 145 CASES
Authors: Kilic S S , Halima A , Chao S T , Neyman G , Guo B , Magnelli A , Kolar M D , Cho Y , Qi P , Barnett G H , Angelov L , Mohammadi A , Woody N M , Chan T , Yu J S , Murphy E S , Suh J H , Stevens G H 
Published: September 2023

Abstract

BACKGROUND
Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases.

MATERIAL AND METHODS
In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method.

RESULTS
118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There were no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN.

CONCLUSION
Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.
P03.11.B MITOTIC ENRICHMENT AS AN EFFICIENT RADIOSENSITIZATION STRATEGY FOR INTRACRANIAL TUMORS
Authors: de Gooijer M C , Çolakoğlu H , Çitirikkaya C H , Fedorushkova D M , El Ouazani A , Shah R , Meel M H , Hulleman E , Borst G R , van Tellingen O 
Published: September 2023

Abstract

BACKGROUND
Radiotherapy remains one of the most effective modalities for anticancer treatment and part of standard of care for many primary and metastatic brain tumors. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens.

MATERIAL AND METHODS
Mitotic enrichment in vitro is established using flow cytometry and radiosensitization is assessed using colony formation assays. In vivo, several independent luciferase-tagged orthotopic brain tumor models are used to investigate mitotic enrichment (phospho-histone 3 immunohistochemistry), tumor growth, survival and healthy tissue toxicity (body weight, blood liver enzymes, γH2AX and cleaved-caspase 3 immunohistochemistry). Pharmacokinetic studies are quantified using LC-MS/MS. All experiments on primary brain tumors included serum-free neurosphere culture models.

RESULTS
We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors. Importantly, ABT-751 also improves survival in mouse models of adult glioblastoma (GBM), but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. Of note, induction of mitotic enrichment does not exacerbate healthy tissue toxicity.

CONCLUSION
Induction of mitotic enrichment by ABT-751 radiosensitizes adult GBM to fractionated radiotherapy. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon.
P04.03.B VENOUS THROMBOEMBOLISM AND OTHER VASCULAR COMPLICATIONS IN PAEDIATRIC PATIENTS FOLLOWING CRANIOPHARYNGIOMA SURGERY: A SINGLE-CENTER, RETROSPECTIVE STUDY
Authors: Castelli B , Scagnet M , Mussa F , Fonte C , Di Nicola M , Guidi M , Tellini M , Genitori L , Sardi I , Stagi S 
Published: September 2023

Abstract

BACKGROUND
Craniopharyngioma (CP), although slow growing and histologically benign, carries considerable morbidity, particularly in the postoperative period: hypothalamus-pituitary dysfunction and electrolyte disorders represent common complications. Moreover, in these patients, the increased risk of deep venous thrombosis (DVT) and the possible development of fusiform intracranial aneurysms are well known. However, data are still poor, especially in the pediatric population. The aim of our study was to describe the occurrence and timing of DVT and other vascular alterations in neurosurgical operated CP patients and to evaluate the role of predisposing factors in the development of post-surgical and late vascular events.

MATERIAL AND METHODS
This was a single-center, retrospective study. We investigated 19 patients (11 males, 8 females, mean age 10.47±4.29) diagnosed with CP, who had been subjected to neurosurgery between December 2016 and August 2022 in Meyer Children’s Hospital IRCCS in Florence. Demographic and clinical characteristics and surgical data were recorded for each participant.

RESULTS
Five patients (26.3%, 3 females, 2 males, median age 15 years) presented vascular events, all during sodium imbalance. Calcium at lower limits was detected in four of them. Three DVT (two with associated pulmonary embolism, including one female patient’s death) developed after surgery, more frequently at 7-10 days (two patients were central catheter carriers, one obese patient showed hypercholesterolemia and hypertriglyceridemia). In a patient in hyponatraemic state a vascular parietal alteration compatible with pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting and prolonged intensive care. Superficial vein thrombophlebitis was a late complication in an overweight female patient on estrogenic replacement therapy.

CONCLUSION
Patients with CP undergoing neurosurgical brain tumor resection are at a higher risk of developing DVT and vascular alterations, thus careful follow-up should be done in these patients. In our study, we found that the phase of transition from central diabetes insipidus (CDI) to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is probably a significative time for developing this complication; so, we recommend careful monitoring of symptoms suggestive of vascular events in CP operated patients. However, we suggest the execution of a deep vein ultrasound examination in the post-neurosurgical two-four weeks for an early diagnosis of this problem for reducing the risk of severe complications.
P04.09.B UNCOVERING GROUP 4 MEDULLOBLASTOMA THROUGH HUMAN CEREBELLARORGANOIDS
Authors: Leva G , Lago C , Ballabio C , Anderle M , Miele E , Tiberi L 
Published: September 2023

Abstract

BACKGROUND
Central nervous system tumors are the second most prevalent cancers in the pediatric population and among them, medulloblastoma (MB) is the most common and malignant one. MB is divided in four major subgroups: WNT, SHH, group 3 and group 4. Despite this classification, recent studies have highlighted many genetic features shared between the last two subgroups making the patients’ stratification less distinct. Particularly, group 4 MB is the most common subtype, but the least understood. Single-cell transcriptomics studies identified Unipolar Brush Cells (UBCs) as putative cell of origin of group 4 MB subtype. Despite G4 MB being the most common subtype, there is still a paucity of models. In this scenario, my aim is to implement and adapt the cerebellar organoids experimental design already established by Ballabio et al. for G3 MB towards G4 MB modeling.

MATERIAL AND METHODS
We generated cerebellar organoids starting from human pluripotent stem cells. Thanks to the PiggyBac/transposon system and the CRISPR/CAS9 technology we electroporated organoids achieving putative genes’ overexpression and downregulation. Organoids were live-imaged weekly checking for proliferative cells clusters formation and, after having reached the tumorigenic phenotype, they were engrafted in nude mice. The classification of the tumor obtained is based on DNA methylation analysis. Immunostainings were performed on mice cerebella and organoids to identify their cell types.

RESULTS
Because of the aggressiveness and the lack of knowledge of G4 MB, we focused on the development of a cerebellar organoids-based model genetically modified to achieve the tumorigenic phenotype. We studied the best time window in which Tbr2+ (UBCs marker) cells are most present in organoids, deciding to electroporate them at day 70 of differentiation. Based on RNA-seq data of G4 MB patients, organoids were modified with different combinations of genetic alterations. Interestingly, some of them showed the appearance of hyperproliferating engineered cells forming clusters. However, only the co-overexpression of MYCN and Otx2 developed a tumor when engrafted in nude mice. The following DNA methylation analysis attributed the tumor to G3 MB. Hence the need to clone the hTbr2 promoter to guide the expression of oncogenes through a Cre-LoxP system in the UBCs neural progenitors. We confirmed the new promoter specificity through an immunofluorescent quantitative analysis and then performed the genetic screening mentioned above to compare the outcome with our previous results.

CONCLUSION
Despite the timing, the mutational screening performed did not show the expected outcome: since G3 and G4 have common genetic features, we can’t rely on the strong ubiquitous non-specific promoter (CAG). Hence, we suppose that the hTbr2 promoter-guided gene expression could be the promising way toward G4 MB modeling.
P06.05.A INTRACEREBROVENTRICULAR TCR-TRANSGENIC T CELL THERAPY TO TREAT GLIOBLASTOMA (INVENT4GB)
Authors: Bunse L , Kratzmann M , Chih Y , Sanghvi K , de Roia A , Harbottle R , Eichmüller S , Benner A , Green E , Poschke I , Schmidt P , Steinbach J , Vajkoczy P , Bullinger L , Tabatabai G , Stenzinger M , Bönig H , Wick W , Platten M 
Published: September 2023

Abstract

BACKGROUND
Novel concepts in immunotherapy have evolved with the identification of potential (neo)epitopes and/or combinations with immune checkpoint inhibitors (ICI). In contrast to many other solid tumors, ICI have not improved outcome for patients with glioblastoma (GB) in phase 3 studies. However, antigen-specific T cells induced by vaccines or adoptively transferred as chimeric antigen receptor (CAR) T cells produced encouraging responses in early clinical trials and case series. From one of these trials, the Actively Personalized Vaccine Consortium (GAPVAC) European Clinical Trial 101, we have identified a human leukocyte antigen (HLA)-A2-restricted T cell receptor (TCR) targeting protein tyrosine phosphatase receptor type zeta 1 (PTPRZ1). PTPRZ1 is strongly overexpressed in malignant gliomas, especially GB, and analyses of intratumoral heterogeneity revealed that the level of PTPRZ1 overexpression is strongly associated with cancer stemness. The PTPRZ1 epitope is naturally presented on HLA-A2.

MATERIAL AND METHODS
INVENT4GB is a German, multicenter, phase 1, first-in-human, first-of-kind dose-escalation window-of-opportunity investigator-initiated trial in recurrent GB, eligible for re-resection, assessing safety and feasibility of therapy with intravenously (iv) and intraventricularly (icv) infused TCR-engineered T cells (TCR-T). FPI is scheduled for 2024. HLA-A*02:01 positive patients will receive one neoadjuvant iv followed by up to three adjuvant icv infusions of PTPRZ1-specific TCR-transgenic autologous T cell therapy (TCR-T-001) with cyclophosphamide- and fludarabine-based lymphodepletion prior to iv infusion. Patient autologous T cells will be engineered by non-integrating nano scaffold matrix attachment region (SMAR) TCR DNA vectors. Icv infusions will be performed via intraventricular catheter implanted during re-resection. Biomarker discovery includes magnetic resonance imaging (MRI) and longitudinal flow cytometry-based immune monitoring of blood and cerebrospinal fluid. Primary endpoints are feasibility and safety (determination of maximum tolerated dose/ MTD), key secondary endpoints are progression-free survival according to the Immunotherapy Response Assessment in Neurooncology (iRANO) criteria.

RESULTS
TCR-T-001 robustly recognizes target-expressing cells in vitro and is efficacious in preclinical tumor models. Preclinical data and the trial concept will be presented.

CONCLUSION
INVENT4GB is a first-of-kind TCR-engineered T cell therapy for GB patients.
P06.06.B PD-1 CHECKPOINT INHIBITION IN CONJUNCTION WITH NK-92/5.28.Z CELLS IS EFFECTIVE IN AN ADVANCED-STAGE GLIOBLASTOMA MOUSE MODEL AND INDUCES A CD4-ENRICHED T CELL RESPONSE
Authors: Strassheimer F , Roller B , Mildenberger I C , Macas J , Alekseeva T , Tonn T , Sevenich L , Reiss Y , Weber K J , Plate K H , Weigert A , Wels W S , Steinbach J P , Burger M C 
Published: September 2023

Abstract

INTRODUCTION
Checkpoint inhibition in combination with adoptive cell therapy holds promise for cancer immunotherapy, and encouraging treatment responses have already been demonstrated for certain tumor types. Glioblastoma (GB) is the most common and aggressive primary brain tumor with limited efficacy of standard therapy. Analysis of the GB tumor immune microenvironment (TIME) has shown prominent immunosuppressive features, including upregulation of exhaustion markers on tumor and infiltrating immune cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. Previous results from mouse glioma models showed efficacy of off-the-shelf NK-92/5.28.z CAR-NK cells targeted against HER2 as monotherapy in early stage tumors.

RESULTS
Combined treatment with NK-92/5.28.z cells and anti-PD-1 checkpoint blockade resulted in strong synergistic effects, with tumor regression and long-term survival observed even in advanced-stage tumor bearing mice. Analysis of tumor tissues using highplex methods (highplex multicolor flow cytometry, bulk RNAseq and multicolor IHC) revealed changes in lymphocyte infiltration and an altered TIME upon combination treatment with NK-92/5.28.z and anti-PD-1 checkpoint therapy. Specifically, infiltrating lymphocytes displayed an activated phenotype with predominance of CD4 cells and reduction of regulatory T cells.

CONCLUSION
Our data demonstrate that efficacy of HER2-specific NK-92/5.28.z cells can be enhanced by combination with checkpoint blockade. The combination therapy reverted the immunosuppressive TIME, resulting in successful treatment even of advanced othotopic tumors refractory to CAR-NK monotherapy. We are currently translating this concept into early clinical testing by including a respective patient cohort in our ongoing CAR2BRAIN phase I clinical trial (NCT03383978).
P06.14.A DIAGNOSIS AND MANAGEMENT OF NEUROPATHIES RELATED TO IMMUNE CHECKPOINT INHIBITORS: A CASE SERIES
Authors: Cuzzubbo S , Lozeron P , Baroudjian B , D’Oria F , Tétu P , Ursu R , Gounant V , Meppiel E , Lambert T , Ng Wing Tin S , Duchemann B , Belin C , Lebbé C , Carpentier A F 
Published: September 2023

Abstract

BACKGROUND
Immune checkpoint inhibitors (ICIs) are associated with a wide range of neurotoxicities. Several types of neuropathies have been associated to immune checkpoint inhibitors (ICIs), from length-dependent sensory neuropathies to radiculoneuropathies similar to Guillain-Barré syndromes, with an overall incidence estimated to be between 0.1-1.2% of patients. Guidelines recommend prompt ICI discontinuation and the

INTRODUCTION
of steroids depending on the severity of the adverse event. However, the usage of IVIG or plasmapheresis (alternatively or in addition to steroids) has been reported in cases of Guillain-Barré-like syndromes.

MATERIAL AND METHODS
In this study, we report a retrospective consecutive series of patients with an ICI-related neuropathy referred to our department between 2016 and 2021, with the intent to describe their clinical and para-clinical features and the outcome after ICI discontinuation and steroids.

RESULTS
We identified 12 cases of acute peripheral nervous system involvement, with a predominant sensory pattern. The median onset of symptoms from ICI initiation was 18 weeks, and the median number of ICIs doses was 3. Electrophysiological studies, done in 11 patients, showed a radiculopathy in 9 cases, associated with an axonal neuropathy in 3, and a demyelinating neuropathy in 2 cases. Altogether, these findings are consistent with Guillain-Barré-like syndrome. ICIs were stopped in all patients and steroids started in 7 patients, leading to a favourable outcome (complete recovery =7, partial recovery =4, stability =1).

CONCLUSION
This consecutive retrospective series identifies Guillain-Barré-like syndrome as the main clinical pattern of immune related neuropathies. We did not observe any case of length-dependent axonal neuropathy without an associated root involvement. Our systematic management, consisting of ICI discontinuation in all patients and steroids in more severe cases, seems a valid strategy. On the other hand, our results do not support the use of IVIG or other treatments.