bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.02.A Gliotarget: a Danish nationwide phase I/II platform trial focusing on individualized targeted treatment for newly diagnosed glioblastoma patients based on genomic profiling
Authors: Fougner V N , Urup T H , Hasselbalch B , Lassen U , Poulsen H S
Published: September 2022

INTRODUCTION

The survival in glioblastoma has been unchanged since 2005. The introduction of targeted treatments, which have improved survival in several cancers has yet to influence the treatment of glioblastoma. In Gliotarget, we will individualize the targeted treatment, and give it in the primary setting alongside standard therapy with the intention to improve the likelihood of effect.

METHODS

Gliotarget is a biomarker enriched phase I/II platform trial with initially 4 predefined biomarker selected arms and one control arm. All patients receive standard therapy with concomitant radiochemotherapy and adjuvant temozolomide. The experimental treatment is given alongside the adjuvant temozolomide. Molecular analysis, including Whole Genome Sequencing, is performed on all patients, to identify actionable biomarkers. Gliotarget includes newly diagnosed IDH-wt glioblastoma patients. In addition, to exclude the patients where the inherent poor prognosis might conceal the drug efficacy, the patients must have a 50% probability of being alive 12 months after initial surgery, according to a prognostic model developed in our institution. The sample size is calculated with Simon’s two-stage design using treatment effect at 9-months progression free survival (PFS9). We anticipate 9 patients for stage one and 24 in total, for each arm. Treatment effect is defined as 65% of the patients in an experimental arm reaching PFS9. For the survival analysis, supplementing the control arm data with leveraged external controls taken from our prospectively registered database will decrease the probability of false positive results.

CONCLUSION

Gliotarget complements the field of ongoing platform trials with its distinctive trial design. The chosen biomarkers and treatments will be presented at the 2022 EANO meeting. Enrollment is set to open in Q4 2022.
P11.03.B BXQ-350: Modulating ceramide and Sphingosine-1-Phosphate for anti-tumor activity and potential mitigation of chemotherapy induced peripheral neuropathy
Authors: Tapolsky G H , Morris J C , Yilmaz E , Villano J L , Muller C , Curry, III R C , Puduvally V K , Wise-Draper T M , Takigiku R , Wesolowski R
Published: September 2022

Background

Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have indicated that among these sphingolipids, sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell survival and proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Many of these publications have also implicated S1P with chemotherapy induced peripheral neuropathy, a debilitating and serious side effect that may impact therapeutic treatments and patient’s quality of life.

Material and Methods

BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that has broad anticancer activity, potentially in part by lowering systemic S1P levels. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies, including CNS tumors (NCT02859857) to determine its safety profile and its potential clinical activity as a single agent in cancer patients. Samples were collected to determine pharmacokinetics and explore potential biomarkers.

Results

11 patients (~15% of evaluable patients) with advanced disease had a clinical benefit and amongst these, 8 patients (~11% of evaluable patients) had PFS> 6 months with 2 patients still on study five years after enrollment. Analysis of patient’s samples revealed that BXQ-350 decreases systemic S1P levels in the majority of the patients experiencing a clinical benefit. In addition, several patients with established CIPN spontaneously reported improvements of their symptoms shortly after BXQ-350 administration. Analysis of these patients’ samples also revealed that S1P systemic levels had decreased, as well as pro-inflammatory cytokines associated with CIPN.

Conclusion

While these results are exploratory and preliminary in nature, they suggest that BXQ-350’s mechanism of action may represent a novel anti-cancer approach that may also mitigate CIPN.
P11.05.B Communication in neuro-oncology multidisciplinary team meetings (MDTM's)
Authors: van der Bruggen S C P , Beerepoot L , Janssens M , Schouten A , Leenders R
Published: September 2022

Background

The aim of MDTM’s is to ensure that all patients receive qualitative care from appropriately skilled professionals. However, empirical research shows that multidisciplinary team discussions do not always live up to their positive expectations. In discussions the team cycles through three main communicative phases: exploration, discussion and conclusion. The goal of this study is to gain insight in the structure of regional neuro-oncology MDTM’s and find an overarching reason why some discussions follow a different structure (or phase shifts) than others.

Material and Methods

We recorded 14 neuro-oncology MDTM’s in an non-academic Dutch Hospital by audio and video. All recordings were transcribed into time stamped sequences of verbal contributions. Every time stamped sequence was coded using a developed coding scheme.

Results

In total 14 regional Neuro-oncology MDMT’s were recorded, this resulted in 437 patient case reviews and 12512 coded verbal contributions. In each meeting the uniquely contributing members ranged from 12-21 members (M= 15.5, SD = 2.71) from 5 different institutions. The average of different disciplines was 7 disciplines (M=7.14, SD = 0.77). In 41% of the patient discussions there are two or three contributing disciplines in the decision making process. The maximum number of uniquely participating members in a patient discussion is 8 members. In only 28% of the case discussions 5 or more participants participated. Different categories for discussing a patient in an MTDM were found, these categories varied in specificity. From high to low specificity we found: justifying actions, pathology reviews, action-directed questions and open questions. We also found that in 20% of all patient case discussions the teams bypass the discussion phase.

Conclusion

MDTM’s are widely accepted and implemented. Therefore we should gain more insight in the structure and functioning of such teams. We found that there are different reasons for presenting a case which vary in their specificity. Our findings show that teams seem to deviate from the overall communication structure by bypassing the discussion phase in 20% of the cases. We also found that in 28% of patient discussions more than five participants contributed to the discussion. A future direction of organisation of MDTMs could be to clearly categorize on beforehand the patient questions in order to make the MDTM more efficient. Further analysis will include quality evaluation of MDTM’s, in neuro-oncology and other oncology domains. Support/Disclosure: this research is funded by WeCare (an collaboration between Tilburg University and Elisabeth-Tweesteden hospital).
P11.07.B What is the role of brain biopsy in the diagnosis of brain lesions?
Authors: Sivakanthan T S , Joannides A
Published: September 2022

Background

Brain biopsies have a role in establishing histological diagnoses for intrinsic tumours not amenable to surgical resection or lesions with an uncertain radiological diagnosis. Despite their utility, they are associated with several risks, particularly surgical complications and non-diagnostic samples. On this background, this study sought to determine the diagnostic yield and outcomes of brain biopsies carried out in a tertiary centre and explore factors which could influence the overall success of such procedures.

Material and Methods

All non-endoscopic brain biopsy procedures performed over a 1-year period (01/04/2020 to 01/04/2021) at one of the largest neurosurgical units in the UK were included. Hospital electronic records were used to identify eligible patients and determine relevant patient, procedure and outcome data. Mortality data were obtained with a minimum follow-up period of 1 year.

Results

A total of 75 cases were identified, including 55 burr hole biopsies and 20 open procedures. Overall, 16 (21%) biopsies were non-diagnostic, including 25% of burr hole biopsies and 10% of open biopsies. Procedures performed by a consultant had a lower non-diagnostic rate (17%) than cases with no consultant involvement (27%). Suspected inflammatory conditions had a higher non-diagnostic rate (55%) than suspected tumours (11%). Excluding non-diagnostic cases, histological diagnosis was in line with suspected pre-operative diagnosis in 70% of cases. Post-operative complications included 3 symptomatic haematomas and 1 subdural empyema, which led to one post-operative death. A total of 40 (55%) patients died within the follow-up period, including 10 (13%) within 60 days of their procedure. Six-month and 1 year survival rates were 35% and 26% for glioblastoma, respectively, and 70% and 70% for lymphoma. The majority (68%) of patients with a performance status (PS) of 3 or 4 prior to surgery died within 1 year, as compared to 42% with a PS of 0-2.

Conclusion

Brain biopsies are an important adjunct to managing CNS lesions due to the limitations of a radiological diagnosis alone. The diagnostic yield was greater for suspected neoplastic lesions, in cases with consultant involvement, and with open procedures.
P11.08.A Clinical practice evidence for perampanel in epilepsy patients with tumour aetiology
Authors: Coppola A , Izumoto S , Rodríguez-Osorio X , Wu T , D’Souza W , Maschio M , Goldman S , Valente Fernandes M , Villanueva V
Published: September 2022

Background

Real-world studies can provide information on those patients routinely excluded from clinical trials such as epilepsy patients with tumour aetiology. Perampanel (PER) is a once-daily oral anti-seizure medication for focal-onset seizures, with or without focal to bilateral tonic-clonic seizures, and generalised tonic-clonic seizures. This study evaluated PER’s effectiveness and safety when used in everyday clinical practice to treat epilepsy patients with tumour aetiology.

Material and Methods

Patients with epilepsy with tumour aetiology were identified from a pooled analysis of 44 prospective/retrospective/cross-sectional clinical practice studies. Retention was assessed after 3, 6 and 12 months of PER treatment. Effectiveness assessments comprised responder rate (≥50% seizure frequency reduction), seizure freedom rate (no seizures since at least the prior visit), and the proportions of patients with unchanged or worsening seizure frequency. Adverse events (AEs), psychiatric AEs, and AEs leading to discontinuation were also evaluated.

Results

Overall, 127 patients with focal-onset and/or generalised-onset seizures with tumour aetiology were identified (mean age, 46.6 years; 54.8% male; mean duration of epilepsy, 9.7 years). Seizure types at baseline were focal-onset only (97.6%), generalised-onset only (1.6%), and focal-onset and generalized-onset (0.8%). Mean (standard deviation) PER doses at baseline and last visit were 2.6 (1.4) and 5.8 (2.5) mg/day, respectively. At 3, 6 and 12 months, retention rates were 88.0%, 79.5% and 65.3%, respectively. Reasons for discontinuation included AEs (16.8%) and lack of efficacy (5.3%). Mean time under PER treatment was 11.0 months. At 12 months, 71.2% of patients were responders and 38.3% were seizure free; 11.9% and 3.4% of patients had unchanged and worsening seizure frequency, respectively. At the last visit (last observation carried forward), responder and seizure freedom rates were 66.9% and 34.2%, respectively, and the percentages of patients with unchanged or worsening seizure frequency were 15.3% and 6.8%, respectively. AEs were reported for 36.2% of patients, most frequently dizziness/vertigo (13.8%) and somnolence (9.5%). AEs led to discontinuation of 16.8% of patients over 12 months and 13.0% of patients experienced psychiatric AEs.

Conclusion

PER was effective and generally well tolerated when used to treat patients with epilepsy with tumour aetiology in clinical practice. Supported by Eisai
P11.09.B Chemotherapy is an efficient treatment in primary CNS MALT lymphoma
Authors: Desjardins C , Larrieu-Ciron D , Choquet S , Mokhtari K , Charlotte F , Nichelli L , Mathon B , Ahle G , Le Garff-Tavernier M , Dehais C , Hoang-Xuan K , Houillier C
Published: September 2022

Background

Mucosae-associated lymphoid tissue (MALT) lymphomas are a rare and still poorly understood form of primary central nervous system lymphoma (PCNSL). The aim of this study was to better describe these tumors and their management, and to better appreciate their long-term prognosis after treatment.

Material and Methods

Adult immunocompetent patients with primary CNS MALT lymphoma (PCNSML) were retrospectively selected from the database on PCNSL of the Pitié-Salpêtrière Hospital. All cases had double-read for pathology.

Results

Eleven PCNSML representing 1.7% of the 662 PCNSL included in the database were selected, There were 9 women and two men, all immunocompetent. Their median age was 56 years (min 29; max 78). The median time from first symptoms to diagnosis was 13 months and the median KPS at diagnosis was 90. Location was dural in 8 cases, suggestive of meningioma in 7 cases and of subdural hematoma in 1 case, and parenchymal in 3 cases. The disease was unifocal/localized in 4 cases and multifocal/diffuse in 7 cases. In 3 cases, it was the second reading that allowed making the diagnosis. In first-line treatment, all patients received chemotherapy (CT): “systemic” CT, i.e usually used in systemic MALT lymphomas, in 7 cases (n=7) and “CNS” CT, i.e usually used in CNS lesions in 4 cases. CT was preceded by surgery in 4 cases. No patient received radiotherapy in first line. According to the IPCG (International PCNSL Collaborative Group) criteria, the overall response rate was 7/11 (64%). At latest news, 5 patients had a persistent contrast enhancement, stable without any treatment since a median of 57 months, raising the question of complete response despite persisting contrast enhancement. No patient developed neurotoxicity except for one of the 2 patients who subsequently received radiotherapy. The median follow-up was 109 months. The median progression-free survival was 78.0 months (95% CI [43.4;NA[) and the 10-year overall survival rate was 90% (95% CI [0.7;1[).

Conclusion

This series confirms the classical clinical and radiological presentation of PCNSML. Compared to the literature where the treatment was based on radiotherapy in almost two thirds of cases, the therapeutic approach presented here appears unconventional. This is the first series demonstrating that chemotherapy is an efficient treatment in PCNSML, with an excellent long-term outcome and the absence of neurotoxicity, and calling into question the relevance of the IPCG criteria for the evaluation of their therapeutic response.
P11.12.A Primary central nervous system neuroblastoma and ganglioneuroblastoma in adult patients. Clinical and molecular features
Authors: Nechaeva A , Matsko M , Zrelov A , Ulitin A
Published: September 2022

Background

The clinical, morphological, molecular features, treatment modalities, and survival of primary central nervous system neuroblastoma and ganglioneuroblastoma (CNS-NB and CNS-GNB) in adult patients are still poorly understood.

Material and Methods

The study included 15 patients with CNS-NB and 16 patients with CNS-GNB aged 18 years and older who were treated in our clinic from 2008 to 2020. Clinical, radiological data and surgical results were analyzed. Analysis of tumor molecular profile was performed using the gene panel, which contained the majority of clinically significant genes.

Results

Progression-free survival (PFS) and overall survival (OS) were higher in patients with CNS-NB than in patients with CNS-GNB. Median PFS in patients with CNS-NB and CNS-GNB was 156 and 46 weeks, respectively (p=0.022), and median OS was 541 and 82 weeks, respectively (p=0.00045). In both groups, disease progression was more favorable for tumor localization in the cerebral hemispheres without involvement of basal structures (p <0.05). Differences for OS in patients with CNS-NB were obtained when tumor volume was removed by more than 50% with a median OS of 541 weeks (p=0.042) compared to biopsy. In patients with CNS-GNB, total resection of the tumor increased both PFS and OS compared to subtotal resection (p=0.014 and p=0.017), respectively. In patients with CNS-NB, no benefit was observed for any of the different first-line chemotherapy regimens (p > 0.05). In the group of patients with CNS-GNB, 6 cycles of temozolomide increased median PFS compared to other chemotherapeutic regimens (p=0.026). In CNS-NB, a high level of expression was observed only in the βIII-tubulin gene (54%, 7/13). In CNS-GNB, high levels of expression were found in three genes: PDGFR-α (54%, 7/13), VEGF (54%, 7/13), and βIII-tubulin (85%, 11/13). No statistically significant effect of mutation in IDH1(R132H) gene on median PFS and OS was observed. The OS of patients with CNS-NB and CNS-GNB was influenced by low or medium levels of VEGF expression (p=0.006), and the OS was influenced by three genes: ERCC1 (p=0.03), MGMT (p=0.029) and VEGF (p=0.002).

Conclusion

The morphologic type of the tumor determined survival. In both groups, median PFS and OS were influenced by tumor localization. The most important prognostic marker in adult patients with CNS-NB and CNS-GNB was VEGF, while MGMT and ERCC1 were predictive markers.
P11.13.B Long-term outcome of patients with WHO grade 3 glioma treated with radiotherapy and temozolomide or radiotherapy alone
Authors: Kiese D , Caliebe A , Haag J , Röcken C , Synowitz M , Ahmeti H
Published: September 2022

Background

For a long time, for patients with WHO grade 3 glioma the gold-standard after surgical treatment has been radiotherapy (RT). Since the combined radio-chemotherapy became the standard as a postoperative therapy for patients with glioblastoma in 2005, the role of radio-chemotherapy with temozolomide (RT/TMZ) for patients with WHO grade 3 glioma has long been controversial. Evidence is growing that RT/TMZ provides advantages in progression-free survival (PFS) and overall survival (OS) in WHO grade 3 gliomas as well. The aim of this study was to compare RT/TMZ (after 2005) and RT alone (before or after 2005) for patients with WHO grade 3 glioma in the long term.

Material and Methods

167 adult patients with first diagnosis of a WHO grade 3 glioma between 1994 and 2019 and treatment with surgery and either RT/TMZ (after 2005) or RT (before or after 2005) were included. Clinical and sociodemographic parameters as well as IDH1/2-mutation-, MGMT-promotor methylation- and 1p/19q-codeletion-status of the patient’s FFPE-tumor-tissue have been retrospectively investigated. Primary outcome was PFS and OS depending on postoperative treatment with RT before 2005 (n = 75) vs. RT after 2005 (n = 33) vs. RT/TMZ after 2005 (n = 48). Therefore, Kaplan-Meier analysis has been performed.

Results

RT before 2005 showed a significant advantage over RT/TMZ after 2005 and RT after 2005 regarding the PFS (p < 0.05) and OS (p < 0.001). Median PFS was 3.34 years (95%-CI = 1.08 - 5.59) for RT before 2005 vs. 1.96 years (95%-CI = 0.89 - 3.02) for RT/TMZ after 2005 and 1.22 years (95%-CI = 0.00 - 2.50) for RT after 2005. RT/TMZ after 2005 showed a significant advantage over RT after 2005 regarding the OS (p < 0.05). Median OS was not reached for RT before 2005 vs. 4.90 years (95%-CI = 2.14 - 7.66) for RT/TMZ after 2005 and 1.60 years (95%CI = 0.43 - 2.78) for RT after 2005. To measure the variability of the therapy groups, a stratified risk analysis of risk factors including IDH1/2-mutation-, MGMT-promotor-methylation- and 1p/19q-codeletion-status, extent of resection, initial Karnofsky Performance Score, Ki67-score, age, gender, tumor entity and dose in gray has been performed by using the Kruskal-Wallis test and Fisher-Freeman-Halton test. There has been a significant difference in IDH1/2-mutation- and MGMT-promotor-methylation-status and dose in gray. Single risk analysis of that parameters resulted in superiority of the RT before 2005 over RT/TMZ after 2005 and RT after 2005 regarding the OS.

Conclusion

There have been several limitations in this study, for example the retrospective setting or the missing randomization of the patients. RT before 2005 resulted in the best long-term outcome, what has to be further investigated. However, RT/TMZ after 2005 showed a significant benefit for the OS in the long term vs. RT after 2005, supporting recent findings regarding the role of RT/TMZ in the therapy of WHO grade 3 gliomas.
P11.17.B Molecular characterization of primary central nervous system lymphoma vs non-CNS lymphoma and correlation between mutational profile and treatment response
Authors: Tuohy K J , Wirk B , Aregawi D , Xiu J , Sumrall A , Glantz M
Published: September 2022

Background

Primary central nervous system lymphoma (PCNSL) is a unique type of non-Hodgkin lymphoma restricted to the central nervous system. Most cases are diffuse large B-cell lymphomas, but prognosis is far less favorable compared to extracerebral cases. Many mutations found in PCNSL converge on the NF-κB signaling pathway, leading to downstream activation of B-cell receptor (BCR) and NF-κB pathway. The differences in mutation frequency when compared to non-CNS lymphoma and how mutational profiles affect treatment response are not well understood. We compared the genomic profile of PCNSL and non-CNS lymphoma, evaluated the association between specific molecular alterations and survival, and analyzed the association between various mutations and response to therapy.

Materials and Methods

A total of 60 patients with PCNSL, 8 with secondary CNS lymphoma, and 202 with non-CNS B-cell lymphomas underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next-generation sequencing of DNA (592 Genes, NextSeq or WES, NovaSeq) and RNA (WTS, NovaSeq). X2/Fisher’s-exact U tests were used for comparison, and significance was determined as p-value adjusted for multiple comparison by the Benjamini-Hochberg method (q<0.05). Overall survival (OS) was calculated from the start of temozolomide (TMZ) or tissue collection to last contact using insurance claims data.

Results

When compared to non-CNS lymphomas, PCNSL tumors showed significantly higher mutation rates in MYD88 (70% vs. 7%), PIM-1 (58% vs. 7%), CD79B (42% vs. 3%) and higher rates of TMB-High (cutoff 10mut/MB; 28% vs. 10%) (q<0.01). In addition, mutations in CARD11 (12% vs. 4%) and IRF4 (8% vs. 1%) trended to be more prevalent in PCNSL (p<0.05). In contrast, mutations in KMT2D (35% vs. 16%), EZH2 (13% vs. 2%), CREBBP (22% vs. 7%), TNFRSF14 (10% vs. 0) and BCL2 (19% vs. 2%) trended to be more prevalent in non-CNS lymphomas compared to PCNSL (p<0.05). In patients with PCNSL, there was no difference in survival in those with or without MYD88, PIM1 or CD79B mutations. No between-group differences were observed in the small cohort of patients with secondary CNS lymphoma (n=8). In the subgroup in whom these data were available, 25% of tumors were MGMT methylated, 71% had a “high or intermediate” tumor mutational burden, 8% were MSI high, and 54% were PD-L1 expression positive when tested by immunohistochemistry. Patients with PCNSL had worse overall survival (OS) than non-CNS lymphomas (30 vs 81 months, p<0.001).

Conclusion

MYD88, PIM-1, and CD79B mutations are more frequent in PCNSL compared to non-CNS lymphomas, but none of these mutations affected OS. Only 25% of PCNSL patients are MGMT methylated, but a majority have expression of PD-L1 suggesting a benefit from PD-1-targeted therapy. Response and survival in patients with mutation-guided therapy will be presented.
P11.20.A Correlation between thyroid function and regorafenib activity in recurrent IDH wild-type(IDHwt) glioblastoma(GBM) patients: a large monocentric study
Authors: Caccese M , Padovan M , Cerretti G , Cavallin F , Zagonel V , Lombardi G
Published: September 2022

Background

Glioblastoma is the most frequent CNS malignant tumor, with high aggressiveness and poor prognosis. Regorafenib has recently demonstrated promising activity in terms of survival in recurrent glioblastoma patients. The impact of thyroid function on regorafenib activity has alreasy described in in patients with other types of tumors. This study aimed to investigate the relationship between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4 ratio) and survival in IDHwt GBM patients who were treated with regorafenib.

Material and Methods

We retrospectively evaluated all consecutive recurrent IDHwt GBM patients who were treated with regorafenib at the Veneto Institute of Oncology in Padua (Italy) for which baseline thyroid function assessment was available prior to starting regorafenib. Major inclusion criteria were: histological diagnosis of IDHwt glioblastoma, regorafenib as second-line treatment, basel thyroid values available.The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4 ratio) and outcomes (PFS, OS) were investigated with Cox regression models, where thyroid variables were modeled with first order polynomial or restricted cubic splines.

Results

We enrolled 108 recurrent IDHwt glioblastoma patients treated with regorafenib at our center From November 2015 to January 2022: 70% were male and median age was 50 years old. All patients received post-surgical treatment with concomitant chemotherapy and subsequent temozolomide according to Stupp protocol as first-line therapy. 32 patients (30%) underwent a second surgery upon recurrence. From starting regorafenib the median follow-up was 7.3 months (IQR 4.0-12.7). MedianPFS was 2.2 months (95% CI 2.0 to 3.4), and PFS rate was 43-13-4% at 3-6-12ms, respectively. MedianOS was 10.4 months (95% CI 7.5 to 14.5), and OS rate was 92-70-46% at 3-6-12 months, respectively. Disease Control Rate (DCR) was 42.7%. Univariate analysis suggested that the relationship between PFS and baseline fT4 may be modelled with first order polynomial (linear term p=0.06, non-linear term p=0.61) and also suggested a non-linear relationship between PFS and baseline fT3/fT4 (linear term p=0.06, non-linear term p=0.04).When adjusting for major clinical confounding factors (age, ECOG PS, second surgery, MGMT), multivariate analysis identified that baseline fT4 (as a continuous variable) is an independent risk factor for PFS (HR 1.09, 95% CI 1.02 to 1.17; p=0.02). We did not find any statistically significant associations between all baseline thyroid variables with OS and response.

Conclusion

Our study demonstrated fT4 value to be a predictive biomarker of PFS in recurrent glioblastoma patients treated with regorafenib. No correlation was showed between baseline thyroid function and survival.
P11.30.A Stereotactic Radiosurgery (SRS) for brain metastases in breast cancer: An evaluation of outcomes at a UK tertiary centre
Authors: Abdul Haris P , Brazil L , Blythe K , Chia K , Hassan S , Loganathan T , Smith D , Swampillai A , Al-Salihi O
Published: September 2022

Background

Brain metastases (BM) occur in approximately 10-30% of patients with breast cancer (BC). Patients with advanced breast cancer are living longer, and the incidence of BM are increasing. Stereotactic Radiosurgery (SRS) has emerged as a strategy to treat BM. We evaluated the outcomes and potential prognostic factors of patients with BM treated with SRS.

Material and Methods

Retrospective review of patients treated with linac-based SRS for BM from BC in a single tertiary centre between August 2017-September 2021. Overall survival (OS), intracranial progression-free survival (IPFS), and prognostic factors were evaluated using Kaplan-Meier analysis, log-rank test, and Cox proportional-hazards model.

Results

76 patients were included in the analysis. Out of these, 56 had first-line local treatment with SRS, either as primary (n=34) or adjuvant to surgery (n=22). Median age was 58 years old (range 37-86), and 88% had PS 0/1. One-year survival rate was 56%.

Median OS and IPFS from SRS was 16 months (95% CI 8-24) and 7 months (95% CI 2-12), respectively. However, there were significant differences in OS (p<0.001) and IPFS (p=0.001) based on molecular subtypes. Patients with triple-negative breast cancer (TNBC) (n=14) had median OS of 7 months (95% CI 2-12), ER+/HER2- (n=22) median OS of 22 months, ER-/HER2+ (n=8) median OS of 4 months (95% CI 0-9), and ER+/HER2+ (n=11) median OS of 36 months. Similar trend was seen with IPFS.

Patients with progressive extracranial disease compared to stable disease had shorter median OS (4 months vs 23 months, HR 2.4, p=0.01) and median IPFS (4 months vs 13 months, HR 2, p=0.03). Age ≥65 years was associated with shorter median OS (4 vs 23 months, HR 2.3, p=0.02). Patients with ≥4 brain metastases had shorter IPFS (4 months vs 11 months, HR 2.4, p=0.012), but no significant difference in OS. Volume of metastases did not affect outcome in this series.

30% of patients progressed intracranially after first-line SRS. 94 % had out-of-field recurrences, and 6% in-field recurrences. 59% had further SRS, 12 % WBRT, 6% surgery, and 23% had no further local treatment.

26 patients had second-line local treatment with SRS after first-line SRS (n=9), WBRT (n=9), or surgery +/- WBRT (n=8). There were no significant differences in outcome based on the modality of first-line local treatment.

Conclusion

SRS is an effective treatment for BM from BC. There were significant differences in survival based on age, molecular subtypes, and extracranial disease status.
P11.31.B Pseudotumor Cerebri - a rare paraneoplastic manifestation
Authors: Ivan R , Nistor L C , Lipan C G , Mezei R M , Sirbu C A
Published: September 2022

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 her 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.
P11.32.A EGFR expression and non-methylated MGMT predict distant recurrence in glioblastoma patients treated with standard therapy
Authors: Urup T , Trip A K , Chiranth S B , Christensen I J , Grunnet K , Møller S , Hasselbalch B , Muhic A , Lassen U , Poulsen H S
Published: September 2022

Background

Infiltrative growth within the central nervous system is hallmark of glioblastoma (GBM) at time of diagnosis. Targeting infiltrative glioma cells by adding chemotherapy to local treatment (surgical resection and radiotherapy) has led to improved tumor control and survival. Still, infiltrative growth is a major factor in therapeutic failure and tumor recurrence is almost inevitable. Herein, we hypothesize that distant recurrence represents a more migratory phenotype and that biomarkers associated with distant recurrence can be used to personalize the treatment. The aim of this study was to identify clinical and molecular factors associated with distance recurrence in glioblastoma patients treated with standard therapy.

Material and Methods

A prospective cohort of consecutive, non-selected GBM patients administered standard therapy as primary treatment between 2005-2020 at Rigshospitalet, Copenhagen, Denmark. Distant recurrence was defined as a new contrast-enhancing tumor lesion outside the radiation field (> 2 cm from the gross tumor volume). Clinical and molecular factors were screened for association with time to distant recurrence (p < 0.30) using univariate analysis. The final model was generated employing multivariate Cox regression analysis to model the association with time to distant recurrence. It was chosen to maintain known prognostic factors in the model and subsequently add significantly associated factors (p < 0.05). Competing risk adjusted analysis were performed with death as a competing risk.

Results

A total of 897 patients were included and at a median follow-up time of 73 (range: 12-198) months, 733 patients were evaluable for recurrence pattern. Out of 733 patients, 146 patients (20%) had distant recurrence. Median time to tumor progression was 7.0 months for patients with a local recurrence and 8.0 months for those with a distant recurrence (p=0.31). The following prognostic factors were not associated with distant recurrence by multivariate analysis: Corticosteroid use (p=0.84), age (p=0.20), multifocal disease (p=0.81), ECOG performance status (p=0.99) and degree of tumor resection (p=0.20). In multivariate analysis, factors independently associated with a higher likelihood of distant recurrence were: Non-methylated promoter of the MGMT gene (HR=1.93; 95% CI: 1.27-2.95; p=0.002) and positive expression of Epidermal Growth Factor Receptor (EGFR) by immunohistochemistry (HR=3.70; 95% CI: 1.61-8.33; p=0.002).

Conclusion

Non-methylated MGMT and positive expression of EGFR were independently associated with a higher likelihood of distant recurrence in GBM patients treated with standard-of-care. These factors, if validated, can be used for risk stratification and to enrich clinical treatment protocols aiming at improved local or distant tumor control.
P11.34.A Pseudoprogression in cases of brain metastases and its neurooncological pitfalls under PD-1 inhibitor therapy in the era of personalized medicine
Authors: Schulz T , Cattaneo A , Löhr M , Dufner V , Monoranu C , Keßler A
Published: September 2022

Background

Immunotherapy plays an increasing role in combating malignant cancers. Recently, there has been a noticeable uptick of pseudoprogression mimicking true tumor growth or even intracranial abscess. PD-1 inhibitors especially have come under scrutiny for imitating progressive diseases. Here, we summarize our departmental findings to this regard.

Material and Methods

We analyzed the clinical, intraoperative and neuropathological findings as well as perioperative radiological imaging in four cases.

Results

Four patients (three males and one female, ranged 52-74 years) underwent resection for brain metastases and were subsequently treated with radiotherapy and with PD-1 inhibitors. Within one-year post-surgery, cranial MRI-imaging showed space-occupying, contrast enhanced lesions in all four patients. In two cases FET-PETs were performed pre-operatively. They showed a significant increase in aminoacid uptake. In two cases, 5-aminolevulineacid (5-ALA) was applied pre-operatively. In one case, there was considerable 5-ALA uptake. The fourth patient presented radiological signs of an abscess and underwent emergency surgery. The neuropathological workup of all tissues in question depicted highly increased activity of lymphocytes and microglia, accompanied by necrosis. All cases were classified as pseudoprogression, which, on top, had developed supramarginally in previously healthy tissue.

Conclusion

Neurooncologists face crescent challenges in the increasing cases of pseudoprogression under/after immunotherapy. Radiological imaging doesn’t seem to be able to clearly differentiate between true and pseudoprogression. Even FET-PETs, in general a valid diagnostic tool, seem to be fooled by checkpoint inhibitors. Furthermore, pseudoprogressive tissue after PD-1 inhibitor therapy might mimic tumor tissue intra-operatively by increased 5-ALA uptake. All these characteristics increase the risk of overly aggressive resection of the suspected cancerous or infectious, but in the end pseudo-progressive tissue. Brain edema and clinical symptoms spurred by pseudoprogression may be an indication for surgery, but the risk of performing possibly unnecessary surgery based on radiological findings fooled by PD-1 inhibitors should be taken into consideration. At this point, there does not seem to be a foolproof diagnostic method to differentiate pseudo- from true progression. And there is the possibility that the pseudoprogression is happening in tissue adjacent to the previously resected lesion. Neurooncologists need to acknowledge that pseudoprogression under/after immunotherapy will become only more prevalent in the future and take this message to their patients.
P11.38.A Case reports on aggressive Pilocytic astrocytoma in TYA and adults: patient tailored approach or standard of care?
Authors: Gupta S , Brazil L , Swampillai A , Al-Salihi O
Published: September 2022

Background

Pilocytic astrocytoma (piloA) is a low grade brain tumour and most of the literature is based on paediatric patients with limited data on adults. Surgical resection followed by adjuvant treatment for recurrent lesions is standard of care. While previous literature was mainly based on historical classification, molecular analysis of tumour is adding to the subgroup classification.

Material and Methods

We are reporting 3 cases of adult piloA treated at our institute.

Results: Case1

31y female with headaches and visual problems was diagnosed with optic nerve glioma, biopsy confirmed piloA, and was treated with conventional radiotherapy 50Gy/30fr. A month later developed CSF dissemination requiring 10xTemozolamide. Two years later, developed L5 and S2 deposits which were resected and confirmed piloA. 5 years later there was progression of primary disease treated with 12xTemozolamide and a year later developed further progression and hydrocephalus. She received 1xPCV and succumbed to disease at the age of 42. Case 2: 29y female with severe dizziness on moving head, worsening headaches, word finding difficulty, and positive family history of anaplastic astrocytoma, was diagnosed with Tectal plate lesion. Surgical debulking was performed and pathology showed piloA with Methylated MGMT promoter, IDH wild-type, H3K27M negative, and no BRAF fusion. 3 years later developed recurrence which was treated with chemotherapy (5xPCV: 6th omitted due to recurrent infections) as patient was reluctant for radiotherapy. Follow up scans 6 months post chemotherapy remain stable. Case 3: 24y female with background of 2 haemorrhagic strokes, left spastic hemi-paralysis and left hemianopia, and negative family history, had a biopsy performed for Right Mesotemopral Cavenous Angioma. Pathology showed low grade neoplasm favouring Ganglioglioma with CD34 and IDH1 negative, ATRX retained, KI-67 focal index 5%, and no BRAF fusion or mutation. Surveillance imaging showed progressively increasing suprasellar mass and right temporal region enhancement which was surgically debulked at the age of 27. Repeat pathology examination favoured piloA considering the radiological progression. Methylation array failed but immunohistochemistry showed tumour cells positive with synaptophysin, ATRX and trimethylated H3K27 retained, H3K27M, NeuN, H3G34R and CD34 negative, p53 negative, and Ki-67 3-4%. Repeat imaging 10 months later showed further progressive suprasellar tumour and enhancing lesion in the right temporal area accompanied by rapid loss of right side vision. We have planned for radical radiotherapy 54Gy/30fr with IMRT.

Conclusion

There is a gap in management of piloA in adults with treatment extrapolated from paediatrics and does require further research. We want to approach other centres to establish consensus on treating such cases.
P11.44.A The impact of heme biosynthesis regulation on glioma aggressiveness: correlations with most recent diagnostic molecular markers
Authors: Mischkulnig M , Kiesel B , Rötzer-Pejrimovsky T , Borkovec M , Lang A , Millesi M , Wadiura L I , Hervey-Jumper S , Penninger J M , Berger M S , Widhalm G , Erhart F
Published: September 2022

Background

The prognosis of patients with diffusely infiltrating gliomas is dismal but varies greatly between individuals. While characterization of gliomas was primarily relied on typical histopathological features, specific molecular markers increasingly gained importance and play a key role in the recently published 5th edition of the World Health Organization (WHO) classification. Heme biosynthesis represents a crucial pathway due to its key role in oxygen transport, energy production or drug metabolism. Recently, we described a “heme biosynthesis mRNA expression signature” that correlates with histopathological glioma grades and patient survival. The aim of the current study was to correlate the heme biosynthesis mRNA expression signature with the most recent diagnostic molecular markers for glioma stratification.

Material and Methods

In this study, patient data were derived from the “The Cancer Genome Atlas” (TCGA) lower-grade glioma and glioblastoma cohorts. We identified diffusely infiltrating gliomas correlating molecular tumor diagnosis according to the most recent WHO classification with heme biosynthesis mRNA expression. The following molecular markers were analyzed: EGFR amplification, TERT promoter mutation, CDKN2A/B homozygous loss, concurrent chromosome 7 gain/10 loss, MGMT methylation, IDH mutation, ATRX loss, p53 mutation and 1p19q co-deletion. Subsequently, we calculated the heme biosynthesis mRNA expression signature and correlated this signature with distinct molecular glioma markers as well as the resulting molecular subgroups.

Results

A total of 649 patients with available data on up-to-date molecular markers and heme biosynthesis mRNA expression were included. According to analysis of individual molecular markers, we found a significantly higher heme biosynthesis mRNA expression signature in gliomas with IDH wildtype (p<0.0005), without 1p19q co-deletion (p<0.0005), with homozygous CDKN2A/B loss (p<0.0005) and with EGFR amplification (p=0.001). Furthermore, we observed that the heme biosynthesis mRNA expression signature increased with the aggressiveness of the molecular subgroups (p<0.0005), being lowest in WHO grade 2 oligodendrogliomas and highest in WHO grade 4 glioblastomas.

Conclusion

Our data demonstrate a significant correlation between diagnostic molecular markers and heme biosynthesis regulation in diffusely infiltrating gliomas. Consequently, heme biosynthesis expression is a promising biomarker for glioma aggressiveness and might constitute a potential target for novel therapeutic approaches.
P11.45.B Improved overall survival following Stereotactic Radiosurgery for brain metastases - a single institution experience
Authors: May C , Forshaw M , Wong H , Brass R , Corns A , Shenoy A , Mehta S
Published: September 2022

Background

Brain metastases are increasingly common due to longer survival associated with advancements in treatment. Approximately 40% of cancer patients are diagnosed with brain metastases at some point during their disease. Stereotactic radiosurgery (SRS) avoids the neuro-cognitive toxicity associated with whole brain radiotherapy and has been increasingly offered as a treatment alternative for brain metastases. Combined with developments in systemic treatments, this approach has resulted in improved overall survival (OS). This study reviewed patients treated with single fraction SRS at our institution with a primary endpoint of overall survival.

Material and Methods

A retrospective review determined overall survival for 237 patients who received single fraction SRS for 451 brain metastases from solid tumours between 1st January 2017 and 31st December 2021. Primary tumour sites were classified as breast, kidney, colorectal, melanoma, lung or other. SPSS v.27 was used for Kaplan Meier OS determination. The median follow up was 10.3 months. Cox regression analysis assessed the association between Gross Tumour Volume (GTV) and OS.

Results

In this patient cohort, 60% (N=142) were female and 40% (N=95) were male, with a median age of 63 [32-85]. 63.7% (N = 151) had a solitary metastasis. Patients received a single fraction of 15, 17.5 or 20 Gy (prescribed to 80% isodose) dependent on the planning target volume (PTV) size and whether it was initial treatment or re-treatment. 71% of all patients were alive at 6 months with median OS of 12.0 months [10.6-13.4]. Primary tumour site significantly affected OS (Log rank, Chi squared 15.656, p0.008) with breast cancer patients (N=58) surviving longest with a median OS 16.0 months [13.6-18.4] followed by melanoma median OS 15.0 months [7.6-22.4], kidney cancer patients (N = 24) median OS 12.0 months [8.3-15.7] and lung patients (N=87) median OS 10.0 months [8.9-11.3]. The lowest median OS was for colorectal patients at 7.0 months [1.4-12.6]. However, considering the small sample size, N = 15, more data is needed to confirm the significance. The larger the GTV volume the lower the survival time (Chi squared 8.692, p 0.003).

Conclusion

71% of patients had an OS of 6.0 months or more with a median of 12.0 months. As expected, primary tumour site has a significant impact on OS, with breast cancer patients living longest. In addition, increasing GTV size is associated with significantly worse survival. Given the improved survival for these patients, the avoidance of neuro cognitive decline remains of paramount importance and outcomes for these patients need to be reported in future work.