bluuebunny/crossref_metadata_2025 huggingface dataset:
P11.49.B MOG antibody positive paraneoplastic brain stem encephalitis associated with cervical cancer: a rare case report
Authors: Bieler L , Hecker C , Machegger L , Wolfrum-Ristau P , Trinka E , Kleindienst W
Published: September 2022

Background

Paraneoplastic neurological syndromes are a rare complication of malignant tumors. Myelin oligodendrocyte glycoprotein (MOG) is an important marker on the surface of oligodendrocytes and is associated with many demyelinating diseases. There are only few reports of MOG antibody positive paraneoplastic syndromes. Here we present the first case of MOG-antibody positive brain stem encephalitis associated with cervical cancer.

Material and Methods: Case report.

Results

A 58-year-old female presented with headache, fever and acute cerebellar signs. 13 months earlier she was diagnosed with cervical cancer and ovarian metastases. Adnexectomy was performed and she received adjuvant chemo- and radiotherapy. At admission cerebrospinal fluid (CSF) analysis showed pleocytosis (90 cells/µl) with a mixed cell profile but no malignant cells could be detected. Protein and lactate were highly elevated. The patient was treated with aciclovir and ceftriaxone until serology and liquor PCR showed no evidence of systemic or cerebral infections. Initial magnetic resonance imaging (MRI) of the brain was unremarkable. The patient was symptomatically treated. CSF two weeks later showed 53 cells/µl, protein and lactate almost normal. Contrary to the mild improvement of CSF parameters, cerebellar symptoms worsened, and the patient complained about impaired vision and diplopia. MRI revealed gadolinium enhancing lesions of the left mesencephalon and the right N. opticus. Visual evoked potentials confirmed a demyelinating lesion of the right N. opticus. We then assumed paraneoplastic brain stem encephalitis and the patient received high dose methylprednisolone and immunoglobulins. Ultimately, lab results came back positive for anti-MOG-antibodies, while paraneoplastic panels were negative. At follow-up three weeks later, CSF analysis showed normal cell count and brain MRI was unremarkable again. MOG-antibodies however remained positive. Since then, the patient has received monthly immunoglobulins leading to a stable neurological status. Unfortunately, the cancer itself is progressive with a local relapse and metastases of liver, lung and bones.

Conclusion

Our patient had an acute presentation of a rare brain stem encephalitis. However, infectious workup as well as all well-known onconeural antibodies showed negative results. This shows that pleocytosis in patients with a history of malignant disease is highly suggestive for paraneoplastic neurological syndromes even if common antibodies show negative results. Clinicians should be aware of other autoimmune antibodies like anti-MOG-antibodies and should extend workup if necessary. Vice versa it is worth considering tumor workup in patients with neurological symptoms and anti-MOG-positivity. Furthermore, the appearance of paraneoplastic neurological syndromes is always suspicious for progressive disease.
P11.50.A Surgical results and long-term outcome in supratentorial intraventricular tumors
Authors: Teske N , Chiquillo M , Skrap B , Blobner J , von Baumgarten L , Kunz M , Tonn J , Thon N , Karschnia P
Published: September 2022

Background

Intraventricular tumors (IVTs) are rare lesions of various entities, which pose a surgical challenge. We aimed to elaborate on surgical approaches and outcomes, postoperative morbidity, and elucidate whether preoperative hydrocephalus necessitates shunting despite surgical resection.

Material and Methods

We retrospectively searched the institutional database for patients with supratentorial intraventricular tumours that were treated in the Department of Neurosurgery of the Ludwig-Maximilians-University Munich, Germany between 2014 and 2022.

Results

We identified 60 patients with supratentorial intraventricular tumors comprising over 10 different tumor entities, most often subependymoma (8/60 patients, 13.4%). Median age at diagnosis was 45.5 ± 3.0 years with 31 male patients (51.6%) and 29 female patients (48.3%). Microsurgical tumor resection was completed in 44 patients (45/60 patients, 75%; gross total resection: 36/45 patients, 80%; subtotal resection: 9/45 patients, 20%). In cases where neurosurgical tumor resection was not feasible, stereotactic biopsy was provided in 15/60 patients (25%), often combined with stereotactic internal shunt implantation (8/60 patients, 13.3%). Mean follow-up was 17 months; median overall survival was not reached. Postoperative persistent hydrocephalus necessitating ventriculoperitoneal shunt placement was rare (4/60 patients, 6.7%). Ventriculocisternostomy was performed in one patient. New postoperative focal neurological deficits - mostly transient - were encountered in 16/60 patients (26.6%) at discharge. Postoperative adverse events rate was 11.7%.

Conclusion

Complete resection of IVT can often be achieved and forms the basis for favourable outcome. Permanent neurological deficits are rare, and hydrocephalus can almost always be alleviated which prevents the need for long-term shunting. If microsurgical resection is not feasible, stereotactic biopsy along with internal shunting represents an effective approach to establish diagnosis and ameliorate symptoms.
P11.52.A Peripheral neuropathies after BRAF and/or MEK inhibitors treatment: a pharmacovigilance study
Authors: Picca A , Birzu C , Berzero G , Sanchez-Pena P , Gaboriau L , Vidil F , Lenglet T , Tafani C , Ricard D , Psimaras D , Bihan K
Published: September 2022

Background

BRAF (BRAFi) and MEK inhibitors (MEKi) demonstrated significant efficacy in the treatment of BRAF-activated tumours, firstly melanoma. Nevertheless, they are not devoid of adverse events. Sparse reports in the literature suggest the potential occurrence of peripheral neuropathies (PN) under BRAFi/MEKi treatment, but their characteristics remain poorly defined. We aimed to characterize the clinical phenotypes of PN occurring under BRAFi/MEKi treatment using a national pharmacovigilance database.

Material and Methods

We queried the French pharmacovigilance database for all cases of PN toxicity attributed to at least one BRAFi or MEKi compound. Only cases with a least symptoms description and nerve conduction studies (NCS) conclusion were included.

Results

Sixteen cases of PN occurred in 15 patients were identified. All patients had underlying melanoma. Two main phenotypes were seen. Six patients (dabrafenib-trametinib, n=3; vemurafenib, n=2; vemurafenib-cobimetinib, n=1) presented a length-dependent axonal polyneuropathy: symptoms were mostly sensory at lower limbs; NCS disclosed an axonal neuropathy; management and outcome were variable. Nine patients (dabrafenib-trametinib, n=5, encorafenib-binimetinib, n=3, and vemurafenib-cobimetinib, n=1) developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness, and ataxia; cranial nerves were involved in four; NCS showed predominantly demyelinating features; most patients received intravenous immunoglobulins (n=6) or glucocorticoids (n=5), but the outcome was variable; one patient was rechallenged with a different BRAFi/MEKi with a rapid relapse.

Conclusion

Patients under treatment with BRAFi/MEKi may develop treatment-induced PN. Two main phenotypes are seen: a symmetric, axonal, length-dependent polyneuropathy, and a demyelinating polyradiculoneuropathy.
P11.56.A Shared and personalized decision-making in pre-surgical consultations of brain tumor patients and neurosurgeons
Authors: Bras I J M , Sitskoorn M M , van Vugt I J M , Joosen M C W , Hoogendoorn A P Y , Rutten G J , Gehring K
Published: September 2022

Background

In order to assess whether the oncological benefits outweigh the functional risks of treatment for an individual patient, it is important that physicians involve patients in decision-making and personalize the process. This is especially important for brain tumor patients considering the limited treatment options available. The aim of this study is to evaluate shared decision-making and the personalization of the decision-making process during consultations of brain tumor patients and their neurosurgeons.

Material and Methods

For this observational study we collected 66 audio-recordings of pre-surgical consultations of adult brain tumor patients (glioma, meningioma) and their neurosurgeons. A preliminary analysis based on a shared decision-making template was conducted on 14/66 transcribed audio-recordings to assess in how many consultations the following key elements of shared decision-making were present, namely 1) offering a choice to the patient and emphasizing that the patient’s perspective is important in making the decision, 2) discussing treatment options with benefits and risks and 3) asking about treatment preferences and personal goals. Next, thematic analysis will be performed by two independent researchers until data saturation is reached to gain insight into personalization of the decision-making process as an integral part of shared decision-making.

Results

Preliminary findings show that 1) offering the patient a choice and emphasizing that the perspective of the patient is important in decisions was done in 12/14 consultations; 2) discussing treatment options with benefits and risks was present in every consultation (14/14); and 3) in 12/14 consultations the neurosurgeon asked the patient about his or her treatment preference. However, explicitly asking the patient about personal goals occurred only in 3/14 consultations. By the time of the conference, we expect to have explored the decision-making process more in-depth and will be able to share the themes we have identified related to personalization of the decision-making process.

Conclusion

Key elements of shared decision-making were present in most pre-surgical consultations, except for asking patients about their personal goals. Discussing personal goals that patients have concerning daily life may facilitate personalization of the decision-making process.
P11.58.A Case of a complex neurocutaneous syndrome characterized by extensive peripheral nerve sheath tumors and somatic ERBB2 mutation
Authors: Barden M , Baehring J
Published: September 2022

Schwannomatosis is a rare genetic tumor predisposition syndrome characterized by the presence of multiple non-intradermal schwannomas and the definitive absence of vestibular nerve involvement. Though considered benign, the burden of tumors can cause significant morbidity in the form of motor dysfunction and refractory neuropathic pain. Treatment is focused on mitigating these symptoms, which includes resection of offending tumors when feasible and anti-angiogenesis therapy with bevacizumab. Options for targeted medical therapies are lacking. Schwannomatosis is molecularly distinct from the other neurofibromatoses and by definition lacks constitutional mutations in NF1 and NF2. Instead, constitutional mutations in SMARCB1 or LZTR1 are often the “first hit” in tumorigenesis. Activating mutations in ERBB2 (also designated HER2) have been identified as oncogenic drivers in peripheral nerve sheath tumors in patients who lack these typical constitutional tumor suppressor gene mutations.

Here we report a case of extensive peripheral nerve sheath tumors in the setting of apparent somatic mosaicism of an ERBB2 mutation. A 48-year-old man with history of chronic back pain presented with diffuse enlarging soft tissues masses primarily involving the left neck and occiput. Examination revealed areas of cutaneous heterogeneous hyperpigmentation, decreased muscle bulk and dorsiflexor weakness in the bilateral lower extremities, and steppage gait. Neuroimaging showed extensive T2 hyperintense, mildly enhancing masses within the bilateral thoracic and lumbar spine neuroforamina, intercostal nerves, paraspinal musculature, and lumbosacral plexus. Tissue from two separate tumor sites was morphologically consistent with schwannoma with some features of neurofibroma. Immunohistochemistry revealed partial loss of staining for SMARCB1. Whole exome sequencing (WES) on blood and tumor tissue did not show pathogenic germline or somatic variants for NF1, NF2, SMARCB1, LZTR1, or an array of tumor predisposition syndromes. WES on tumor tissue from both sites however did reveal a somatic ERBB2 variant (p.D769Y), suggesting mosaicism. ERBB2 D769Y has previously been classified as an activating mutation that confers sensitivity to some small molecule receptor tyrosine kinase inhibitors. Patients with ERRB2-mutated peripheral nerve sheath tumors may have broader therapeutic options in the variety of available tyrosine kinase inhibitors studied in other cancers.
P11.60.A Quantitative analysis of the MGMT methylation status of glioblastomas in the light of the 2021 WHO classification
Authors: Häni L , Kopcic M , Branca M , Schütz A , Murek M , Söll N , Raabe A , Hewer E , Schucht P
Published: September 2022

Background

Glioblastomas with methylation of the promotor region of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene exhibit increased sensitivity to alkylating chemotherapy. Quantitative assessment of the MGMT promotor methylation status might provide additional prognostic information. The aim of our study was to determine a quantitative threshold of MGMT methylation for better survival among patients with isocitrate dehydrogenase (IDH) wildtype glioblastomas.

Material and Methods

We included consecutive patients treated at our department between 11/2010 and 08/2018. Inclusion criteria were i) diagnosis of glioblastoma, IDH wildtype according to the 2021 WHO classification of tumors of the central nervous system, ii) availability of a quantitative MGMT promotor methylation analysis, iii) absence of an IDH mutation as determined by immunohistochemistry and/or sequencing, and iii) age ≥ 18 years. The primary endpoint was overall survival. To evaluate a threshold for a benefit from temozolomide (TMZ), a secondary analysis included only tumors exposed to TMZ, which were compared to a historical cohort treated by radiotherapy only with a median survival of 13.0 months.

Results

Between 11/2010 and 08/2018, 321 patients diagnosed with a glioblastoma, IDH wildtype meeting our inclusion criteria were included. Mean age at diagnosis was 64.1 years (± 11.4). Median overall survival was 12.6 months. Kaplan-Meier analysis showed better survival for all groups with ≥ 16% methylation. Similarly, Cox regression analysis confirmed significantly better survival in the groups with 16-30%, 31-60%, and 61-100% methylation. In contrast, survival in the group with 1-15% methylation was similar to that with unmethylated promotor regions. When the percentage of methylation of each patient treated with TMZ was plotted on an ROC curve using survival > 13.0 months as outcome parameter, the Youden index was maximal at ≥ 16% methylation.

Conclusion

Better survival is seen in patients with glioblastomas with ≥ 16% methylation of the MGMT promotor region than with < 16% methylation. Survival with tumors with 1-15% methylation is similar to with unmethylated tumors. Above 16% methylation, we found no additional benefit with increasing methylation.
P11.61.B Capecitabine treatment of CNS metastases from breast cancer: intracranial response and survival
Authors: Luitse M J A , Boles G , Sonke G S , Brandsma D
Published: September 2022

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 Institute - 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.
P11.66.A Immune checkpoint inhibitors related peripheral nerve disorders: clinical and electrophysiological particularities
Authors: Birzu C , Farina A , Pegat A , Devic P , Lenglet T , Viala K , Debs R , Fargeot G , Picca A , Le Guennec L , Mongin M , Villette B , Joubert B , Maisonobe T , Psimaras D
Published: September 2022

Background

The immune-checkpoint inhibitors (ICIs) announced a new era in cancer treatment allowing long-term survival in advanced cancers. However, immune related adverse events impose treatment limitations being one of the main challenges when dealing with ICI treated patients. Neurologic toxicities have unique presentations and can progress rapidly, requiring prompt recognition. Among them, ICI-related peripheral nerve disorders are highly heterogeneous, profoundly debilitating, and insufficiently explored.

Material and Methods

We reviewed the clinical and electrodiagnostic features of a retrospective cohort of patients hospitalized in our centre for ICI related neuropathies. We applied the EFNS 2021 electrodiagnostic criteria for neuropathies and we researched the outcome according to the treatment received.

Results

We included 16 patients: 4 men and 12 women, median age 61 years (31-72) treated by anti-PD1 monotherapy (10) or antiCTLA4-antiPD1 combination (6). Median delay from ICIs initiation to neuropathy symptoms was 58,5 days (4 cycles), it seemed lower in combination group (median 33,5 days vs 81,5 days in monotherapy patients p=0,02). Half of patients presented with concurrent non-neurological irAE. CSF was inflammatory in 56% of cases, pleocytosis was seen in 57% of these. Cranial nerve involvement was rare (3/16) the most frequent phenotype was demyelinating polyneuropathy fulfilling EFNS 2021 EMG criteria in 10 cases. The other 6 presented with non-length dependent sensory neuropathy, (3) dysautonomic neuropathy (1) or sensory motor neuropathy with incomplete EFNS 2021 EMG criteria (2). ICI treatment was stopped, and steroids were the first line of treatment for all patients. However, 12/16 patients received additional iv immunoglobulin. Supplementary immunomodulation (cyclophosphamide, tocilizumab) was required in 2 cases. 75% of patients improved within a median of 4.5 months, median decrease in mRS was 2 points. Noteworthy, the rechallenge by antiPD1 monotherapy was proposed in 4 patients with a single neuropathy relapse.

Conclusion

Our series expand the knowledge on the clinical and electrophysiological phenotype of ICI related neuropathies improving their recognition in clinical practice. Moreover, our findings argue for the benefit of adding iv immunoglobulin to steroids as a first line treatment for different phenotypes of ICI related neuropathies.
P11.70.A The yield of screening brain MRI among stage IV non small cell lung cancer patients
Authors: Waizman E , Lavie I , Amiel A , Siegal T , Dudnick E , Yust-Katz S
Published: September 2022

Background

Brain metastases are a common complication of non small cell lung cancer (NSCLC). Approximately 10 percent of newly diagnosed patients with advanced NSCLC have brain metastases. The purpose of this study was to determine whether using magnetic resonance imaging (MRI) for early screening of brain metastases can improve survival.

Material and Methods

A retrospective analysis of newly diagnosed stage IV NSCLC treated at Davidoff Cancer Center, Israel, between the years 2019-2020. Only patients who were neurologically asymptomatic were included in the study. The study population was divided into two groups. Group A included patients who underwent screening MRI within 12 weeks form diagnosis and group B included those who did not undergo screening MRI. Clinical and radiographic data were collected form the medical records.

Results

379 patients were included in the study, of whom 170 underwent screening MRI. Of the patients who underwent screening MRI 54 were diagnosed with brain metastases. On univariate analysis screening MRI was correlated with better survival [group A median survival 24 month, group B median survival 18 month, p=0.003 HR 1.4 CI 1.12-1.75]. On multivariate analysis that included functional status (ECOG 0-2 compared to 3 and above) and age- screening MRI correlated with survival (p=0.04 HR 1.28 CI 1.02-1.6). Subgroup analysis according to molecular subgroup will be presented in the conference.

Conclusion

In this study screening MRI among stage IV NSCLC correlated with better survival even when adjusted to functional status and age.
P11.72.A Glioblastoma in elderly patients. Which is the best treatment option?
Authors: Costa C A , Sousa M , Pires M R , Monteiro J C , Caetano A , Póvoa S , Pêgo A , Sousa G
Published: September 2022

Background

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, and it is associated with a poor prognosis in the elderly. The current standard of care for newly diagnosed GBM is maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ). In elderly patients with GBM, short-courses of radiotherapy with TMZ are used.

Material and Methods

We performed a single-center retrospective analysis of elderly GBM patients treated from 2013 to 2020. The primary endpoint was to evaluate progression free survival (PFS) and overall survival (OS) according to treatment received (TMZ and standard radiotherapy (60 Gy over a period of 6 weeks) vs TMZ and short-course radiotherapy (40 Gy in 15 fractions)). Secondary endpoints were analysis of population demographics and major toxicities associated to treatment.

Results

Twenty-two patients were identified. The median age was 72 years (range 65- 80), 18 (85.7%) patients were in ECOG-PS 0-1, 12 (57.1%) were males and all patients had undergone partial or complete resection surgery. Eleven (52.4%) patients received TMZ and standard radiotherapy and 10 (47.6%) patients received TMZ and short-course radiotherapy. Three (14.3%) patients had complete remission, 11 (52.4%) patients had partial response, 2 (9.5%) patients presented stable disease and 5 (23.8%) patients had disease progression. Median OS was 9 months (95% CI, 3.6 to 14.4) with TMZ with standard radiotherapy and 8 months (95% CI, 1.8 to 14.2) with TMZ and short-course radiotherapy (p=0.322). Median PFS was 5 months (95% CI, 2.8 to 7.2) with TMZ with standard radiotherapy and 6 months (95% CI, 3.1 to 8.9) with TMZ and short-course radiotherapy (p=0.944). Most common toxicities were hematological, with 5 (23.8%) patients presented thrombocytopenia grade 2 or higher. Five (23.8%) patients presented grade 3/4 toxicities (2 (9.5%) patients presented thrombocytopenia grade 4, 1 (4.8%) patient presented thrombocytopenia grade 3, and 2 (9.5%) patients presented anemia grade 3.

Conclusion

The prognosis of GBM remains poor besides standard therapy. TMZ and short-course radiotherapy should be an option in elderly patients due to its non-inferiority. Elderly patients should undergo a careful geriatric evaluation before starting treatment.
P11.73.B The diagnostic value of frame-based stereotactic biopsies in the age of precision oncology: A cross-sectional study
Authors: Alhalabi O T , Sahm F , Unterberg A W , Jakobs M
Published: September 2022

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-satisfying 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 cases 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.
P11.76.A Retrospective evaluation of Overall Survival and Progression Free Survival in patients with glioblastoma comparing 6 vs 12 cycles of Adjuvant Temozolomide
Authors: Martinez Perez, 1993 D , Debén Méndez, 1993 B , Rodríguez Roldán M , Garrido Botella, 1993 M , García Cuesta, 1993 J , Pedregosa Barbas, 1993 J , Vilches Aguirre Y , Martinez Marin V
Published: September 2022

Background

The standard of care for glioblastoma multiforme (GBM) is surgery followed by adjuvant concomitant chemo-radiotherapy and adjuvant temolomide (TMZ) for 6 cycles. Extending the duration of adjuvant TMZ did not demonstrate an overall survival (OS) benefit in a meta-analysis including 2214 GBM patients. A phase II randomized clinical trial including 166 GBM patients compared 6 vs 12 cycles of TMZ, showing no differences in progression-free-survival (PFS), although MGMT methylated patients showed better outcomes. The objective of this study is to analyze PFS and OS of GMB patients receiving 6 vs 12 cycles of adjuvant TMZ.

Material and Methods

Patients with a pathological diagnosis of GBM between 1 December 2016 and 31 December 2020 in a single center (Hospital Universitario La Paz) were retrospectively reviewed. Inclusion criteria were confirmed pathological diagnosis and patients receiving multimodality treatment (surgery, radiation and chemotherapy). Two cohorts were analyzed, cohort A patients receiving 6 cycles of adjuvant TMZ and cohort B patients receiving 12 cycles of adjuvant TMZ. Statistical analysis was performed via SPSS v.21 (differences between both cohorts were calculated using χ² and T Student and survival outcomes with Kaplan Meier curves, comparing its differences using log-rank test).

Results

Sixty-eight patients were included in the final analysis, with a median age of 58 years at diagnosis. Fourty-two patients (62%) received 6 cycles of adjuvant TMZ (cohort A), whereas 26 patients (38%) received 12 cycles (cohort B). Median OS was 10 months for cohort A and 20 months for cohort B (p<0,001), median PFS was 8 months for cohort A and 19 months for cohort B (p=0,001). No significant differences were shown between both cohorts regarding age at diagnosis, being 60 years in cohort A and 54 years in cohort B (p = 0,06), and positive-margins after surgery (p=0,796), being 9,5% and 7,7% respectively in each cohort. Significant differences were found regarding MGMT methylation (30% in cohort A and 68% in cohort B).

Conclusion

In our study, patients receiving 12 cycles of adjuvant TMZ had better median OS and median PFS, compared to patients receiving 6 cycles, although the latter group had significantly less MGMT methylated patients, which is a known prognostic and predictive factor of response to TMZ.
P12.05.B Impact of GAP-43 and actin expression on the outcome and overall survival in diffuse and anaplastic gliomas
Authors: Krigers A , Demetz M , Moser P , Kerschbaumer J , Brawanski K R , Thomé C , Freyschlag C F
Published: September 2022

Background

Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli (TMs), where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial epidemiologic, radiological and neuropathological prognostic factors.

Material and Methods

FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. Clinical, neuropathological as well as follow-up-data were gained from the institutional neuro-oncological database.

Results

118 patients with a median age of 46 years (IqR: 35 - 57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. 96 (82%) cases presented with intermediate or strong GAP-43 expression and 78 (67%) with no or light actin expression. Tumors with higher expression of GAP-43 (p=0.024, HR=1.71/rank) and actin (p<0.001, HR=2.28/rank) showed significantly reduced OS. IDH wildtype glioma demonstrated significantly more expression of both proteins: GAP-43 (p=0.009) and actin (p<0.001). The same was confirmed for anaplasia (GAP-43 p=0.028, actin p=0.029), higher proliferation rate (GAP-43 p=0.016, actin p=0.038), contrast-enhancement in MRI (GAP-43 p=0.023, actin p=0.037) and age (GAP-43 p=0.004, actin p<0.001).

Conclusion

The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and unfavorable prognostic features.
P12.08.A Uncovering the glioblastoma tumor-microenvironment by high-end multiplexing with imaging mass cytometry
Authors: Anand A , Harwood D S , Bishop C , Todd K , Ellis R , Ellis R , Poulsen F R , Kristensen B W
Published: September 2022

Background

Glioblastoma is one of the most aggressive cancers, and hypoxia plays an essential role in its tumor- microenvironment. Tumor-associated microglia and macrophages (TAMs) have been reported to constitute up to 30 % of the cells, a fraction that is even higher in hypoxic areas. Single-cell mRNA sequencing of glioblastoma tumors has revealed vast heterogeneity, but the spatial aspects are not entirely defined yet. The aim of this study was to uncover differences between the hypoxic and normoxic tumor-microenvironment of human glioblastoma by high-end multiplexing with imaging mass cytometry.

Material and Methods

A tissue microarray (TMA) with normoxic and hypoxic areas from 4 IDH-wildtype glioblastomas was prepared based on the hypoxia marker hypoxia-inducing factor 1 alpha (HIF1 alpha). The TMA was stained with 18 metal-tagged antibodies covering TAMs, lymphocytes, immune checkpoints, vessels, tumor cells and proliferation. The Hyperion-CYTOF technology was used to ablate the samples and the images were analyzed by MCD viewer, Visiopharm software, and customized R scripts.

Results

Single-cell analysis of 160 fields covering around 45,000 cells in the glioblastoma microenvironment revealed multiple cellular phenotypes. It was revealed that proliferating TAMs (IBA1+, Ki67+) were more frequent in hypoxia, whereas proliferating vessels (CD34+, Ki67+) were more frequent in normoxia. Additionally, proliferating stem-like tumor cells (OLIG-2+, Ki67+) were more frequent in normoxia regions.

Conclusion

Our study revealed multiple cellular phenotypes in the glioblastoma microenvironment. The TAMs, endothelial and tumor cell phenotypes revealed may play a critical role in glioblastoma biology however this needs to be elucidated in future studies.
P12.12.A Resolving the cellular architecture of infiltration zones in glioblastoma
Authors: Ritter M , Blume C , Patel A , Sievers P , Dogan H , Herold-Mende C , Wick W , von Deimling A , Sahm F
Published: September 2022

Background

Therapy resistance and infiltration still pose major challenges in the treatment of glioma. In the tumour border niche, an interaction between different healthy cell types and malignant cells leads to therapy resistance, acquisition of stem-cell like features, and recurrence. However, studying the tumour border is quite challenging due to the lack of specific glioma markers. Although single cell datasets contain information about the abundance of different cell types, they still lack the spatial arrangement at the border niche. Spatial transcriptomic approaches might overcome these problems, but are still limited by a low resolution or a limited number of detectable transcripts.

Material and Methods

We applied the Visium spatial transcriptomics platform on 18 FFPE and 11 fresh frozen gliomas to image the cellular architecture of the tumour border niche. In addition, the transcriptome of single nuclei isolated from the fresh frozen sections was also analysed. Using Seurat and a single cell reference set from Darmanis et al. (2017) the cell types were mapped onto the section and the copy number variation profile (CNV) was determined.

Results

Using a single cell reference set we were able to map different cell types onto different areas of the tumour border niche of gliomas. To control the mapping the expression of cellular markers was used to detect healthy brain cells and the CNV profile was used to identify the tumour. The mapping matched the expression of markers and the CNV profile and only showed minor differences. First analysis confirmed distinct distribution of oligodendrocytes and neurons at the tumour border. We could not detect an enrichment of any tumour subtypes at the tumour border so far. However, one sample showed an enrichment of the mesenchymal subtype at the perinecrotic region. CNVs also showed low intratumoural heterogeneity for most sections.

Conclusion

Although the first results of the mapping of different cell types look promising, a larger reference set including a larger variety of cell types and tumour subtypes could improve the mapping even further. Nevertheless, we were able to show the cell type distribution at the tumour border and generate robust CNVs for most sections using spatial transcriptomics.
P13.03.A Radiomics for the non-invasive assessment of the PDL-1 expression in patients with non-small cell lung cancer brain metastases
Authors: Meißner A , Gutsche R , Galldiks N , Kocher M , Jünger S , Eich M , Nogova L , Schmidt N , Ruge M , Goldbrunner R , Proescholdt M , Grau S , Lohmann P
Published: September 2022

BACKGROUND

The expression level of programmed cell death ligand 1 (PDL-1) might be an indicator for response to immunotherapy using checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). As intra-tumoral differences and discrepancies between the PDL-1 expression in the primary tumor and the brain metastases may occur, a method for a reliable non-invasive assessment of the intracranial PDL-1 expression would be of clinical value. We evaluated the potential of MRI radiomics for a non-invasive assessment of the PDL-1 expression in patients with NSCLC brain metastases.

PATIENTS AND METHODS

Fifty-three patients with brain metastases from NSCLC from two university brain tumor centers (group 1, 36 patients; group 2, 17 patients) underwent tumor resection with subsequent immunohistochemical assessment of the PDL-1 expression. Brain metastases were manually segmented on preoperative T1-weighted contrast-enhanced MRI. Group 1 was used for model training and validation, group 2 for model testing. After image pre-processing and radiomics feature extraction from T1-weighted contrast-enhanced MRI, a test-retest analysis was performed to identify robust features prior to feature selection. The radiomics model was trained and validated using five-fold cross validation. Finally, the best performing radiomics model was applied to the test data. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analyses.

RESULTS

An intracranial PDL-1 expression was found by immunohistochemistry in 18 of 36 patients (50%) in group 1, and 7 of 17 patients (41%) in group 2. Univariate analysis identified tumor volume as a significant clinical feature for PDL-1 expression (area under the ROC curve (AUC), 0.77). A random forest classifier using a four-parameter radiomics signature including tumor volume yielded an AUC of 0.83 ± 0.18 in the training data (group 1). Finally, the classifier achieved an AUC of 0.84 in the external test data (group 2).

CONCLUSION

The developed radiomics classifiers allows a non-invasive assessment of the intracranial PD-L1 expression in patients with NSCLC brain metastases with a high diagnostic performance.
P14.01.B Isolation and characterization of circulating tumor cells in a glioblastoma case with recurrence at distance and correlation with tumor mutational status
Authors: Lessi F , Morelli M , Aretini P , Menicagli M , Franceschi S , Pasqualetti F , Gambacciani C , Di Stefano A , Santonocito O , Mazzanti C M
Published: September 2022

Background

Circulating Tumor Cells (CTCs) are considered to be one of the important causes of tumor recurrence and distant metastasis. For many years, glioblastoma (GB) was thought to be restricted to the brain. Nevertheless, a growing body of evidence indicates that, like many other cancers, hematogenic dissemination is a reality. The absence of a procedural uniformity in literature prompted us to develop an innovative and sensitive method to obtain CTCs in GB. Our aim is to define the genetic background of single CTCs compared with the primary GB tumor and its recurrence to assess whether or not their presence in the peripheral circulation correlates with GB migration and dissemination.

Material and Methods

CTCs were enriched from whole blood of one patient with recurrent GB with Parsortix Cell Separation System and analysed on DEPArray system. After that, CTCs Copy Number Aberrations (CNAs) and sequencing analysis was performed to compare CTCs genetic background with the same patient’s primary and recurrence tissues, analysed by NextSeq 500 (whole exome sequencing).

Results

We obtained 211 mutations in common between primary and recurrence tumor. Among these, three somatic mutations (c.430 G>A in PRKCB gene, c.815 C>T in TBX1 gene and c.1554 T>G in COG5 gene) were selected to investigate their presence in recurrence CTCs. Almost all of the sorted CTCs (9/13) had at least one of the mutations tested.

Conclusion

In confirmation of the hypothesis, the CTCs detected in the patient's blood were actually cancer cells deriving from GB tumor.
P14.04.A TrackingTERTpromoter andIDH1mutations in liquid biopsies - suitable biomarkers for disease monitoring in glioma patients?
Authors: Bruckner K , Madlener S , Lang A , Kiesel B , Furtner-Srajer J , Hainfellner J , Haberler C , Spiegl-Kreinecker S , Dorfer C , Slavc I , Gojo J , Rössler K , Lötsch-Gojo D
Published: September 2022

Background

Mutations within the telomerase reverse transcriptase promoter (TERTprom) and isocitrate dehydrogenase (IDH) account for the most common genetic alterations in gliomas. Each of these mutations impact clinicopathologic diagnosis and course of diseases. While TERTprom mutations are frequently detected in glioblastoma, IHD mutations are assigned to astrocytoma of grade 2-4, thus mostly associated with better prognosis. In the era of precision oncology, molecular profiling and continuous monitoring of treatment response or relapse are of increasing importance. Accordingly, this study aims to detect TERTprom and IDH mutations in plasma-derived cell-free (cf)DNA of gliomas. The mutant allele frequencies (MAF) will be compared retrospectively to clinico-pathological parameters including extent of resection and tumor progression.

Material and Methods

Digital droplet PCR (ddPCR) analyses were performed using the QX200TM Digital Droplet System from BioRad. First, to evaluate probes for ddPCR, genomic DNA of several brain tumor cell models (n=6) and tumor tissue (n=1), as well as cfDNA of plasma (n=3) from samples with known TERTprom and IDH mutation status was investigated. For detection of IDH mutations, the unique assay ID dHSaMDV2010055 (IDH1p.R132H) and for TERTprom mutations the TaqMan dPCR Liquid Biopsy Assays for C228T (Hs000000092) and C250T (Hs000000093) were used. The results of ddPCR were analyzed with QuantaSoftTM software and the MAF was calculated

Results

To validate the detection method for IDH1R132H, we analyzed the MAF in one tissue and corresponding plasma sample of a confirmed IDH1-mutated astrocytoma. In addition, plasma from one astrocytoma grade 2-3 as well as from an IDH1-mutated glioblastoma was tested. Interestingly, both astrocytoma cases exhibited undetectable or very low MAF ranging from 0.1 to 1% in tissue as well as in plasma samples, while in plasma from the high-grade glioblastoma case, IDH1R132H was detected with a frequency of 1.9%. Due to the high GC content of the TERT promoter region, amplification steps are challenging. Accordingly, we first optimized ddPCR conditions for C228T and C250T probes by adding 7-deaza-2-deoxyguanosine-5-triphosphate (7-ddGTP) in varying concentrations to each ddPCR reaction. When using 4µM of 7-ddGTP per sample, a clear separation between mutant and wild-type droplets was reached, detecting MAF between 36-63% in DNA from cell culture models.

Conclusion

Within this pilot study we optimized the ddPCR method for the detection of IDH1R132H and TERTprom mutations in plasma and tissue samples. Subsequently, we hypothesize that these mutations are suitable liquid biomarkers correlating with extent of resection and tumor progression in gliomas.
P15.02.B Spatial habitat analysis in high-grade gliomas combining perfusion, diffusion, and hypoxia features derived from multiparametric MRI and 18F-FAZA PET
Authors: Bailo M , Pecco N , Callea M , Scifo P , Gagliardi F , Fallanca F , Picchio M , Mortini P , Falini A , Castellano A
Published: September 2022

Background

Heterogeneity represents one of the main issues in high-grade gliomas (HGGs) management and presumably is the key to understanding treatment failure. Spatial habitat imaging embodies a novel, non-invasive method to cluster different tumor biological microenvironments and characterize intratumoral heterogeneity through a quantitative radiomic approach. So far, habitat imaging has been chiefly explored on morphological magnetic resonance imaging (MRI): the aim of our study was to evaluate this technique on advanced imaging techniques as perfusion (PWI) and diffusion (dMRI) MRI, as well as 18F-FAZA PET, to subdivide the tumor into different biological compartments.

Materials and Methods

A preoperative PWI, dMRI, and 18F-FAZA PET acquisition was obtained in 17 HGG patients to assess intratumoral vascularization, cellularity, and hypoxia, respectively. A tumor mask was created including contrast-enhancing/necrotic regions on T1 imaging and surrounding FLAIR hyperintensity, and each parametric map (plasma volume from dynamic contrast-enhanced PWI, mean diffusivity from diffusion tensor imaging, and standardized uptake value from 18F-FAZA PET) underwent OTSU’s binary clustering by grouping together voxels with high and low-intensity values. Cluster intersections were then generated by combining all possible high and low-intensity regions of each map, and the final habitat map was composed. Habitats’ quantitative features, spatial distribution, and histopathological characteristics were analyzed.

Results

The eight habitats generated were carefully inspected, and their distribution pattern, in relation to morphological landmarks (as contrast-enhancing, necrotic, infiltrative and edematous areas), showed an excellent reproducibility among different HGGs, offering complementary data to conventional imaging. A consistent correlation was noted between each habitat’s awaited microenvironment and the corresponding histopathological characteristics among the ten patients for whom precise coordinates of stereotactic biopsies were available. Clusters considered more aggressive were more represented in WHO grade IV (vs. grade III) tumors. The habitat possibly representing edematous areas was significantly larger in IDH-1 wild-type (vs. IDH-1 mutated) tumors.

Conclusions: PET and MRI hypoxia, perfusion, and tissue diffusion habitat maps proved an excellent reproducibility among HGGs and correlation with expected histopathological features, making it a way to characterize intratumoral heterogeneity. However, further study is needed to elucidate clinical implications and confirm the spatio-temporal evolution of the identified habitats.

Funding

Italian Ministry of Health, grant number GR-2018-12365670; Italian Association for Cancer Research (grant IG 2014 Id.1524).