Anne-Marie Vanbinst

Purpose: Automated glioblastoma segmentation from magnetic resonance imaging is generally performed on a four-modality input, including T1, contrast T1, T2 and FLAIR. We hypothesize that information redundancy is present within these image combinations, which can possibly reduce a model’s performance. Moreover, for clinical applications, the risk of encountering missing data rises as the number of required input modalities increases. Therefore, this study aimed to explore the relevance and influence of the different modalities used for MRI-based glioblastoma segmentation. Methods: After the training of multiple segmentation models based on nnU-Net and SwinUNETR architectures, differing only in their amount and combinations of input modalities, each model was evaluated with regard to segmentation accuracy and epistemic uncertainty. Results: Results show that T1CE-based segmentation (for enhanced tumor and tumor core) and T1CE-FLAIR-based segmentation (for whole tumor and overall segmentation) can reach segmentation accuracies comparable to the full-input version. Notably, the highest segmentation accuracy for nnU-Net was found for a three-input configuration of T1CE-FLAIR-T1, suggesting the confounding effect of redundant input modalities. The SwinUNETR architecture appears to suffer less from this, where said three-input and the full-input model yielded statistically equal results. Conclusion: The T1CE-FLAIR-based model can therefore be considered as a minimal-input alternative to the full-input configuration. Addition of modalities beyond this does not statistically improve and can even deteriorate accuracy, but does lower the segmentation uncertainty.

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5–7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021). Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w. 20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing. Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disorder of the central nervous system. Accelerated brain volume loss (BVL) has emerged as a promising magnetic resonance imaging marker (MRI) of neurodegeneration, correlating with present and future clinical disability. We have systematically selected MS patients fulfilling ‘no evidence of disease activity-3′ (NEDA-3) criteria under high-efficacy disease-modifying treatment (DMT) from the database of two Belgian MS centers. BVL between both MRI scans demarcating the NEDA-3 period was assessed and compared with a group of prospectively recruited healthy volunteers who were matched for age and gender. Annualized whole brain volume percentage change was similar between 29 MS patients achieving NEDA-3 and 24 healthy controls (−0.25 ± 0.49 versus −0.24 ± 0.20, p = 0.9992; median follow-up 21 versus 33 months; respectively). In contrast, we found a mean BVL increase of 72%, as compared with the former, in a second control group of MS patients (n = 21) whom had been excluded from the NEDA-3 group due to disease activity (p = 0.1371). Our results suggest that neurodegeneration in MS can slow down to the rate of normal aging once inflammatory disease activity has been extinguished and advocate for an early introduction of high-efficacy DMT to reduce the risk of future clinical disability.

We report a case of anti-protein death 1-induced sarcoid-like reaction in a 63-year-old Caucasian male who was diagnosed with stage IV-M1a melanoma. He was initially treated with pembrolizumab monotherapy (Q3W) and had a complete response after 14 cycles. However, relapse was suspected 3 months later with appearance of hilar, mediastinal and hepatic hilar lymph nodes as well as a skin lesion. Biopsy of both the hilar lymph nodes and the skin lesion demonstrated sarcomatoid granulomatosis. Pembrolizumab was discontinued temporarily. While on ¹⁸F-FDG-PET/CT, all sarcoid-like lesions regressed in size and activity, a new hypermetabolic solitary skeletal lesion was detected in a lumbar vertebra, suspicious for metastasis. However, since the patient was asymptomatic, a watchful-waiting attitude was taken. During this period, a spontaneous and complete resolution of the metabolic activity was observed of the skeletal lesion. Until today, the patient remains in complete remission. Current case presents an atypical presentation and evolution of anti-PD-1-induced sarcoid-like reaction, illustrating the difficulty of differentiating it from disease progression. Before considering (re-)initiation of anti-melanoma therapy, a tissue biopsy of one of the suspected lesions may be performed to confirm diagnosis. Physicians treating patients with ICI should be aware of this difficulty and critically assess the nature of lesions suspect of progression in patients responding to ICI and presenting with a sarcoid-like reaction.

Background: Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan. Objective: To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms. Methods: 27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients. Results: Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms. Conclusions: Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood.

2534 Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has low activity in recurrent glioblastoma (rGB). Intratumoral (IT) and intracavitary (IC) administration of IPI and NIVO is under evaluation in the GlITIpNi phase I clinical trial. Methods: Patients (pts) with resectable rGB were recruited to cohorts C1, C2 and C4; pts with non-resectable rGB were recruited in C3 (biopsy only). IT administration (brain tissue lining the resection cavity during surgery) of IPI (10 mg)(C1), or IPI (5 mg) plus NIVO (10 mg)(C2, C3 and C4), was followed by IC administration of NIVO at escalating doses of 1, 5 or 10 mg Q2w in both C3 and C4 (via an Ommaya reservoir). In all cohorts, pts received 10 mg NIVO IV Q2w (6x in C1/C2, and 12x in C3/C4). Corticosteroids were contraindicated. Results: Forty-six pts (31 male; median age 56y (38-74); IDH1 R132H mutation in 2 pts in C1/C2; NGS somatic mutation analysis for C3/C4 ongoing) with rGB following resection, RT and temozolomide were enrolled (3, 24, 13 and 6 pts in C1, C2, C3 and C4, respectively). All pts received IT administrations. Pts in C1/C2 received a median of 5 IV NIVO administrations. Study treatment has been completed in all pts in C1/C2, in 9 pts in C3, and in 3 pts in C4; pts received a median of 4 (0-10) and 3 (0-7) postoperative IC/IV administrations in C3 and C4, respectively. Two pts in C2 and 1 pt in C3 had an increased perilesional cerebral edema (G3) with neurological deterioration after surgery/IT-injection, that was reversible with steroids. Most frequent AE were fatigue (32 pts, 64%), fever (20 pts, 44%), and headache (25 pts, 50%). In 4 pts from C3, the Ommaya was removed because of bacterial colonization (asymptomatic). There were no G5 AE. There was no dose/AE correlation with increasing IC NIVO doses in C3/C4. Repetitive CSV analysis during therapy (C3/C4) revealed increased lymphocyte counts in 4 pts; scRNA- and TCR-sequencing is ongoing. Gene expression profiling for C1/C2, and pharmacokinetic analysis of NIVO and IPI in CSV for C3/C4 are ongoing. After a median FU of 62w (16-165) for pts in C1/C2, 16 pts have died; median OS is 71w (95% CI 8-134), 1- and 2y-OS% are respectively 51% (95% CI 31-71), and 34% (95% CI 10-59). OS compares favorably to a historical cohort of Belgian rGB pts (n = 469; Log-Rank p .001). After a median FU of 10w (1-37) for pts in C3/C4, 2 pts have died; median OS has not been reached. One pt in C3 achieved a PR that is ongoing at 12m. Conclusions: IT/IC administration of NIVO and IPI is feasible and sufficiently safe to warrant further investigation in pts with rGB. Clinical trial information: NCT03233152 .

Spleen volume reduction followed by re-expansion has been described in acute ischemic stroke in both animal and human studies. Splenic contraction might be partially due to sympathetic hyperactivity and might be accompanied by release of splenocytes in the peripheral circulation, leading to immunodepression. To investigate whether spleen volume changes in the first week after stroke are associated with post-stroke infections, changes in lymphocytes count and autonomic dysfunction. In patients with acute ischemic stroke, spleen sizes were calculated from abdominal CT images on day one and day seven. Spleen size reduction was defined as > 10% spleen size reduction between day one and day seven. Post stroke infections were diagnosed during the first seven days after stroke onset using the modified criteria of the US Center of Disease Control and Prevention. We assessed the time course of leukocyte subsets and analysed pulse rate variability (PRV) indices. Post-stroke infections occurred in six out of 11 patients (55%) with spleen size reduction versus in five out of 27 patients (19%) without spleen size reduction (p = 0,047). Spleen size reduction was associated with a drop in lymphocytes and several lymphocyte subsets from admission to day one, and a higher NIHSS at admission and at day three (p = 0,028 and p = 0,006 respectively). No correlations could be found between spleen volume change and PRV parameters. Post-stroke infections and a drop in lymphocytes and several lymphocyte subsets are associated with spleen volume reduction in acute ischemic stroke.