Bevacizumab for Cerebral Radionecrosis: A Single-Center Experience.

BACKGROUND: Cerebral radionecrosis, a subacute or late effect of radiotherapy, can be debilitating and difficult to treat. Steroids can reduce symptoms, but have significant long-term side effects. Bevacizumab has been shown to reduce edema and other radiologic features associated with radionecrosis and improve patient symptoms. We report our experience using bevacizumab for cerebral radionecrosis. METHODS: We retrospectively reviewed the charts of all patients treated at our institution with bevacizumab for non-glioma-associated cerebral radionecrosis. We recorded change in symptoms, change in steroids, change in performance status, time to tumor progression, and time to death. We delineated the volume of necrosis pre- and post-bevacizumab on T1-post-gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI scans. RESULTS: We identified 15 patients, 8 with brain metastases, 6 with meningioma, and 1 with nasopharyngeal carcinoma. Most received four doses of bevacizumab, 7.5 mg/kg q 3 weeks × 4 doses. Neuroimaging demonstrated a reduced T1 gadolinium-enhancing volume and edema in 14/15 patients (the average reduction in T1-post-gadolinium volume was 3.0 cm3, and average reduction in FLAIR volume was 27.9 cm3). There was no appreciable change in patient performance status. Steroid doses decreased in five of nine patients. There was a high rate (26%) of adverse events, including pulmonary embolism, stroke, and wound dehiscence. The median progression-free survival was 6.5 months. CONCLUSION: Although bevacizumab is commonly prescribed for cerebral radionecrosis, in our retrospective cohort, the clinical benefits were modest and there was significant toxicity.

Neuro-oncology clinicians' perspectives on factors affecting brain cancer patients' access to medical assistance in dying: A qualitative study.

In most jurisdictions where medical assistance in dying (MAiD) is legal, patients must have decision-making capacity. Brain cancer often damages the cognitive networks required to maintain decision-making capacity. Using qualitative methodology guided by a relational ethics conceptual framework, this study explored neuro-oncology clinicians' perspectives on access to and eligibility for MAiD for patients diagnosed with brain cancer. We interviewed 24 neuro-oncology clinicians from 6 countries. Participants described the unique challenges facing brain cancer patients, potentially resulting in their inequitable access to MAiD. The findings highlight the importance of early end-of-life conversations, advance care planning, and access to end-of-life treatment options.

Clinical features of glioma patients who develop pneumocystis pneumonia with temozolomide chemoradiotherapy.

INTRODUCTION: The treatment of glioma with temozolomide chemoradiotherapy predisposes patients to pneumocystis pneumonia (PCP). Because PCP is a rare outcome, very little is known about specific clinical risk factors for its development in patients with glioma. METHODS: We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. We compared clinical features of patients who did not versus did develop PCP within one year of chemoradiotherapy. We examined the overall survival of patients by PCP status. RESULTS: There were 5130 patients with glioma treated with temozolomide chemoradiotherapy. Ultimately, 38 patients (0.74%) were diagnosed with PCP within 1 year of chemoradiotherapy. Most (71%) infections occurred between 0-90 days and 29% occurred between 91-365 days. Median survival was 12.3 months in patients who did not develop PCP and 8.6 months in those who did develop PCP (P < 0.001). Trough 90-day lymphocyte counts were lower in the PCP group. When the lymphocytes fell below 0.19 × 109/L (or 0.25 × 109/L among patients without PCP prophylaxis), the risk of PCP was > 3.5%. CONCLUSIONS: Pneumocystis pneumonia is rare in glioma patients who receive temozolomide chemoradiotherapy. Infection is associated with shorter survival and the development of lymphopenia. Reserving PCP prophylaxis for patients whose lymphocyte counts drop below 0.25 × 109/L may be a reasonable strategy.

Leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) case report: diagnosis and management of a rare neurological disease.

BACKGROUND: Leukoencephalopathy with brain calcifications and cysts (LCC; also known as Labrune syndrome) is a rare genetic microangiopathy caused by biallelic mutations in SNORD118. The mechanisms by which loss-of-function mutations in SNORD118 lead to the phenotype of leukoencephalopathy, calcifications and intracranial cysts is unknown. CASE PRESENTATION: We present the histopathology of a 36-year-old woman with ataxia and neuroimaging findings of diffuse white matter abnormalities, cerebral calcifications, and parenchymal cysts, in whom the diagnosis of LCC was confirmed with genetic testing. Biopsy of frontal white matter revealed microangiopathy with small vessel occlusion and sclerosis associated with axonal loss within the white matter. CONCLUSIONS: These findings support that the white matter changes seen in LCC arise as a consequence of ischemia rather than demyelination.

Neuro-Oncology Clinicians' Attitudes and Perspectives on Medical Assistance in Dying.

BACKGROUND: Medical assistance in dying (MAiD), also known as physician-assisted death, is currently legal in several locations across the globe. Brain cancer or its treatments can lead to cognitive impairment, which can impact decision-making capacity for MAiD. OBJECTIVE: We sought to explore neuro-oncology clinicians' attitudes and perspectives on MAiD, including interpretation of decision-making capacity for patient MAiD eligibility. METHODS: An online survey was distributed to members of national and international neuro-oncology societies. We asked questions about decision-making capacity and MAiD, in part using hypothetical patient scenarios. Multiple choice and free-text responses were captured. RESULTS: There were 125 survey respondents. Impaired cognition was identified as the most important factor that would signal a decline in patient capacity. At least 26% of survey respondents had moral objections to MAiD. Respondents thought that different hypothetical patients had capacity to make a decision about MAiD (range 18%-58%). In other hypothetical scenarios, fewer clinicians were willing to support a MAiD decision for a patient with an oligodendroglioma (26%) vs. glioblastoma (41%-70%, depending on the scenario). Time since diagnosis, performance status, and patient age seemed to affect support for MAiD decisions (Fisher's exact P-values 0.007, < 0.001, and 0.049, respectively). CONCLUSION: While there are differing opinions on the moral permissibility of MAiD in general and for neuro-oncology patients, most clinicians agree that capacity must be assessed carefully before a decision is made. End-of-life discussions should happen early, before the capacity is lost. Our results can inform assessments of patient capacity in jurisdictions where MAiD is legal.

Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients.

INTRODUCTION: Tumor-related epilepsy may respond to chemotherapy. In a previously-published multi-centre randomized clinical trial of 562 elderly glioblastoma patients, temozolomide plus short-course radiotherapy conferred a survival benefit over radiotherapy alone. Seizure outcomes were not reported. METHODS: We performed an unplanned secondary analysis of this trial's data. The trial design has been previously reported. Seizures were recorded by clinicians as adverse events and by patients in quality of life questionnaires. A Chi-square test of seizure rates between the two groups (α = 0.05) and a Kaplan-Meier estimator of time-to-first self-reported seizure were planned. RESULTS: Almost all patients were followed until they died. In the radiotherapy alone group, 68 patients (24%) had a documented or self-reported seizure versus 83 patients (30%) in the temozolomide plus radiotherapy group, Chi-square analysis showed no difference (p = 0.15). Patients receiving radiotherapy alone tended to develop seizures earlier than those receiving temozolomide plus radiotherapy (p = 0.054). Patients with seizures had shorter overall survival than those without seizures (hazard ratio 1.24, p = 0.02). CONCLUSIONS: This study was not powered to detect differences in seizure outcomes, but temozolomide seemed to have minimal impact on seizure control in elderly patients with glioblastoma. CLINICAL TRIAL REGISTRATION: NCT00482677 2007-06-05.

Determining Corticospinal Tract Injury from Stroke Using Computed Tomography.

INTRODUCTION: Damage to the corticospinal tract (CST) from stroke leads to motor deficits. The damage can be quantified as the amount of overlap between the stroke lesion and CST (CST Injury). Previous literature has shown that the degree of motor deficits post-stroke is related to the amount of CST Injury. These studies delineate the stroke lesion from structural T1-weighted magnetic resonance imaging (MRI) scans, often acquired for research. In Canada, computed tomography (CT) is the most common imaging modality used in routine acute stroke care. In this proof-of-principle study, we determine whether CST Injury, using lesions delineated from CT scans, significantly explains the variability in motor impairment in individuals with stroke. METHODS: Thirty-seven participants with stroke were included in this study. These individuals had a CT scan within the acute stage (7 days) of their stroke and underwent motor assessments. Brain images from CT scans were registered to MRI space. We performed a stepwise regression analysis to determine the contribution of CST injury and demographic variables in explaining motor impairment variability. RESULTS: Using clinically available CT scans, we found modest evidence that CST Injury explains variability in motor impairment (R2adj = 0.12, p = 0.02). None of the participant demographic variables entered the model. CONCLUSION: We show for the first time a relationship between CST Injury and motor impairment using CT scans. Further work is required to evaluate the utility of data derived from clinical CT scans as a biomarker of stroke motor recovery.

Survey of Canadian Myotonic Dystrophy Patients' Access to Computer Technology.

BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant condition affecting distal hand strength, energy, and cognition. Increasingly, patients and families are seeking information online. An online neuromuscular patient portal under development can help patients access resources and interact with each other regardless of location. It is unknown how individuals living with myotonic dystrophy interact with technology and whether barriers to access exist. We aimed to characterize technology use among participants with myotonic dystrophy and to determine whether there is interest in a patient portal. METHODS: Surveys were mailed to 156 participants with myotonic dystrophy type 1 registered with the Canadian Neuromuscular Disease Registry. RESULTS: Seventy-five participants (60% female) responded; almost half were younger than 46 years. Most (84%) used the internet; almost half of the responders (47%) used social media. The complexity and cost of technology were commonly cited reasons not to use technology. The majority of responders (76%) were interested in a myotonic dystrophy patient portal. CONCLUSIONS: Patients in a Canada-wide registry of myotonic dystrophy have access to and use technology such as computers and mobile phones. These patients expressed interest in a portal that would provide them with an opportunity to network with others with myotonic dystrophy and to access information about the disease.

Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma.

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

The Incidence and Prevalence of Primary Central Nervous System (CNS) Tumours in Canada (2010-2017), and the Survival of Patients Diagnosed with CNS Tumours (2008-2017).

Primary central nervous system (CNS) tumours are heterogeneous, with different treatment pathways and prognoses depending on their histological and molecular classification. Due to their anatomical location, all CNS tumours, regardless of malignancy, can be debilitating. We used vital statistics linked to Canadian Cancer Registry data to estimate the age-standardized incidence rates (ASIR), Kaplan-Meier survival rates (SR), and limited-duration prevalence proportions (PP) of 25 histology-specific CNS tumour groups that were classified based on site and histology. During 2010-2017, 45,115 patients were diagnosed with 47,085 primary CNS tumours, of which 19.0% were unclassified. The average annual ASIR was 21.48/100,000 person-years and did not vary by sex. The ASIR increased with age, particularly for meningioma, unclassified tumours, and glioblastoma. The eight-year PP was 102.1/100,000 persons (index date 1 January 2018). The most common histology was meningioma (ASIR: 5.19; PP: 31.6). The overall five-year SR among 51,310 patients diagnosed during 2008-2017 was 57.2% (95% CI: 56.8-57.7%). SRs varied by tumour behaviour, histology, and patient age, with the lowest SR among glioblastoma patients (5-year SRs ranged from 1.3-25.7%). For non-malignant tumours, the 5-year SRs ranged from 37.4-100%. We provide the most up-to-date histology-specific surveillance estimates for primary CNS tumours in Canada.

Review of 20 years of adult medulloblastoma treatment: Chemotherapy prescription trends and survival.

Background: The historic standard of care for adult medulloblastoma has been considered surgery and radiation, while chemotherapy is increasingly being prescribed. This study reviewed 20-year chemotherapy trends at a high-volume center, as well as overall and progression free-survival. Methods: Adults with medulloblastoma treated at an academic center from January 1, 1999 to -December 31, 2020 were reviewed. Patient baseline data were summarized and Kaplan-Meier estimators were used for survival. Results: Forty-nine patients were included; median age was 30 years and male: female ratio was 2:1. Desmoplastic and classical histologies were most common. Of all patients, 23 (47%) were high risk and 7 (14%) metastatic at diagnosis. Only 10 (20%) received initial chemotherapy, of which 70% were high risk and 30% metastatic, with most treated from 2010 to 2020. Forty percent of initial chemotherapy patients received salvage chemotherapy for recurrence or metastases (of all patients, 49% required salvage). Initial chemotherapy regimens were mainly cisplatin/lomustine/vincristine, and at recurrence cisplatin/etoposide. Median overall survival was 8.6 years (95% CI 7.5-∞), with 1-, 5-, and 10-year survival at 95.8%, 72%, and 46.7%. Median overall survival for those who did not receive initial chemotherapy was 12.4 years and 7.4 years for those who did (P-value .2). Conclusions: Twenty years of adult medulloblastoma treatment was reviewed. Initial chemotherapy patients, most of whom were high risk, trended towards worse survival, but this was nonsignificant. The ideal timing and choice of chemotherapy for adult medulloblastoma is unknown-challenges of administering chemotherapy following photon craniospinal irradiation may have prevented it from becoming routine.

Neurocognitive impairment, neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms in patients with newly diagnosed glioblastoma.

Background: In addition to poor survival rates, individuals with glioblastoma (GBM) are at risk of neurocognitive impairment due to multiple factors. This study aimed to characterize neurocognitive impairment, neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms in newly diagnosed GBM patients; and to examine whether neurobehavioral symptoms, fatigue, sleep, and depressive symptoms influence neurocognitive performance. Methods: This study was part of a prospective, inception cohort, single-arm exercise intervention in which GBM patients underwent a neuropsychological assessment shortly after diagnosis (median 4 weeks; ie, baseline) and 3, 6, 12, and 18 months later, or until tumor progression. Here, we present baseline data. Forty-five GBM patients (mean age = 55 years) completed objective neurocognitive tests, and self-report measures of neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms. Results: Compared to normative samples, GBM patients scored significantly lower on all neurocognitive tests, with 34 (76%) patients exhibiting neurocognitive impairment. Specifically, 53% exhibited impairment in memory retention, 51% in executive function, 42% in immediate recall, 41% in verbal fluency, and 24% in attention. There were high rates of clinically elevated sleep disturbance (70%), fatigue (57%), depressive symptoms (16%), and neurobehavioral symptoms (27%). A multivariate regression analysis revealed that depressive symptoms are significantly associated with neurocognitive impairment. Conclusions: GBM patients are vulnerable to adverse outcomes including neurocognitive impairment, neurobehavioral symptoms, fatigue, sleep disturbance, and depressive symptoms shortly after diagnosis, prior to completing chemoradiation. Those with increased depressive symptoms are more likely to demonstrate neurocognitive impairment, highlighting the need for early identification and treatment of depression in this population.

Effectiveness and safety of pneumocystis pneumonia prophylaxis for patients receiving temozolomide chemoradiotherapy.

BACKGROUND: Malignant gliomas are treated with temozolomide chemoradiotherapy. Because pneumocystis pneumonia (PCP) can occur in patients receiving temozolomide, the product monograph recommends PCP prophylaxis during temozolomide chemoradiotherapy. Not all neuro-oncologists follow these recommendations, though. METHODS: We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. A propensity score model was used to predict the use of PCP prophylaxis. We compared the risk of PCP within 90 days of starting radiotherapy with versus without PCP prophylaxis using inverse probability of treatment weighting (IPTW). We also examined overall survival, hospitalizations, and myelosuppression. RESULTS: There were 3,225 patients included in the cohort (648 received antibiotics and 2,434 did not). Only 18 patients developed PCP within 90 days of therapy. The IPTW-adjusted absolute risk reduction in PCP with antibiotics was 0.0035 (95% CI, -0.0013 to 0.0083), number needed to treat: 288. Neither overall survival nor hospitalization count differed between the groups. The number needed to harm by causing grade 3/4 neutropenia was 39. CONCLUSIONS: In regions (like Ontario) where PCP is rare, routine PCP prophylaxis with trimethoprim-sulfamethoxazole should not be offered, since the harms may outweigh the benefits.

Ovarian resection in anti-N-methyl-D-aspartate receptor encephalitis: A comparison of surgical approaches.

Background: For patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) and ovarian teratoma, "conservative" surgical approaches (complete or partial unilateral oophorectomy or bilateral partial oophorectomies) are associated with clinical improvement. "Aggressive" ovarian resections (complete bilateral oophorectomy or "blind" ovarian resections without pre-operative evidence of teratoma) are also reported, although the evidence supporting these approaches is unclear. Objective: To compare the one-year functional outcomes of patients with NMDARE who underwent conservative vs. aggressive ovarian resections. Methods: Patients with NMDARE undergoing ovarian resection between January 1st, 2012 and December 31st, 2021 were retrospectively identified from three North American tertiary care centers. Primary outcome was a modified Rankin Scale score of 0-2 one year after ovarian resection. Fisher exact and Wilcoxon rank sum tests were used to compare demographic features, disease characteristics, and functional outcomes between the two surgical groups. A fixed-effects meta-analysis of studies reporting functional outcomes based on surgical approach was also performed. Results: Twenty-three patients were included. Eight underwent aggressive surgical management. There was a non-significant trend toward an association between aggressive surgical management and younger age-at-onset, higher baseline disease severity, and longer delays to treatment. There was no difference between "aggressive" (3/8, 38%) and "conservative" (11/15, 73%) management groups in achieving the primary outcome (OR95% = <0.1-1.9; p = 0.18). Findings were similar when considering data from 52 patients in two published studies (RR = 0.74; CI95% = 0.48-1.13; p = 0.16). Conclusions: Aggressive ovarian resection was not associated with improved outcomes in patients with NMDARE in this series. Group differences may have contributed, recognizing that patients who underwent aggressive resection tended to be sicker, with procedures performed later in the disease course. Based on available evidence, we advocate for function-sparing resection in patients with imaging-confirmed/suspected teratoma, and repeated multi-modal imaging in at-risk patients with NMDARE refractory to conventional treatment.