Global health status and fatigue score in isocitrate dehydrogenase-mutant diffuse glioma grades 2 and 3: A longitudinal population-based study from surgery to 12-month follow-up.

Background: At the group level, health-related quality of life (HRQoL) in patients with IDH-mutant diffuse glioma grades 2 and 3 seems to remain stable over time. However, clinical experience indicates that there are patients with unfavorable outcomes on key HRQoL subdomains. The aim of this longitudinal population-based study, following patients over a period of 12 months from surgery, was to describe individual-level data on global health status and fatigue score and explore possible predictors of deterioration. Methods: All patients undergoing surgery for presumed glioma grades 2 or 3 at the Sahlgrenska University Hospital during 2017-2022, were screened for the study. Patients were invited to complete the European Organization of Research and Treatment of Cancer core questionnaires and brain module at baseline, 3 and 12 months postoperatively. Data is reported with respect to minimal clinical important difference (MCID). Results: We included 51 patients with IDH-mutant diffuse glioma grades 2 or 3. There was no difference in group-level data of either global health status or fatigue score from baseline to the 12-month follow-up (P-value > .05). Unfavorable individual changes (beyond MCID) in global health status and fatigue score were observed in 12 and in 17 patients, respectively (23.5% and 33.3%). A lower proportion of proton radiotherapy was found in patients with unfavorable changes in fatigue (10/15, 66.7%) compared to all other patients undergoing radiotherapy (22/23, 95.7%, P-value .03). Conclusions: Deterioration beyond MCID was seen in approximately one-third of patients. Changes in global health status could not be predicted, but changes in fatigue may be influenced by tumor-targeted and symptomatic treatment.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Changes in clinical management of diffuse IDH-mutated lower-grade gliomas: patterns of care in a 15-year period.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutated diffuse lower-grade gliomas (dLGG) are infiltrating brain tumors and increasing evidence is in favor of early multimodal treatment. In a Scandinavian population-based setting, we wanted to study treatment patterns over the last 15 years, focusing on the short-term postoperative course to better understand the potential negative consequences of treatment. METHODS: Patients ≥ 18 years with primary IDH-mutated dLGG grade 2 and 3, operated between January 2007-June 2021 were identified. Patients were divided into subgroups (2007-2011, 2012-2016, and 2017-2021) and comparisons regarding tumor- and disease characteristics, treatment, and postoperative outcome were performed. RESULTS: We identified 202 patients (n = 61, 2007-2011; n = 72, 2012-2016; n = 69, 2017-2021), where of 193 underwent resection without change in proportion of resections over time. More patients underwent complete resections in recent times (6.1%; 15.7%; 26.1%, respectively; p = 0.016). Forty-two patients had any neurological deficit postoperatively (14.8%; 23.6%; 23.2%; p = 0.379), mostly minor and transient. Differences in oncological therapy were seen between the investigated subgroups. Early radiotherapy alone (32.8%; 7%; 2.9%; p < 0.001), concomitant chemoradiotherapy (23%; 37.5%; 17.4%; p = 0.022), sequential chemoradiotherapy (0%; 18%; 49.3%; p < 0.001), and no adjuvant treatment (42.6%; 23.6%; 18.8%; p = 0.009) shifted during the studied period. Increasingly more patients received proton radiotherapy compared to photon radiotherapy during the later time periods (p < 0.001). CONCLUSION: Complete resections were performed more often in later time periods without an apparent increase in surgical morbidity. Early adjuvant oncological treatment shifted towards providing chemotherapy and combined chemoradiotherapy more often in later time periods. Protons replaced photons as the radiation modality of choice.

Seizures in patients with IDH-mutated lower grade gliomas.

PURPOSE: Most patients with Lower Grade Gliomas (LGG) present with epileptic seizures. Since the advent of molecular diagnostics, more homogenous sub-entities have emerged, including the isocitrate dehydrogenase-mutated (IDH-mutated) astrocytomas and 1p19q-codeleted oligodendrogliomas. We aimed to describe the occurrence of seizures in patients with molecularly defined LGG pre- and postoperatively and to analyze factors affecting seizure status postoperatively. METHODS: A population-based cohort of 130 adult patients with IDH-mutated WHO grade 2 or 3 astrocytomas and oligodendrogliomas was assessed pertaining to seizure burden before and after surgery. RESULTS: Fifty-four (79.4%) patients with astrocytoma and 45 (72.6%) patients with oligodendroglioma had a history of seizures before surgery. At 12 months postoperatively, 51/67 (76.1%) patients with astrocytoma and 47/62 (75.8%) patients with oligodendrogliomas were seizure free. In a multivariable logistic regression analysis, lower extent of resection (EOR) (OR 0.98; 95% CI 0.97-1.00, p = 0.01) and insular tumor location (OR 5.02; 95% CI 1.01-24.87, p = 0.048) were associated with presence of seizures within 1 year postoperatively in the entire LGG cohort. In sub-entities, EOR was in a similar manner associated with seizures postoperatively in astrocytomas (OR 0.98; 95% CI 0.96-0.99, p < 0.01) but not in oligodendrogliomas (p = 0.34). CONCLUSION: Our results are well in line with data published for non-molecularly defined LGG with a large proportion of patients being seizure free at 1 year postoperative. Better seizure outcome was observed with increased EOR in astrocytomas, but this association was absent in oligodendrogliomas.

Neuropsychological functioning in childhood cancer survivors following cranial radiotherapy - results from a long-term follow-up clinic.

Treatment of malignant childhood posterior fossa tumors (CPFT) often includes surgical resection and craniospinal radiotherapy (CSI). Nasopharyngeal tumors in childhood (CNPHT) are often treated with surgery and radiotherapy (RT), leading to incidental brain irradiation. RT to the developing brain is associated with risks for cognitive impairments. We studied cognitive functioning, health-related quality of life (HRQOL), fatigue, and psychological distress, in adult survivors of CPFT and CNPHT, representing two groups, which had received high and low radiation dose-exposure to the brain, respectively. Cognitive tests were used to compare CPFT (n = 12) and CNPHT (n = 7) survivors to matched healthy controls (n = 28). HRQOL data was compared to the general population (GP) (n = 1415-1459). Average follow-up was 23 (CPFT) and 19 years (CNPHT). CPFT survivors had significant deficits in all cognitive domains. CNPHT survivors showed results below the control group but differed statistically only on one executive test. HRQOL-ratings indicated that both groups had similar self-reported cognitive problems. CPFT survivors reported more emotional problems and fatigue. Anxiety was seen in both CPFT and CNPHT survivors. This study confirmed long-term cognitive sequelae after RT in adult survivors of CPFT,and possible RT-induced cognitive deficits in adult CNPHT survivors.

Depression and ability to work after vestibular schwannoma surgery: a nationwide registry-based matched cohort study on antidepressants, sedatives, and sick leave.

BACKGROUND: In patients with vestibular schwannomas (VS), tumor control is often achieved, and life expectancy is relatively good. The main risks of surgical treatment are hearing loss and facial nerve function. The occurrence of mood and sleeping disorders in relation to surgery is an important aspect of health that has rarely been studied. Similarly, only limited data exist on the rate of sick leave for patients with VS. In this nationwide registry-based study, we define the use of antidepressants and sedatives and the sick leave pattern before and after VS surgery. METHODS: Adult patients with histopathologically verified VS were identified in the Swedish Brain Tumor Registry (SBTR) and clinical data were linked to relevant national registries after assigning five matched controls to each patient. We studied patterns of dispensed antidepressants and sedative drugs as well as patterns of sick leave compared to respective controls at 2 years before and 2 years following surgery. RESULTS: We identified 333 patients and 1662 matched controls. The rate of antidepressant use was similar between patients and controls 2 years before surgery (6.0% vs 6.3%) and 2 years after surgery (10.1% vs 7.5%). The rate of sedative use was also similar 2 years before surgery (3.9% vs 4.3%) and 2 years after surgery (4.8% vs 5.3%). The rate of sick leave was similar at baseline between patients and controls, but at 2 years after surgery, 75% of patients vs 88% of controls (p < 0.01) had no registered sick leave. Long-term sick leave after surgery was predicted by use of sedatives (OR 0.60, 95% CI 0.38-0.94, p = 0.03), more preoperative sick leave (OR 0.91, 95% CI 0.89-0.93, p < 0.001), and new-onset neurological deficits after surgery (OR 0.42, 95% CI 0.24-0.76, p = 0.004). CONCLUSION: This nationwide study shows no significant differences in the use of antidepressants and sedatives between patients and controls, while the rate of postoperative sick leave was higher in patients than in controls after VS surgery. Our findings underpin the importance of avoiding surgical sequelae and facilitating return to normal professional life.

Psychotropic and anti-epileptic drug use, before and after surgery, among patients with low-grade glioma: a nationwide matched cohort study.

BACKGROUND: Low-grade glioma (LGG) is a relatively rare type of brain tumour. The use of antidepressant, sedative and anti-epileptic drugs can reflect the burden of the disease. While epilepsy is well-described in patients with LGG, less is known about depression and anxiety. METHODS: We used nationwide registers to study the use (dispense) of antidepressants, sedatives, and anti-epileptic drugs (AEDs) before and after histopathological LGG diagnosis (WHO grade II). A total of 485 adult patients with a first-time diagnosis and a matched control cohort (n = 2412) were included. Patterns of use were analysed from one year prior to until one year following index date (date of surgery). Logistic regression analysis identified predictors for postoperative use. RESULTS: At one year before index date, patients were dispensed AEDs 4 times more than controls, while antidepressants and sedatives were similar. Sedatives and AED peaked shortly after index date at 25 and 69%, respectively. AEDs then stabilized while sedatives decreased rapidly. For antidepressants, a delayed increase was seen after index date, stabilizing at 12%. At one year after index date, the use of antidepressants, sedatives, and AEDs among patients was 2, 3, and 26 times higher, respectively, compared to controls. Predictor for use of AEDs and sedatives at one year following index was previous use and/or a related diagnosis. Female sex and later index year were additional predictors for antidepressants. CONCLUSIONS: Use of antidepressants, sedatives and AEDs is elevated following diagnosis of LGG. Antidepressants were more commonly dispensed to female patients and in recent years.

Impact of meningioma surgery on use of antiepileptic, antidepressant, and sedative drugs: A Swedish nationwide matched cohort study.

BACKGROUND: Meningioma is the most common primary intracranial tumor and surgery is the main treatment modality. As death from lack of tumor control is rare, other outcome measures like anxiety, depression and post-operative epilepsy are becoming increasingly relevant. In this nationwide registry-based study we aimed to describe the use of antiepileptic drugs (AED), antidepressants and sedatives before and after surgical treatment of an intracranial meningioma compared to a control population, and to provide predictors for continued use of each drug-group two years after surgery. METHODS: All adult patients with histopathologically verified intracranial meningiomas were identified in the Swedish Brain Tumor Registry and their data were linked to relevant national registries after assigning five matched controls to each patient. We analyzed the prescription patterns of antiepileptic drugs (AED), antidepressants and sedative drugs in the two years before and the two years following surgery. RESULTS: For the 2070 patients and 10312 controls identified the use of AED, antidepressants and sedatives was comparable two years before surgery. AED use at time of surgery was higher for patients than for controls (22.2% vs. 1.9%, p < 0.01), as was antidepressant use (12.9% vs. 9.4%, p < 0.01). Both AED and antidepressant use remained elevated after surgery, with patients having a higher AED use (19.7% vs. 2.3%, p < 0.01) and antidepressant use (14.8% vs. 10.6%, p < 0.01) at 2 years post-surgery. Use of sedatives peaked for patients at the time of surgery (14.4% vs. 6.1%, p < 0.01) and remained elevated at two years after surgery with 9.9% versus 6.6% (p < 0.01). For all the studied drugs, previous drug use was the strongest predictor for use 2 years after surgery. CONCLUSION: This nationwide study shows that increased use of AED, antidepressants and sedatives in patients with meningioma started perioperatively, and remained elevated two years following surgery.

Preoperative Patient-Reported Outcomes in Suspected Low-Grade Glioma: Markers of Disease Severity and Correlations with Molecular Subtypes.

This prospective study aims to determine the overall health-related quality of life (HRQoL), functioning, fatigue, and psychological distress preoperatively in patients with suspected diffuse low-grade glioma (dLGG). We were particularly interested if these parameters differed by molecular tumor subtypes: oligodendroglioma, IDHmut astrocytoma and IDHwt astrocytoma. Fifty-one patients answered self-assessed questionnaires prior to operation (median age 51 years; range 19-75; 19 females [37%]). Thirty-five (69%) patients had IDH-mutated tumors, of which 17 were 1p/19q codeleted (i.e., oligodendroglioma) and 18 non-1p/19q codeleted (i.e., IDHmut astrocytoma). A lower overall generic HRQoL was associated with a high level of fatigue (rs = -0.49, p < 0.001), visual disorder (rs = -0.5, p < 0.001), motor dysfunction (rs = -0.51, p < 0.001), depression (rs = -0.54, p < 0.001), and reduced functioning. Nearly half of the patients reported high fatigue (23 out of 51 patients) and anxiety (26/51 patients). Patients with IDHwt had worse generic HRQoL, worse functioning, and more severe fatigue, though differences were not statistically significant between the molecular subtypes. In conclusion, fatigue and anxiety are prominent self-assessed symptoms of patients with suspected dLGG in a preoperative setting, but do not seem to be a reliable method to make assumptions of underlying biology or guide treatment decisions.

Classification of Adverse Events Following Surgery in Patients With Diffuse Lower-Grade Gliomas.

BACKGROUND: Recently, the Therapy-Disability-Neurology (TDN) was introduced as a multidimensional reporting system to detect adverse events in neurosurgery. The aim of this study was to compare the novel TDN score with the Landriel-Ibanez classification (LIC) grade in a large cohort of patients with diffuse lower-grade glioma (dLGG). Since the TDN score lacks validation against patient-reported outcomes, we described health-related quality of life (HRQoL) change in relation to TDN scores in a subset of patients. METHODS: We screened adult patients with a surgically treated dLGG World Health Organization (WHO) grade 2 and 3 between 2010 and 2020. Up until 2017, it consists of a retrospective cohort (n = 158). From 2017 and onwards, HRQoL was registered using EuroQoL-5-dimension, three levels of response (EQ-5D 3L) questionnaire at baseline and 3 months follow-up, in a prospectively recruited cohort (n = 102). Both the LIC grade and TDN score were used to classify adverse events. RESULTS: In total, 231 patients were included. In 110/231 (47.6%) of the surgical procedures, a postoperative complication was registered. When comparing the TDN score to LIC grades, only a minor shift towards complications of higher order could be observed. EQ-5D 3L was reported for 45 patients. Patients with complications related to surgery had pre- to postoperative changes in EQ-5D 3L index values (n = 27; mean 0.03, 95% CI -0.06 to 0.11) that were comparable to patients without complications (n = 18; mean -0.06, 95% CI -0.21 to 0.08). In contrast, patients with new-onset neurological deficit had a deterioration in HRQoL at follow-up, with a mean change in the EQ-5D 3L index value of 0.11 (n = 13, 95% CI 0.0 to 0.22) compared to -0.06 (n = 32, 95% CI -0.15 to 0.03) for all other patients. CONCLUSIONS: In patients with dLGG, TDN scores compared to the standard LIC tend to capture more adverse events of higher order. There was no clear relation between TDN severity and HRQoL. However, new-onset neurological deficit caused impairment in HRQoL. For the TDN score to better align with patient-reported outcomes, more emphasis on neurological deficit and function should be considered.

Return to work following diagnosis of low-grade glioma: A nationwide matched cohort study.

OBJECTIVE: Return-to-work (RTW) following diagnosis of infiltrative low-grade gliomas is unknown. METHODS: Swedish patients with histopathologic verified WHO grade II diffuse glioma diagnosed between 2005 and 2015 were included. Data were acquired from several Swedish registries. A total of 381 patients aged 18-60 were eligible. A matched control population (n = 1,900) was acquired. Individual data on sick leave, compensations, comorbidity, and treatments assigned were assessed. Predictors were explored using multivariable logistic regression. RESULTS: One year before surgery/index date, 88% of cases were working, compared to 91% of controls. The proportion of controls working remained constant, while patients had a rapid increase in sick leave approximately 6 months prior to surgery. After 1 and 2 years, respectively, 52% and 63% of the patients were working. Predictors for no RTW after 1 year were previous sick leave (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88-0.96, p < 0.001), older age (OR 0.96, 95% CI 0.94-0.99, p = 0.005), and lower functional level (OR 0.64 95% CI, 0.45-0.91 p = 0.01). Patients receiving adjuvant treatment were less likely to RTW within the first year. At 2 years, biopsy (as opposed to resection), female sex, and comorbidity were also unfavorable, while age and adjuvant treatment were no longer significant. CONCLUSIONS: Approximately half of patients RTW within the first year. Lower functional status, previous sick leave, older age, and adjuvant treatment were risk factors for no RTW at 1 year after surgery. Female sex, comorbidity, and biopsy only were also unfavorable for RTW at 2 years.

Socioeconomic factors affect treatment delivery for patients with low grade glioma: a Swedish population-based study.

BACKGROUND: Despite aspirations to achieve equality in healthcare we know that socioeconomic differences exist and may affect treatment and patient outcome, also in serious diseases such as cancer. We investigated disparities in neurosurgical care and outcome for patients with low-grade glioma (LGG). METHODS: In this nationwide registry-based study, patients who had undergone surgery for LGG during 2005-2015 were identified (n = 547) through the Swedish Brain Tumor Registry. We linked data to multiple national registries with individual level data on income, education and comorbidity and analyzed the association of disease characteristics, surgical management and outcome, with levels of income, education and sex. RESULTS: Patients with either low income, low education or female gender showed worse pre-operative performance status. Patients with low income or education also had more comorbidities and those with low education endured longer waiting times for surgery. Median time from radiological imaging to surgery was 51 days (Q1-3 27-191) for patients with low education, compared to 32 days (Q1-3 20-80) for patients with high education (p = 0.006). Differences in waiting time over educational levels remained significant after stratification for age, comorbidity, preoperative performance status, and tumor size. Overall survival was better for patients with high income or high education, but income- and education-related survival differences were not significant after adjustment for age and comorbidity. The type of surgical procedure or complications did not differ over socioeconomic groups or sex. CONCLUSION: The neurosurgical care for LGG in Sweden, a society with universal healthcare, displays differences that can be related to socioeconomic factors.

Boston Naming Test automatic credits inflate scores of nonaphasic mild dementia patients.

INTRODUCTION: The Boston Naming Test (BNT), a 60-item test of confrontation naming, may be administered either from Item 1 or Item 30, depending on assumptions of performance. If the BNT is administered from Item 30, 29 automatic credits are given for preceding items, allowing identical norms for either administration. We aimed to compare effects of automatic credits. METHOD: We compared effects of automatic credits in the Gothenburg Mild Cognitive Impairment Study, first between normal controls (n = 23) and patients (n = 259), and then between the same patients grouped by stage of impairment: subjective cognitive impairment (SCI, n = 75), mild cognitive impairment (MCI, n = 117), or mild dementia (n = 67). RESULTS: Automatic credits added to all groups. Both administrations from Item 1 and those from Item 30 discriminated between controls (n = 23) and all patients (n = 259), as well as between the above stages of impairment. However, neither administration discriminated between normal controls and SCI patients. When earned scores were compared, with scores counted from Item 30 plus 29 automatic credits, mild dementia patients on average received a 3.4-credit boost. This equals 82% of the standard deviation of Tallberg's Swedish norms [Brain and Language, 94(1), 19-31 (2005)] or 117% of our normal controls' standard deviation. CONCLUSIONS: In our homogenous material, administration of BNT from Item 30 distinguished between stages of deterioration as well as administration from Item 1. In line with recent literature, we also find BNT results skewed. Thus, for clinical accuracy, we recommend use of cumulative percentages, careful consideration of education and demographic factors, and, most importantly, never to mix forms of administrations with and without automatic credits. While BNT automatic credits diminish accuracy on all levels, they inflate scores significantly for nonaphasic mild dementia patients.