Ingeborg Bosma’s research while affiliated with University of Groningen and other places

Background Increasing numbers of patients diagnosed with advanced cancer survive long-term after treatment with immune checkpoint inhibitors (ICIs). To design adequate interventions for these survivors, knowledge regarding quality of life (QOL) and its association with long-term and late effects of ICI treatment is required. Therefore, this study aimed to evaluate QOL, neurocognitive function, psychological issues, sexuality, and comorbidities in patients surviving at least 2 years after commencing ICI treatment. Methods We performed a cross-sectional study in patients with stage III-IV melanoma, non-small cell lung cancer (NSCLC), urothelial cell carcinoma (UCC), or renal cell carcinoma (RCC) who survived at least 2 years after the start of ICIs. We assessed QOL, neurocognitive function, psychological issues, sexual function and comorbidity in survivors. Additionally, we evaluated QOL of informal caregivers. Results 132 survivors (70 melanoma, 50 NSCLC, 12 UCC or RCC) and 80 caregivers were included. Median age was 65 years (range 30–85) and 50 survivors were women (38%). Median time since start and cessation of ICI treatment was 33 (range 21–91) and 18 (range 0–68) months, respectively. Average survivor QOL was comparable to the reference population, but 37 (28%) survivors had poor QOL. Depression and anxiety were negatively correlated with all QOL domains. Although immune-related adverse events were common, there was no association with lower QOL. Caregiver and survivor QOL were only weakly related. Neurocognitive concerns and formally tested neurocognitive impairment were present in 22 (17%) and 13 (15%) survivors, respectively, and were not associated with a diagnosis of brain metastases. Men had a high prevalence of erectile dysfunction and low sexual satisfaction. Half of the survivors met the criteria for the metabolic syndrome. Conclusions At least 2 years after the start of ICI treatment, one-quarter of cancer survivors had a clinically relevant lower QOL. This was associated with symptoms of depression and anxiety, but not with immune-related adverse events. Sexual issues and metabolic syndrome are prevalent. Survivorship care should address these issues in this population.

Purpose To determine neurocognitive function (NCF) profiles of patients with lower grade glioma (LGG) eligible to undergo proton radiotherapy (PRT), and how these relate to clinical and radiological characteristics. PRT is offered to those patients for whom sparing of NCF is considered important given their favorable prognosis. To date it is unknown to which extent their NCF profiles are favorable as well. Methods A consecutive cohort of 151 LGG patients eligible for PRT according to prevailing Dutch criteria, referred between 2018 and 2023, were assessed with standardized neuropsychological tests prior to PRT. Scores were compared to norm-scores. Composite scores were calculated for the total NCF and 6 separate cognitive domains, and profiles were related to tumor location. Clinical and radiological factors characterizing overall NCF impaired patients were investigated, comparing 3 definitions for impairment. Results Patients had on average significantly lower NCF than their norm-group, but interindividual variability was large. For 100/151 patients (66.2%), all cognitive domains were intact, whereas 15/151 patients (9.9%) displayed multiple domain impairments. Poorer NCF was related to right-sided LGG laterality, larger PRT target volume, no Wait & Scan policy, worse neurological function and worse radiological indices (Fazekas and global cortical atrophy, respectively). LGG involvement of the left temporal and occipital lobes was associated with, respectively, lower verbal memory and processing speed. Conclusion Prior to PRT, the majority of selected LGG patients display favorable NCF profiles. However, a subgroup showed NCF impairments, with multiple relevant clinical and radiological covariates.

Background: Diffusion weighted imaging (DWI) is used for monitoring purposes for lower-grade glioma (LGG). While the apparent diffusion coefficient (ADC) is clinically used, various DWI models have been developed to better understand the micro-environment. However, the validity of these models and how they relate to each other is currently unknown. Therefore, this study assesses the validity and agreement of these models. Methods: Fourteen post-treatment LGG patients and six healthy controls (HC) underwent DWI MRI on a 3T MRI scanner. DWI processing included diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), white matter tract integrity (WMTI), neurite orientation dispersion and density imaging (NODDI), and fixel-based analysis (FBA). Validity was assessed by delineating surgical cavity, peri-surgical cavity, and normal-appearing white matter (NAWM) in LGG patients, and white matter (WM) in HC. Spearman correlation assessed the agreement between DWI parameters. Results: All obtained parameters differed significantly across tissue types. Remarkably, WMTI showed that intra-axonal diffusivity was high in the surgical cavity and low in NAWM and WM. Most DWI parameters correlated well with each other, except for WMTI-derived intra-axonal diffusivity. Conclusion: This study shows that all parameters relevant for tumour monitoring and DWI-derived parameters for axonal fibre-bundle integrity (except WMTI-IAS-Da) could be used interchangeably, enhancing inter-DWI model interpretability.

BACKGROUND Low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors. Although all patients with LGG face similar challenges in coping with an incurable disease, interestingly, a subset of patients reports no (significant) problems in daily functioning and appear to resume their activities without changes. It is crucial to identify the group of patients that seem to cope so well, in order to find possible indications to help patients who do experience problems in daily functioning. Therefore, the present study aims to characterize the LGG patient group without problems in daily functioning. MATERIAL AND METHODS 144 patients with LGG were included post-surgery and before adjuvant therapy. Patients were divided into two groups: patients with and without problems in daily functioning, based on the Patient Competency Rating Scale (PCRS). Demographic variables, disease characteristics (tumor location, tumor volume), anxiety, depression (HADS), coping (UCL) and general cognition (neuropsychological tests) were analysed to identify characteristics specific to the patient group without problems in daily functioning. RESULTS Of the entire LGG cohort (mean age= 43 ± 12), 26.4% of the patients no (significant) problems in daily functioning. No significant differences were found for demographics (gender, age and educational level), disease characteristics and general cognition between patients with and without problems in daily functioning (p>0.05). However, patients without problems had significantly lower scores for anxiety (p<.01), depression (p<.01), avoidant (p=<.01) and passive coping (p<.001), compared to patients with problems in daily functioning. CONCLUSION More than a quarter of the patients with LGG experience no (significant) problems in daily functioning, after surgery and before adjuvant therapy. Notably, this subset of patients did not differ from patients with problems in daily functioning considering demographics, disease characteristics and cognitive functioning. However, the cohort of patients with no problems in daily functioning report lower levels of anxiety and depression, and use a more effective coping style, compared to patients who do experience problems in daily functioning. Therefore, it seems to be crucial addressing coping strategies, serving as a potential to help patients who do experience problems in daily functioning. Future research should focus on whether the patient group without problems in daily functioning continues to report zero complaints after adjuvant therapy, i.e. examining if an initial problem-free status serves as a protective factor during and after treatment.

Purpose Diffuse low-grade gliomas (dLGG) often have a frontal location, which may negatively affect patients’ executive functions (EF). Being diagnosed with dLGG and having to undergo intensive treatment can be emotionally stressful. The ability to cope with this stress in an adaptive, active and flexible way may be hampered by impaired EF. Consequently, patients may suffer from increased mental distress. The aim of the present study was to explore profiles of EF, coping and mental distress and identify characteristics of each profile. Methods 151 patients with dLGG were included. Latent profile analysis (LPA) was used to explore profiles. Additional demographical, tumor and radiological characteristics were included. Results Four clusters were found: 1) overall good functioning (25% of patients); 2) poor executive functioning, good psychosocial functioning (32%); 3) good executive functioning, poor psychosocial functioning (18%) and; 4) overall poor functioning (25%). Characteristics of the different clusters were lower educational level and more (micro)vascular brain damage (cluster 2), a younger age (cluster 3), and a larger tumor volume (cluster 4). EF was not a distinctive factor for coping, nor was it for mental distress. Maladaptive coping, however, did distinguish clusters with higher mental distress (cluster 3 and 4) from clusters with lower levels of mental distress (cluster 1 and 2). Conclusion Four distinctive clusters with different levels of functioning and characteristics were identified. EF impairments did not hinder the use of active coping strategies. Moreover, maladaptive coping, but not EF impairment, was related to increased mental distress in patients with dLGG.

Background Patients with low-grade gliomas (LGG) treated with surgery, generally function well and have a favourable prognosis. However, LGG can affect neurocognitive functioning. To date, little is known about social cognition (SC) in these patients, although impaired SC is related to social-behavioral problems and poor societal participation. Frontal brain areas are important for SC and LGG frequently have a frontal location. Therefore, the aim of the present study was to investigate whether emotion recognition, a key component of SC, was impaired, and related to general cognition, tumor location laterality, tumor volume and histopathological characteristics in patients with LGG, post-surgery and before start of adjuvant therapy. Methods 121 patients with LGG were matched with 169 healthy controls (HC). Tumor location (including (frontal) subregions; insula, anterior cingulate cortex, lateral prefrontal cortex (LPFC), orbitofrontal-ventromedial PFC) and tumor volume were determined on MRI scans. Emotion recognition was measured with the Ekman 60 faces test of the Facial Expressions of Emotion-Stimuli and Tests (FEEST). Results Patients with LGG performed significantly lower on the FEEST than HC, with 33.1% showing impairment compared to norm data. Emotion recognition was not significantly correlated to frontal tumor location, laterality and histopathological characteristics, and significantly but weakly with general cognition and tumor volume. Conclusions Emotion recognition is impaired in patients with LGG but not (strongly) related to specific tumor characteristics or general cognition. Hence, measuring SC with individual neuropsychological assessment of these patients is crucial, irrespective of tumor characteristics, to inform clinicians about possible impairments, and consequently offer appropriate care.

BACKGROUND The introduction of proton radiotherapy in the Netherlands resulted in the centralization of proton craniospinal irradiation (pCSI) for patients with medulloblastoma (MB) to a single center. For optimal outcome of MB patients, timely start of pCSI and treatment without interruptions is important. However, national-scale referrals and the complexity of delivering pCSI pose a risk for treatment delays in these patients. Therefore, to aid in high quality care, integration of pCSI within the national pediatric oncology center and collaboration within the Dutch neuro oncology society - rare cancer working group was established. In this study, we evaluated the care infrastructure for pCSI for a nationwide defined MB patient cohort in the Netherlands. MATERIAL AND METHODS All Dutch MB patients referred for pCSI to our center were included in this analysis. The interval between surgery and start of pCSI was calculated, excluding patients who received neo-adjuvant chemotherapy. Overall treatment time, use of (back-up) photon fractions and plan adaptations were evaluated. Data regarding planned and additional multidisciplinary care during pCSI were extracted from the medical records. RESULTS Between February 2018 and December 2022, 79 MB patients, including 25 (32%) adult (>18 years) patients, were treated with pCSI. The median interval between surgery and start of pCSI for pediatric and adult patients was 32 days (IQR 30, 35) and 41 days (IQR 35, 55) respectively, and 91% and 47% started within 40 days from surgery. The median overall treatment time for all patients was 41 days (range 11). The longest treatment interruption was 3 days in one adult patient. Eight patients received a median of 9 photon fractions (IQR 2, 11); most often because of the need to start treatment quickly. In 30% of all patients a plan adaptation was needed, mostly because of changes in patient weight during treatment. In our center, it is considered standard of care to involve the (pediatric) medical oncologist and neurologist during pCSI. Clinical care (hospitalization) was required in 42% of the patients for a median of 10 days. Anesthesia was necessary predominantly for patients aged 8 years and younger. Other (para)medical disciplines involved during pCSI were neurosurgery (6%), neuropsychology (22%), speech therapy (25%), rehabilitation therapy (46%) and nutritional specialist (73%). CONCLUSION The Dutch pCSI infrastructure for MB patients facilitated a timely start of treatment in over 90% of pediatric patients and in nearly half of the adult patients. During pCSI treatment, a well-orchestrated interplay between several (para)medical disciplines is required to provide all potential necessary care. More disciplines were involved and more clinical care was required for pediatric patients. We were able to deliver pCSI treatment with less than 3 days interruption in 98% of patients.

BACKGROUND The cause for neurocognitive function (NCF) impairments in patients with lower grade glioma (LGG) is typically multifactorial. The aim of this study was to explore the relationship between NCF and the radiological appearance of the brain before start of radiotherapy (RT) in LGG patients. MATERIAL AND METHODS Around start of RT we evaluated NCF of LGG patients treated with proton therapy. The assessment included 10 neuropsychological tests with 20 measures that could be categorized over 6 cognitive domains. Raw test scores were converted to Z scores based on normative data. Mild cognitive impairment (MCI) was defined as a Z score of less than -2 on a single measure, or Z score of less than -1.5 on multiple measures. An impaired cognitive domain was defined as a mean composite Z score of less than -1.5. The radiological appearance of the brain outside the tumor region was assessed on a pre-RT planning MRI using the Fazekas score and Global Cortical Atrophy (GCA) score. For statistical analysis we used Chi Square tests and Mann-Whitney U tests. RESULTS Between 2018 and March 2022, 126 LGG patients started RT treatment, 119 patients (94%) had NCF assessment pre-RT and were available for analysis. Median age was 41 years, 51% of patients was male, reported comorbidities included hypertension in 7%, diabetes mellitus in 3% and cardiovascular 13% of patients. The World Health Organization (WHO) performance scores and the Neurologic Assessment in Neuro-Oncology (NANO) scores were 0 - 1, in 98%, and 92% of patients. The Fazekas score was 0 in 75%, 1 in 18% and 2 in 6% and 3 in 2% of patients. The GCA score was 0 in 59%, 1 in 38%, 2 in 3% of patients. In 77 (65%) patients the performance on the NCF assessment indicated the presence of MCI. Patients with MCI had a significant radiologically worse appearance of the brain (Fazekas score 1 or higher 31.2% versus 14.3%, p = 0.043; and GCA score 1 or higher 49.4% versus 26.2%, p = 0.014). Domain impairments were present in executive functions and attention (26%); verbal memory (23%); verbal functions (20%); non-verbal memory (20%); processing speed (18%); and working memory (14%). Fazekas score 1 or higher was significantly associated with lower composite Z scores of verbal functions (median (IQR) -0.84 (1.12) versus -0.40 (0.94), p=0.014); verbal memory (median (IQR) -0.66 (1.26) versus -0.20 (1.35), p=0.045) and non-verbal memory (median (IQR) -0.45 (2.10) versus -0.20 (1.36), p=0.037). There were no significant associations found between the GCA score and domain composite scores. CONCLUSION This cohort of LGG patients had a good clinical and neurological baseline function pre-RT. We found significant relationships between NCF and both white matter damage and atrophy of the brain. The Fazekas and GCA score are objective and easily obtained radiological measures, that could be a relevant parameter to record in LGG patients.

BACKGROUND Fatigue is a frequent consequence of low-grade glioma (LGG), but the causes are still barely understood. Specifically mental fatigue might be related to cognitive impairment such as mental slowness and decreased attention. Also, patients with greater tumor volumes or tumors in certain locations (such as the frontal cortex) might have more cognitive impairments and experience more fatigue. The aim of the present study was twofold: (1) to examine the relationship between mental fatigue and information processing speed and complex attention and (2) to investigate the associations between mental fatigue and tumor volume and location in patients with LGG. MATERIAL AND METHODS 124 patients with LGG (IDH mutated astrocytoma and oligodendroglioma grade 2 and 3) were included before the start of proton therapy. Different facets of fatigue, including mental fatigue, were measured after surgery, with a multidimensional fatigue scale, the Dutch Multifactor Fatigue Scale (DMFS). The Vienna Test System was used to examine simple information processing speed, response inhibition, and divided attention. Tumor location and tumor volume (radiation target volume) were scored on the pre-radiotherapy MRI scan. Descriptive statistics, Spearman’s correlations, and between group comparisons were performed. RESULTS 41% of patients with LGG reported severe mental fatigue. No significant differences were found in mean performance on simple information processing speed, response inhibition and divided attention between severely mental fatigued patients and non-severely mental fatigued patients. However, the percentage of patients with impaired divided attention was significantly higher in the severely mental fatigued group (39%) compared to the non-severely mental fatigued group (16.2%), χ2 = 7.6, p < 0.05. No significant relationships were found between mental fatigue and tumor volume and location. Also, tumor location was not related to neurocognitive functioning, but larger tumor volume was significantly associated with poorer performance on divided attention (r = -0.19, p < 0.05). CONCLUSION A high rate of mental fatigue was found in patients with LGG. Furthermore, a relationship between impaired divided attention and severe mental fatigue was found. This implies that patients may develop mental fatigue due to increased cognitive efforts to compensate for attentional deficits. This might be especially important in patients with larger tumors, considering the relationship between tumor volume and divided attention. The results stress the importance of neuropsychological assessment in this patient group before the start of adjuvant treatment, to timely offer individual rehabilitation.

BACKGROUND Patients with low-grade gliomas (LGG), generally function well at the time of diagnosis and have a favourable prognosis. However, LGG can have impact on cognitive functioning of patients. To date, little is known about social cognition (SC) in patients with LGG. Social cognitive functions allow the processing of complex social information, with as important element the ability to recognize other people’s emotional expressions. Inaccurate recognition or misinterpretation of emotional facial expressions can lead to impairments in social functioning, which can have adverse effects on quality of life. Therefore, the aim of the present study was to investigate emotion recognition in patients with LGG and the relationship with tumor location and tumor volume. MATERIAL AND METHODS 125 patients with IDH mutated astrocytoma and oligodendroglioma grade 2 and 3, were matched with 169 healthy controls (HC). Tumor location and volume were evaluated pre-radiotherapy based on MRI scans. As a parameter for LGG volume the clinical radiotherapy target volume was used. SC was measured with a test for emotion recognition, i.e. the Facial Expressions of Emotion Stimuli and Tests (FEEST), after surgery. Descriptive statistics and between-group comparisons were performed. RESULTS On a group level, patients with LGG performed significantly lower on the FEEST total score compared to HC. Also, compared to norm data used in clinical practice, 32.8% of the patients showed an impaired performance. Larger LGG volume was significantly associated (p < 0.001) with poorer performance on emotion recognition. However, no direct association between LGG location (frontal, temporal, parietal) and emotion recognition was found. CONCLUSION In patients with LGG, impaired emotion recognition is often present before start of radiotherapy, and is related to larger LGG volume but not to location. Because of the relatively favourable prognosis of patients with LGG, maintaining quality of life is of high importance. Therefore, a thorough neuropsychological examination, including measurements for SC, is necessary to inform patients with LGG about possible changes in SC, and offer appropriate psychoeducation and care.