Health-related quality of life and neurocognitive functioning in patients with recurrent glioblastoma treated with intracerebral immune checkpoint inhibition.

PURPOSE: After glioblastoma (GB) recurrence, prognosis is very cumbersome. Therefore, health-related quality of life (HRQoL) and neurocognitive functioning (NCF) have become important endpoints in clinical trials when evaluating novel treatments. We aimed to evaluate the HRQoL and NCF in patients with recurrent glioblastoma (rGB) treated with a combination of surgical intervention (reoperation or biopsy) and intracerebral immune checkpoint inhibition. METHODS: Patients who participated in the trial (N = 23), at a single-center university hospital were included. Data were collected using 3 patient-reported outcome measures (EORTC-QLQ-C30, EORTC-QLQ-BN20, and HADS) and computerized NCF testing. In the responder group, baseline values were compared to results at a 6-month follow-up. Additionally, exploratory analyses compared baseline HRQoL and NCF between responders and non-responders. RESULTS: There were five responders and 18 non-responders. When comparing the mean and individual baseline with follow-up results for the responders, we observed overall a stable to slight clinically relevant improvement of HRQoL in multiple subsets of the questionnaires while maintaining a stable NCF. One patient deteriorated on anxiety and depression symptoms from baseline to follow-up. CONCLUSIONS: In patients that responded to intracerebral immunotherapy in our institutional trial, HRQoL and NCF remained stable over time, suggesting that no detrimental effect on cognitive function or quality of life may be expected with this treatment approach. Furthermore, there seems to be an overall tendency for responders to score better on HRQoL and NCF than non-responders at baseline.

Adesão à quimioterapia antineoplásica oral, apoio social e bem- estar de pacientes com câncer cerebral: estudo correlacional / Adhesión a la quimioterapia antineoplásica oral, apoyo social y bienestar de pacientes con cáncer cerebral: estudio correlacional / Adherence to oral antineoplastic chemotherapy, social support and well-being of patients with brain cancer: a correlational study

Objetivos: identificar as percepções sobre o bem-estar, apoio social, intensidade dos sintomas e o seu impacto nas atividades diárias de pacientes com cânceres cerebrais e correlacionar os achados com os níveis de adesão aos quimioterápicos antineoplásicos orais. Método: estudo correlacional e transversal, realizado num ambulatório hospitalar universitário de São Paulo, Brasil, entre 2019 e 2020. Utilizou-se instrumento para caracterização da amostra e escalas específicas. Resultados: 26 participantes, mediana de 36,5 anos, 61,5% sexo masculino, 53,9% diagnosticados com glioblastoma; 73,1% apresentaram adesão, rede de apoio social e índice alto de bem-estar. O escore médio de intensidade dos sintomas foi de baixo para médio, com pior pontuação para preocupação no pior estado. A maior adesão relacionou-se ao apoio afetivo, apoio informação, interação social e apoio emocional. Conclusão: a maioria declarou níveis positivos de bem-estar, suporte social e poucos sintomas. A percepção de apoio social e bem-estar influenciaram positivamente na adesão medicamentosa.

Objetivos: identificar las percepciones sobre el bienestar, apoyo social, intensidad de los síntomas y su impacto en las actividades diarias de pacientes con cánceres cerebrales y correlacionar los resultados con los niveles de adhesión a los quimioterápicos antineoplásicos orales. Método: estudio correlacional y transversal, realizado en un ambulatorio hospitalario universitario de São Paulo, Brasil, entre 2019 y 2020. Se utilizó un instrumento para la caracterización de la muestra y escalas específicas. Resultados: 26 participantes, mediana de 36,5 años, 61,5% sexo masculino, 53,9% diagnosticados con glioblastoma; 73,1% presentaron adhesión, red de apoyo social y índice alto de bienestar. El puntaje promedio de intensidad de los síntomas fue de bajo a medio, con peor puntuación para preocupación en el peor estado. La mayor adhesión se relacionó al apoyo afectivo, apoyo información, interacción social y apoyo emocional. Conclusión: la mayoría declaró niveles positivos de bienestar, apoyo social y pocos síntomas. La percepción de apoyo social y bienestar influyó positivamente en la adhesión medicamentosa.

Objectives: to identify perceptions about well-being, social support, intensity of symptoms and their impact on the daily activities of patients with brain cancers and correlate the findings with levels of adherence to oral antineoplastic chemotherapy. Method: correlational and cross-sectional study, conducted in a university hospital outpatient clinic in São Paulo, Brazil, between 2019 and 2020. An instrument was used to characterize the sample, in addition to specific scales. Results: 26 participants, median 36.5 years, 61.5% male, 53.9% diagnosed with glioblastoma; 73.1% showed adherence, social support network and high well-being index. The mean symptom intensity score was low to medium, with a worse score for worry in the worst state. Greater adherence was related to affective support, information support, social interaction and emotional support. Conclusion: most reported positive levels of well-being, social support and few symptoms. The perception of social support and well-being positively influenced drug adherence.

Selective effects of a brain tumor on the metric representation of the hand: a pre- versus post-surgery comparison.

Body representation disorders are complex, varied, striking, and very disabling in most cases. Deficits of body representation have been described after lesions to multimodal and sensorimotor cortical areas. A few studies have reported the effects of tumors on the representation of the body, but little is known about the changes after tumor resection. Moreover, the impact of brain lesions on the hand size representation has been investigated in few clinical cases. Hands are of special importance, as no other body part has the ability for movement and interaction with the environment that the hands have, and we use them for a multitude of daily activities. Studies with clinical population can add further knowledge into the way hands are represented. Here, we report a single case study of a patient (AM) who was an expert bodybuilder and underwent a surgery to remove a glioblastoma in the left posterior prefrontal and precentral cortex at the level of the hand's motor region. Pre- (20 days) and post- (4 months) surgery assessment did not show any motor or cognitive impairments. A hand localization task was used, before and after surgery (12 months), to measure possible changes of the metric representation of his right hand. Results showed a post-surgery modulation of the typically distorted hand representation, with an overall accuracy improvement, especially on width dimension. These findings support the direct involvement of sensorimotor areas in the implicit representation of the body size and its relevance on defining specific size representation dimensions.

Clinical Uncertainty and Equipoise in the Management of Recurrent Glioblastoma.

BACKGROUND: A significant proportion of glioblastoma (GBM) patients are considered for repeat resection, but evidence regarding best management remains elusive. Our aim was to measure the degree of clinical uncertainty regarding reoperation for patients with recurrent GBM. METHODS: We first performed a systematic review of agreement studies examining the question of repeat resection for recurrent GBM. An electronic portfolio of 37 pathologically confirmed recurrent GBM patients including pertinent magnetic resonance images and clinical information was assembled. To measure clinical uncertainty, 26 neurosurgeons from various countries, training backgrounds, and years' experience were asked to select best management (repeat surgery, other nonsurgical management, or conservative), confidence in recommended management, and whether they would include the patient in a randomized trial comparing surgery with nonsurgical options. Agreement was evaluated using κ statistics. RESULTS: The literature review did not reveal previous agreement studies examining the question. In our study, agreement regarding best management of recurrent GBM was slight, even when management options were dichotomized (repeat surgery vs. other options; κ=0.198 [95% confidence interval: 0.133-0.276]). Country of practice, years' experience, and training background did not change results. Disagreement and clinical uncertainty were more pronounced within clinicians with (κ=0.167 [0.055-0.314]) than clinicians without neuro-oncology fellowship training (κ=0.601 [0.556-0.646]). A majority (51%) of responders were willing to include the patient in a randomized trial comparing repeat surgery with nonsurgical alternatives in 26/37 (69%) of cases. CONCLUSION: There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with recurrent glioblastoma to support the need for a randomized controlled trial.

The effects of releasing early results from ongoing clinical trials.

Most trials do not release interim summaries on efficacy and toxicity of the experimental treatments being tested, with this information only released to the public after the trial has ended. While early release of clinical trial data to physicians and patients can inform enrollment decision making, it may also affect key operating characteristics of the trial, statistical validity and trial duration. We investigate the public release of early efficacy and toxicity results, during ongoing clinical studies, to better inform patients about their enrollment options. We use simulation models of phase II glioblastoma (GBM) clinical trials in which early efficacy and toxicity estimates are periodically released accordingly to a pre-specified protocol. Patients can use the reported interim efficacy and toxicity information, with the support of physicians, to decide which trial to enroll in. We describe potential effects on various operating characteristics, including the study duration, selection bias and power.

Management, functional outcomes and survival in a French multicentric series of 118 adult patients with cerebellar glioblastoma.

PURPOSE: To analyze the outcomes and predictors in a large series of cerebellar glioblastomas in order to guide patient management. METHODS: The French brain tumor database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie retrospectively identified adult patients with cerebellar glioblastoma diagnosed between 2003 and 2017. Diagnosis was confirmed by a centralized neuropathological review. RESULTS: Data from 118 cerebellar glioblastoma patients were analyzed (mean age 55.9 years, 55.1% males). The clinical presentation associated raised intracranial pressure (50.8%), static cerebellar syndrome (68.6%), kinetic cerebellar syndrome (49.2%) and/or cranial nerve disorders (17.8%). Glioblastomas were hemispheric (55.9%), vermian (14.4%) or both (29.7%). Hydrocephalus was present in 49 patients (41.5%). Histologically, tumors corresponded either to IDH-wild-type or to K27-mutant glioblastomas. Surgery consisted of total (12.7%), subtotal (35.6%), partial resection (33.9%) or biopsy (17.8%). The postoperative Karnofsky performance status was improved, stable and worsened in 22.4%, 43.9% and 33.7% of patients, respectively. Progression-free and overall survivals reached 5.1 months and 9.1 months, respectively. Compared to other surgical strategies, total or subtotal resection improved the Karnofsky performance status (33.3% vs 12.5%, p < 0.001), prolonged progression-free and overall survivals (6.5 vs 4.3 months, p = 0.015 and 16.7 vs 6.2 months, p < 0.001, respectively) and had a comparable complication rate (40.4% vs 31.1%, p = 0.29). After total or subtotal resection, the functional outcomes were correlated with age (p = 0.004) and cerebellar hemispheric tumor location (p < 0.001) but not brainstem infiltration (p = 0.16). CONCLUSION: In selected patients, maximal resection of cerebellar glioblastoma is associated with improved onco-functional outcomes, compared with less invasive procedures.

Neurobehavioral effects in rats with experimentally induced glioblastoma after treatment with the mTOR-inhibitor rapamycin.

Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidities are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)- signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM animals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplantation medicine, immunotherapy, and oncology.

Illness perceptions and perceived social support among glioblastoma survivors during hospitalization.

BACKGROUND: Glioblastoma (GBM) is a terminal form of illness. Illness perceptions play vital role in illness behavior and managing the disease. GBM cancer survivor's illness perceptions and their perceived social support is not systematically studied. Therefore, study aimed to understand the illness perceptions and perceived social support of GBM survivors during hospitalization. METHODOLOGY: The study used cross sectional-descriptive research design. A total of 40 GBM survivors were recruited by using convenience sampling method. The Illness Perception Questionnaire Revised (IPQ-R) by Moss-Morris, Weinman et al. (2002), and Perceived Social Support from Family (FSS-Family) and Perceived Social Support from Friends (PSS-Friends) scales by Mary E. Procidano and Kenneth (1983) were administered on recruited participants. Semi-structured questionnaire was used to collect the personal and illness details of participants. Free R software was used to analyse the data. Descriptive statistics such as frequency, percentage, mean and standard deviation were calculated on selected variables. RESULTS: Half of the participants 50% (n = 20) did not aware of illness and 50% (n = 20) partially aware of their illness. Past sins 90% (n = 36), personal stress 90% (n = 36), increased work load 65% (n = 26), head Injury/smoking 55% (n = 22), personal dietary habits 50% (n = 20) were attributed as reasons for GBM. Participant's partially believed GBM was life threatening illness, causes emotional disturbances but not aware of consequences of illness. Perceived social support from family members and friends during hospitalization was found to be poor. CONCLUSION: GBM survivor's informational and educational needs were not met adequately. Psychoeducational programmes, addressing negative believes associated with brain cancer and enhancing social support for glioma patients are recommended during hospitalization.

Surviving glioblastoma and a sense of disconnection.

Given the poor prognosis of glioblastoma, little focus has been placed on the needs of long-term survivors (those alive at least two years following diagnosis). The aim of this project was to explore the lived experience of long-term survivors of glioblastoma using a qualitative approach. Long-term survivors of glioblastoma diagnosed between 1/1/2006-31/12/2016 were identified at the tertiary centre involved. Participants underwent a semi-structured qualitative interview and caregiver dyads were collected if available. Thematic analysis was undertaken where themes were gradually generated from the data alongside data collection and confirmed or contrasted as data collection proceeded. Participants were selected and interviewed until data saturation was reached at 10 interviews. The overarching theme explaining the data was a sense of disconnection, beginning with the shock of diagnosis, and evolving over time, leading survivors to feel disconnected from (1) 'who I was', redefining their work, independence and social self; (2) 'who I am', contributing to social isolation, disavowal, and anxiety and depression; and (3) 'who I could be', reassessing their future. This unique study highlights the acute emotional distress and disconnection that begins with diagnosis and its evolving impact on the lived experience. Clinicians need to consider the emotional impact of survival when managing these patients and adopt a holistic approach, including the early introduction of psychosocial support to patients and their caregivers. Further validation of these findings in a larger cohort is desirable.

Health-related quality of life and emotional well-being in patients with glioblastoma and their relatives.

PURPOSE: The health-related quality of life (HRQoL) for patients with glioblastoma is known to be largely affected. Little is known about the HRQoL for relatives and the relationship between these two. To optimize family care, such issues need to be addressed early on, preferably from the time of diagnosis. This study aimed to describe and compare the HRQoL of patients with glioblastoma and their relatives before surgery. METHODS: A prospective cohort study including 89 patients diagnosed with glioblastoma and their relatives. HRQoL (Short Form Health Survey, SF-36) and emotional well-being (hospital anxiety and depression scale, HADS) were analysed with descriptive, comparative and multivariable regression analyses. RESULTS: Relatives scored worse for mental HRQoL (p < 0.001) and for symptoms of anxiety (p < 0.001) and depression (p = 0.022) compared to patients. The multivariable regression showed an increased risk of affected mental HRQoL in relatives of patients with poor functional status (WHO) (p = 0.01) and higher levels in symptoms of anxiety (p = 0.03), or when relatives had low physical HRQoL themselves (p = 0.01). There was increased risk of affected mental HRQoL in patients with comorbidities (p = 0.003), and when the respective relative showed higher levels in symptoms of anxiety (p = 0.005). CONCLUSION: Relatives scored worse for mental HRQoL and emotional well-being than patients, suggesting that HRQoL in patients and relatives might be connected to symptoms of anxiety in the respective individual at disease onset. The results illustrate the need to screen HRQoL and emotional well-being in both patients and relatives from an early stage-before surgery.

Subtle neuropsychiatric symptoms of glioblastoma multiforme misdiagnosed as depression.

Glioblastoma multiforme (GBM) is the most common of the aggressive primary brain tumours arising in adults and has a dire prognosis. Neuropsychiatric symptoms can vary significantly among afflicted persons; psychiatric disturbances may be the predominant presenting symptoms. Distinguishing between functional psychiatric disorders, particularly depression, from other subtle neuropsychiatric disturbances that may accompany GBM can be challenging. The authors present a clinical case and review of the literature in an attempt to highlight the special considerations that should be taken into account when evaluating patients who present with late-onset or atypical symptoms, refractory psychiatric symptoms, or subtle neurological disturbances signalling the need for diagnostic assessment, particularly neuroimaging, for the presence of a tumour. Early diagnosis is critical for improvement in quality of life.

Health-related quality of life and distress in elderly vs. younger patients with high-grade glioma-results of a multicenter study.

OBJECTIVE: Half of all newly diagnosed patients with glioblastoma are > 65 years still with a poor prognosis. Preserving quality of life is of high importance. However, patient reported outcome (PRO) data in this patient group is rare. The aim was to compare health-related quality of life (HRQoL) and distress between elderly and younger patients with high-grade glioma (HGG). METHODS: We used baseline data of a prospective study where HGG patients were enrolled from 4 hospitals. Distress was measured using the distress thermometer (DT), HRQoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) plus brain module (BN20). We compared distress and HRQoL by age (≥ 65 vs. < 65 years), gender, performance score, and time since diagnosis using multivariate linear and logistic regressions. RESULTS: A total of n = 93 (30%) out of n = 309 patients were ≥ 65 years (mean 70 years, range 65-86 years). Mean DT score of elderly patients (5.2, SD 2.6) was comparable with younger patients (4.9, SD 2.6). Elderly patients reported significantly lower global health (GHS, mean elderly vs. younger; 50.8 vs. 60.5, p = 0.003), worse physical (56.8 vs. 73.3, p < 0.001) and lower cognitive functioning (51.1 vs. 63.2, p = 0.002), worse fatigue (52.5 vs. 43.5, p = 0.042), and worse motor dysfunction (34.9 vs. 23.6, p = 0.030). KPS and not age was consistently associated with HRQoL. CONCLUSION: Physical functioning was significantly reduced in the elderly compared with younger HGG patients, and at the same time, emotional functioning and DT scores were comparable. KPS shows a greater association with HRQoL than with calendric age in HGG patients reflecting the particular importance for adequate assessment of HRQoL and general condition in elderly patients.

Effect of early palliative care for patients with glioblastoma (EPCOG): a randomised phase III clinical trial protocol.

​INTRODUCTION: Randomised controlled trials (RCTs) have shown a positive effect of early integration of palliative care (EIPC) in various advanced cancer entities regarding patients' quality of life (QoL), survival, mood, caregiver burden and reduction of aggressiveness of treatment near the end of life. However, RCTs investigating the positive effect of EIPC for patients suffering from glioblastoma multiforme (GBM) are lacking. After modelling work identifying the specific needs of GBM patients and their caregivers, the aim of this study is to investigate the impact of EIPC in this particular patient group. ​METHODS AND ANALYSIS: The recruitment period of this multicenter RCT started in May 2019. GBM patients (n=214) and their caregivers will be randomly assigned to either the intervention group (receiving proactive EIPC on a monthly basis) or the control group (receiving treatment according to international standards and additional, regular assessment of QoL ('optimised' standard care)).The primary outcome is QoL assessed by subscales of the Functional Assessment of Cancer Therapy for brain tumour (FACT-Br) from baseline to 6 months of treatment. Secondary outcomes are changes in QoL after 12 (end of intervention), 18 and 24 months (end of follow-up), the full FACT-Br scale, patients' palliative care needs, depression/anxiety, cognitive impairment, caregiver burden, healthcare use, cost-effectiveness and overall survival. ​ETHICS AND DISSEMINATION: The study will be conducted in accordance with the Declaration of Helsinki and has been approved by the local ethics committees of the University Clinics of Cologne, Aachen, Bonn, Freiburg and Munich (LMU). Results of the trial will be submitted for publication in a peer-reviewed, open access journal and disseminated through presentations at conferences. TRIAL REGISTRATION NUMBER: German Register for Clinical Studies (DRKS) (DRKS00016066); Pre-results.

Depression and glioblastoma, complicated concomitant diseases: a systemic review of published literature.

Glioblastoma multiforme (GBM) is the most common primary brain cancer. Depression is a common co-morbidity of this condition. Despite this common interaction, relatively little research has been performed on the development of GBM-associated depression. We performed a literary search of the PubMed database for articles published relating to GBM and depression. A total of 85 articles were identified with 46 meeting inclusion criteria. Depression significantly impacts care, decreasing medication compliance, and patient survival. Diagnostically, because depression and GBM share intricate neuro-connectivity in a way that effect functionality, these diseases can be mistaken for alternative psychological or pathological disorders, complicating care. Therapeutically, anti-depressants have anti-tumor properties; yet, some have been shown to interfere with GBM treatment. One reason for this is that the pathophysiological development of depression and GBM share several pathways including altered regulation of the 5-HT receptor, norepinephrine, and 3':5'-cyclic monophosphate. Over time, depression can persist after GBM treatment, affecting patient quality of life. Together, depression and GBM are complicated concomitant diseases. Clinicians must be aware of their co-existence. Because of overlapping molecular pathways involved in both diseases, careful medication selection is imperative to avoid potential adverse interactions. Since GBMs are the most common primary brain cancer, physicians dealing with this disease should be prepared for the development of depression as a potential sequela of this condition, given the related pathophysiology and the known poor outcomes.

The Impact of Gliomas on Cognition and Capacity.

Brain tumors, particularly gliomas, can have profound effects on cognitive functioning. The cognitive effects that can occur due to a glioma are not just due to the tumor itself, but also from the treatment modalities used. In-depth neuropsychiatric testing or screening is typically necessary to determine the extent of cognitive impairments and the rate of progression, especially given that physical functioning may be better than cognitive functioning. Given the high mortality rate and fast-growing nature of gliomas, patients often have to make significant and consequential decisions in relatively short periods of time, such as consent for treatments and personal planning (e.g., preparing a will, assigning power of attorney). In a postmortem context, forensic psychiatrists may have to make determinations regarding whether a person had capacity at the time many of these decisions were made. This article discusses some of the unique cognitive concerns that arise from gliomas and their impact on patient care and personal decision-making, both contemporaneously and in a postmortem context.