[Better assessment, better care: Quetci, a questionnaire for assessing cognitive disorders in nursing practice]. / Mieux évaluer, mieux soigner : le Quetci, un questionnaire d'évaluation des troubles cognitifs IDE.

Cognitive disorders can have significant repercussions on the quality of care and daily life for patients. We have developed a new tool specifically designed for nursing practice to identify these problems in patients with brain tumors. The Cognitive Impairment Assessment Questionnaire for nursing practice is an objective, quick and easy-to-administer tool that is readily accepted by patients.

Long-term Neurologic Safety in Patients With B-Cell Lymphoma Treated With Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy.

OBJECTIVES: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a promising treatment in relapsing B-cell lymphoma but is frequently associated with acute neurotoxicity. Neurologic long-term safety has not been thoroughly assessed. METHODS: All patients with consecutive refractory lymphoma admitted in our center for CAR T-cell therapy underwent neurologic examination, extensive neuropsychological assessment, and brain MRI (except 1 patient) and completed self-administrated questionnaires at baseline. The patients who remained disease-free at 2 years were re-evaluated similarly. All neurologic assessments were conducted by senior neurologists. RESULTS: None of the 19 disease-free patients developed new neurologic deficits or MRI changes when compared with baseline. There was no difference in cognitive performances before and 2 years after, even for the 11 patients who had developed acute neurotoxicity after CAR T cells. In self-questionnaire assessments, cognitive complaint was stable, reported by 32% of the patients at 2 years. We observed a reduction in HADS anxiety scores 2 years after treatment when compared with baseline (median score: 7/21 vs 4/21, p = 0.01). DISCUSSION: In conclusion, no significant neurocognitive or neurologic disorders were observed in this cohort of patients, 2 years after treatment with anti-CD19 CAR T cells.

Descriptive and retrospective analysis of diffuse glioma patients with symptomatic SARS-CoV2 infection during the first wave of the pandemic.

BACKGROUND: Little is known about diffuse glioma patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). METHODS: We performed a descriptive and retrospective analysis of 41 diffuse glioma patients with symptomatic SARS-CoV2 infection during the first wave of the COVID-19 pandemic. RESULTS: Confusion with or without fever was the most common neurological symptom (32%) supporting SARS-CoV2 testing in glioma patients with acute and unexplained confusion. Sixteen patients (39%) died after a median delay of 13 days. While multiple clinical, biological, and pathological features, COVID-19- or diffuse glioma-related, at hospital admission appeared to have a pejorative prognostic impact, none was significantly associated with death. Oncological treatments were interrupted at COVID-19 diagnosis and re-initiated with a median delay of 30 days after the end of COVID-19 symptoms. CONCLUSIONS: Interestingly, our retrospective study describes for the first time the characteristics of a cohort of diffuse glioma patients with symptomatic COVID-19. Diffuse glioma patients with poorly symptomatic COVID-19 did not come to the attention of physicians and were not enrolled in the study skewing the denominator for prognostic analysis. Further studies are warranted to specify prognosis of overall population of diffuse glioma patients with COVID-19, including asymptomatic patients, and interactions of prognostic factors of both COVID-19 and diffuse gliomas.

Evaluation of mid-term (6-12 months) neurotoxicity in B-cell lymphoma patients treated with CAR T cells: a prospective cohort study.

BACKGROUND: Chimeric antigen receptor-modified T (CAR T) cells are profoundly changing the standard of care in B-cell malignancies. This new therapeutic class induces a significant number of acute neurotoxicity, but data regarding mid- and long-term neurological safety are scarce. We evaluated mid-term neurological safety, with special emphasis on cognitive functions, in a series of adults treated with CAR T cells. METHODS: Patients treated in a single center with CD19-targeted CAR T cells for a relapsing B-cell lymphoma were prospectively followed up by neurologists. Before CAR T-cell infusion, all patients underwent neurological examinations with neuropsychological testing and filled out questionnaires assessing anxiety, depression, and cognitive complaints. Patients surviving without tumor progression were re-evaluated similarly, 6-12 months later. RESULTS: In this prospective cohort of 56 consecutive adult patients treated with CAR T cells, 27 were eligible for mid-term evaluation (median time 7.6 months). Twelve patients developed an acute and reversible neurotoxicity with median duration time of 5.5 days. In all patients, neurological examination on mid-term evaluation was similar to baseline. In self-assessment questionnaires, 63% of patients reported clinically meaningful anxiety, depression, or cognitive difficulties at baseline, a number reduced to 44% at the time of mid-term evaluation. On cognitive assessments, no significant deterioration was found when compared to baseline, in any cognitive functions assessed (verbal and visual memory, executive functions, language, and praxis), even in patients who developed acute neurotoxicity. CONCLUSION: In this cohort of patients treated with CD19-targeted CAR T cells, we found no evidence for neurological or cognitive toxicity, 6-12 months after treatment.

Description of neurotoxicity in a series of patients treated with CAR T-cell therapy.

Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1-2 severity and 34% had grade 3-4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3-4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

Reintroduction of immune-checkpoint inhibitors after immune-related meningitis: a case series of melanoma patients.

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated antigen-4 and programmed cell death ligand-1) are associated with several immune-related neurological disorders. Cases of meningitis related to ICIs are poorly described in literature and probably underestimated. Several guidelines are available for the acute management of these adverse events, but the safety of resuming ICIs in these patients remains unclear. We conducted a retrospective case series of immune-related meningitis associated with ICIs that occurred between October 1 2015 and October 31 2019 in two centers: Saint-Louis and Cochin hospitals, Paris, France. Diagnosis was defined by a (1) high count of lymphocytes (>8 cells/mm3) and/or high level of proteins (>0.45 g/L) without bacteria/virus or tumor cells detection, in cerebrospinal fluid and (2) normal brain and spine imaging. Patients were followed-up for at least 6 months from the meningitis onset. Seven cases of immune-related meningitis are here reported. Median delay of meningitis occurrence after ICIs onset was 9 days. Steroid treatment was introduced in four patients at a dose of 1 mg/kg (prednisone), allowing a complete recovery within 2 weeks. The other three patients spontaneously improved within 3 weeks. Given the favorable outcome, ICIs were reintroduced in all patients. The rechallenge was well tolerated and no patients experienced meningitis recurrence. In conclusion, in our series, the clinical course was favorable and steroids were not always required. Resuming ICIs in these patients appeared safe and can thus be considered in case of isolated meningitis. However, a careful analysis of the risk/benefit ratio should be done on a case-by-case basis.

How to assess and manage cognitive impairment induced by treatments of non-central nervous system cancer.

A number of neurotoxicity associated with oncological treatments has been reported in non-central nervous system cancers. An expert group presents the state of the art and a guide to help the choice of appropriated tools to assess patient cognition in studies on oncology and neurobehavior in animal models. In addition, current cognitive rehabilitation programs currently under evaluation are also discussed. Cognitive assessments in oncology depend on the research question, study design, cognitive domains, patients' characteristics, psychometric properties of the tests, and whether the tests are supervised or not by a neuropsychologist. Batteries of electronic tests can be proposed, but several of them are characterized by weak psychometric developments. In order to improve the comprehension on the impact of cancer treatments on cognition, new animal models are in development, and would in the future include non-human primate models. By bringing together the skills and practices of oncologists, neurologists, neuropsychologists, neuroscientists, we propose a series of specific tools and tests that accompany the cognitive management of non-CNS cancer patients.

Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders.

BACKGROUND: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies. OBJECTIVE: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders. METHODS: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults. RESULTS: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations. CONCLUSIONS: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.

Impact of Angiotensin-II receptor blockers on vasogenic edema in glioblastoma patients.

Glioblastoma patients often require chronic administration of steroids due to peri-tumoral edema. Preliminary studies showed that treatment with Angiotensin-II Receptor Blockers (ARBs) for high blood pressure might be associated with reduced peri-tumoral edema. In this study, we aim to radiologically assess the effect of ARBs on peri-tumoral edema. We conducted a cross-sectional survey on patients with newly diagnosed GBM. Patients treated with ARBs for high blood pressure were paired to non ARB-treated patients based on similar age, tumor location and tumor size. Patients taking steroids at the time of pre-operative Magnetic Resonance Imaging were excluded from the study. In each pair of patients, we compared the volumes of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal and the Apparent Diffusion Coefficient (ADC) in the same area. Eleven (11) ARB-treated patients were selected and paired to 11 non ARB-treated controls. Volumes of peri-tumoral hyper T2-FLAIR signal were significantly lower in the ARB-treated group than in the non ARB-treated group (p = 0.02). Additionally, peri-tumoral ADCs were also significantly lower in the treated group (p = 0.02), suggesting that the peri-tumoral area in this group had less edematous features. These results suggest that ARBs may reduce the volume of peri-tumoral hyper T2-FLAIR signal by decreasing edema.

Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.

TLR-9 agonists are immunostimulating agents that have antitumor effects in animal models. A phase I trial was conducted to define the safety profile of subcutaneous injections, combined with intrathecally administration of CpG-28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3-6 patients with NM were treated for 5 weeks with escalating doses of CpG-28. The primary endpoint was tolerance. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Twenty-nine patients were treated with CpG-28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma, ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70%. The treatment was well tolerated. Adverse effects that were possibly or probably related to the studied drug were grade 2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were five serious adverse events: two confusions, two infections of ventricular devices and one grade 4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the eight patients who were concomitantly treated with bevacizumab (19 weeks vs 15 weeks; P = 0.11). CpG-28 was well tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Additional trials are warranted.

Evolution of the Karnosky Performance Status throughout life in glioblastoma patients.

Functional independence in glioblastoma (GBM) patients is a key factor in measuring the quality of life. Progression free survival (PFS) and overall survival (OS) have been largely described. However, the evolution over time of the performance status during the patients' life remains understudied. We thus studied the time to loss of functional independence as assessed by a Karnosky Performance Status (KPS) below 70 % in GBM patients. We analysed all GBM patients treated in our institution between 2008 and 2013 and meeting the following criteria: age >18 years, supratentorial location, post-surgical KPS ≥ 70 %, initially treated with concomitant radiotherapy (RT) and Temozolomide. Within the 84 patients studied, the median PFS was 9 months and the median OS was 18.7 months. The median survival time with functional independence (KPS ≥ 70 %) was 14.5 months. On average, the patients spent 73 % of their lifespan with a KPS ≥ 70 %. Surgical resection and low steroid dosage were statistically associated with increased survival time with KPS ≥ 70 % (p = 0.015 and p = 0.03, respectively). Sixty-two (62) patients received one or several lines of chemotherapy at recurrence. Under treatment with Bevacizumab (42 Bev-based regimens), radiological responses were seen in 35 % and improvement in KPS occurred in 24 % whereas no response and rare improvement of KPS (3 %) were seen with other type of chemotherapy (97 non Bev-based regimens). In GBM patients, median survival with KPS ≥ 70 % largely exceeds PFS. Surgical resection and low steroids dosage at RT-onset appeared as good prognosis factors for survival with functional independence.

[Brain metastasis: clinical and cognitive assessments]. / Métastases cérébrales intracrâniennes : signes cliniques et évaluations cognitives.

The incidence of brain metastases (BM) has increased due to the improvement of therapeutics and diagnostic imaging, but also to an aging population. The initial symptoms may develop suddenly or insidiously over weeks or months. The symptoms depend on the location of the BM and related complications (hydrocephalus, tumor hemorrhage, cerebral herniation). Headaches are the most frequent symptoms (50%); they are related to intracranial hypertension. Cognitive deficits are commonly described at diagnosis (67 to 90.5%). Cognitive assessment is essential because of its impact on patients' prognosis and quality of life. Nevertheless, these deficits remain underestimated. The Karnofsky Perfomance Scale and the Mini Mental State Examination (MMSE) seem inadequate. A short battery was proposed and internationally validated, assessing seven domains: attention (Digit Symbol Test WAIS-III), episodic memory (Hopkins Verbal Learning Test [HVLT]), working memory (Digit Span Test WAIS-III), verbal fluency (Controlled Oral Word Association Test [COWA]), fine motor dexterity (Grooved Pegboard Test), information processing speed (Trail Making Test [TMT] A) and executive functions (TMT B). This battery is relevant, feasible and associated with a good compliance. These cognitive tests are currently recommended to assess cognitive functions in patients with BM.

Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma.

Approximately 10% of patients with non-small cell lung cancer (NSCLC) have brain metastases at the time of diagnosis. When surgical resection is not possible, whole brain radiotherapy is the standard of care, with a cerebral response rate of approximately 30%. We report our experience with an upfront association of carboplatin and pemetrexed (areas under the curve, 5 and 500 mg/m(2), respectively), every 3 weeks, in 30 patients presenting with newly diagnosed brain metastases and NSCLC. Cerebral MRIs were performed every 6-9 weeks. The radiologic response rates were assessed according to Response Evaluation Criteria in Solid Tumors. Overall survival was also determined. Twenty-six patients were evaluable for response, and the objective cerebral response rate (complete and partial response) in the intent-to-treat population was 40% (12 of 30 patients). Event-free survival was 31 weeks, and median overall survival was 39 weeks. The upfront association of carboplatin plus pemetrexed allows simultaneous treatment of cerebral and systemic disease in patients with NSCLC with newly diagnosed brain metastases and appears to be particularly interesting in terms of radiologic response and overall survival. Further clinical studies are warranted.

Steroid requirements during radiotherapy for malignant gliomas.

Radiotherapy (RT) is the standard treatment for high-grade gliomas. However, toxicity may develop during RT, such as brain edema or worsening of neurological symptoms. Surprisingly, no dedicated study had focused on steroid requirements during RT in adult patients with malignant gliomas. We evaluated prospectively all patients with malignant gliomas treated by RT in a single center from July 2006 to May 2009. Age, sex, initial Karnofsky performance status (KPS), tumor localization and histology, type of surgical resection, clinical target volume, total dose and duration of RT, concomitant treatment with temozolomide, and steroid dosage during RT and at 1 and 3 months after RT were recorded in all patients. Most of the 80 patients (70%) were already taking steroids before RT. Half of them (55%) required initiation or further steroids increase during RT. The median time to steroid increase was 8 days. Only 13% of patients remained free of steroids during RT, and the mean maximal dosage of prednisone was 55 ± 48 mg. At 3 months after RT, 29% of patients were free of steroids, and the mean prednisone dosage was 32 ± 50 mg. Unresected tumors and initial KPS ≤80% were the only variables associated with higher steroid requirements on multivariate analysis. In our series, almost all patients required steroids during RT. Poor initial KPS and biopsy were associated with higher steroid requirements.

[Assessment of episodic memory in illiterate elderly]. / Evaluation des capacités de mémoire épisodique de sujets âgés illettrés.

Assessing cognitive functions in illiterate people is a difficult task because most of the neuropsychological tests exploring episodic memory have been validated in formally educated people, are based on verbal material and, therefore, require a good knowledge of language. Two episodic memory tests (TNI93 and TMA93) designed to be used for cognitive impairment screening in illiterate people have been designed, then validated in a multicultural low-educated population. Four hundred and thirty seven subjects aged 60 and over, living in the Seine-Saint-Denis district, received a medical check up offered by the National Health Service and their episodic memory performance was examined with these screening tests. The performance obtained on these tests depends both on age and educational level, as expected. Normative data for screening purpose in population with low education and/or not fluent with the language of the examiner are presented.