Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

CAR T-cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real-life results of the LOC network.

The prognosis of relapsed primary central nervous system lymphoma (PCNSL) remains dismal. CAR T-cells are a major contributor to systemic lymphomas, but their use in PCNSL is limited. From the LOC network database, we retrospectively selected PCNSL who had leukapheresis for CAR-T cells from the third line of treatment, and, as controls, PCNSL treated with any treatment, at least in the third line and considered not eligible for ASCT. Twenty-seven patients (median age: 68, median of three previous lines, including ASCT in 14/27) had leukapheresis, of whom 25 received CAR T-cells (tisa-cel: N = 16, axi-cel: N = 9) between 2020 and 2023. All but one received a bridging therapy. The median follow-up after leukapheresis was 20.8 months. The best response after CAR-T cells was complete response in 16 patients (64%). One-year progression-free survival from leukapheresis was 43% with a plateau afterward. One-year relapse-free survival was 79% for patients in complete or partial response at CAR T-cell infusion. The median overall survival was 21.2 months. Twenty-three patients experienced a cytokine release syndrome and 17/25 patients (68%) a neurotoxicity (five grade ≥3). The efficacy endpoints were significantly better in the CAR T-cell group than in the control group (N = 247) (median PFS: 3 months; median OS: 4.7 months; p < 0.001). This series represents the largest cohort of PCNSL treated with CAR T-cells reported worldwide. CAR T-cells are effective in relapsed PCNSL, with a high rate of long-term remission and a reassuring tolerance profile. The results seem clearly superior to those usually observed in this setting.

Early use of high efficacy therapies in pediatric forms of relapsing-remitting multiple sclerosis: A real-life observational study.

BACKGROUND: Pediatric forms of multiple sclerosis are more active than those in adults. Yet, the effectiveness of different therapeutic approaches is not well studied in this population. Our objective was to compare the effectiveness of the early use of high efficacy therapies (HETs) with the effectiveness of moderate efficacy therapies (METs) in children with MS. METHODS: This observational study included patients diagnosed with pediatric MS, at 4 hospital centers in France, during a 10-year period. METs included: interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide; HETs included: fingolimod, natalizumab, ocrelizumab, alemtuzumab. The primary endpoint was the occurrence of a new relapse, the secondary endpoint was EDSS worsening. RESULTS: Sixty-four patients were included in the analysis (80% women; mean age 15.5 years, 81% treated with MET) with a median follow-up of 22.5 months. At baseline, 52 patients were on MET (interferon ß-1a, glatiramer acetate, dimethyl fumarate, teriflunomide) and 12 patients were on HET (natalizumab, ocrelizumab). The cumulative probability of being relapse-free at 6.5 years was 23.3% on MET, vs 90.9% on HET (p = 0.013). The cumulative probability of no EDSS worsening did not differ between the 2 groups. CONCLUSION: Patients starting with METs had much higher clinical disease activity than those starting early with HETs. Rapid initiation of more aggressive treatment may allow better disease control; however, the data on EDSS worsening are not conclusive.

Isolated intraocular relapses of primary cerebral lymphomas: An LOC network study.

Most relapses of primary central nervous system lymphoma (PCNSL) occur in the brain and are associated with a poor prognosis. Isolated intraocular relapses (IIORs) are rare and poorly described. We retrospectively selected from the French Lymphome Oculo-Cérébral database PCNSL patients who initially presented with cerebral localization and who experienced IIOR during the course of the disease. Of the 1472 patients included in the database, 55 patients presented an IIOR. Their median age was 68 years, and median Karnofsky Performance Status 80. IL-10 levels in the aqueous humor and/or in the vitreous were increased in 42/46 patients. 45/55 patients received systemic chemotherapy, and 11/55 received high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) as consolidation treatment. After a median follow-up of 69 months, 42/55 patients had relapsed, including 90% of the patients who did not receive HCT-ASCT at IIOR and 40% of the patients who received HCT-ASCT at IIOR (p < 0.001). The first relapse after the initial IIOR was exclusively in the eye in 23/42 patients, and 29/42 patients had a subsequent brain relapse during the course of the disease. The median progression-free survival, brain-free survival and overall survival from IIOR were 12.2, 48.6 and 57.1 months, respectively. Isolated intraocular relapse is not exceptional in the course of PCNSL and deserves systematic ophthalmological follow-up. Its prognosis is much better than the prognosis of brain relapse, with an evolution close to that of primary vitreoretinal lymphoma. With the exception of patients who received HCT-ASCT at IIOR, almost all patients subsequently relapsed, often with other IIORs.

Metronomic Cyclophosphamide With Cisplatin and Bevacizumab for Refractory Anaplastic Ependymoma: A Retrospective Study.

BACKGROUND/AIM: Anaplastic ependymoma is a rare cancer of the central nervous system. The treatment includes optimal resection with focal radiotherapy. Some case reports or retrospective studies have suggested efficacy of regimens containing platinum or bevacizumab. We describe the feasibility and clinical benefit of the cisplatin-bevacizumab-cyclophosphamide treatment of anaplastic ependymoma. PATIENTS AND METHODS: Patients were identified through the Adolescent and Young Adults (AYAS) brain tumor national Web conference. We estimated the median progression-free (PFS) and overall survival (OS). RESULTS: There were eight patients with anaplastic ependymoma, with a median age of 36 years. The median OS was 19.9 months and median PFS was 12.3 months. Three patients obtained partial response, four stable disease, and one patient had disease progression during induction. Six patients received maintenance with a median duration of 224 days. CONCLUSION: This study confirms the tolerance of bevacizumab-cyclophosphamide-cisplatin treatment of anaplastic ependymoma. The clinical benefit seems even superior to that described in the literature.

Chemotherapy is an efficient treatment in primary CNS MALT lymphoma.

BACKGROUND: Mucosae-associated lymphoid tissue (MALT) lymphomas are a rare and poorly understood form of primary central nervous system lymphoma (PCNSL). The aim of this study was to better describe these tumors, their management and their long-term prognosis. METHODS: Patients with primary CNS MALT lymphoma (PCNSML) were retrospectively selected from the database on PCNSL of the Pitié-Salpêtrière Hospital. RESULTS: Of 662 PCNSL, 11 (1.7%) PCNSML (9 females and 2 males, median age: 56 years) were selected. The median time from first symptoms to diagnosis was 13 months. Location was dural in 8 cases and parenchymal in 3 cases. The disease was multifocal/diffuse in 7 cases. In first line, all patients received chemotherapy (high-dose methotrexate (HD-MTX) based chemotherapy (n = 4) and non-HD-MTX-based chemotherapy (n = 7)), preceded by surgery in 4 cases. None received radiotherapy. According to the IPCG (International PCNSL Collaborative Group) criteria, the overall response rate was 7/11 (64%). At latest news, 5 patients had persistent contrast enhancement, stable with no treatment since a median of 57 months, raising the question of complete response despite persisting contrast enhancement. No patient developed neurotoxicity except for one patient who subsequently received radiotherapy. The median follow-up was 109 months. The median progression-free survival was 78.0 months and the 10-year overall survival rate was 90%. CONCLUSION: This is the largest series demonstrating that chemotherapy is an efficient treatment in PCNSML, with an excellent long-term outcome and the absence of neurotoxicity, and calling into question the relevance of the IPCG criteria for the evaluation of response.

Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French Network.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

[Central nervous system disorders on lorlatinib: How to detect and manage in practice?] / Troubles du système nerveux central sous lorlatinib : comment les détecter et les gérer en pratique ?

The therapeutic arsenal for advanced ALK positive non-small cell lung cancer has been enriched by specific treatments targeting this molecular abnormality, with five molecules available, including lorlatinib, approved since July 2020. This treatment can have side effects common to other tyrosine kinase inhibitors, as well as other less common disorders affecting the central nervous system such as impaired cognitive function, speech or mood. The prevalence of neuro-psychiatric effects under treatment with lorlatinib reported in studies is nearly 40 % with a mild to moderate intensity in most cases. Given the potential impact on patients' quality of life and even on compliance with treatment, it is essential to include their detection during consultations. The main problem is still to have simple screening tools adapted to clinical practice. A multidisciplinary expert panel (pulmonologist, medical oncologist, psychiatrist, neurologist, pharmacist, nurse) therefore met to propose, based on data from the literature and their clinical experience, elements of management in order to detect these cognitive disorders at an early stage and optimize treatment tolerance. The subjects discussed concern screening and assessment tools, the management of side effects, and their prevention. The use of the practical elements proposed by the group could help optimize the identification and management of central nervous system disorders occurring on lorlatinib.

Ocrelizumab versus fingolimod after natalizumab cessation in multiple sclerosis: an observational study.

BACKGROUND: Exit strategy after natalizumab cessation in multiple sclerosis (MS) is a crucial point because the risk of disease reactivation is high during this period. The objective of this observational study was to compare ocrelizumab to fingolimod after natalizumab cessation in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: All RRMS patients starting fingolimod or ocrelizumab within 6 weeks after natalizumab cessation were included. The primary endpoint was the annualized relapse rate (ARR) at 1 year. RESULTS: We included 54 patients receiving fingolimod and 48 patients receiving ocrelizumab after natalizumab cessation. In multivariate analysis, ARR at 1 year was significantly lower in the ocrelizumab group than in the fingolimod group (0.12 ± 0.39 versus 0.41 ± 0.71, p = 0.026), i.e. a 70.7% lower relapse rate. The cumulative probability of relapses at 1 year was 31.5% (17/54 patients) with fingolimod and 10.4% (5/48 patients) with ocrelizumab, corresponding to a hazard ratio of 3.4 (95% confidence interval: 1.1-11, p = 0.04). CONCLUSIONS: Our results suggest ocrelizumab is potentially a better exit strategy than fingolimod after natalizumab cessation.

Multifocal and Microvascular Involvement in Ischemic Stroke During COVID-19: A Cohort Study With Comparison With Non-COVID-19 Stroke.

Introduction: Thromboembolic events, including ischemic stroke, are major complications of coronavirus disease 2019 (COVID-19). The clinical characteristics of COVID-19-related stroke are not clearly defined, and few controlled studies assessed the underlying mechanisms of cerebrovascular complications of COVID-19. This single-center retrospective observational study compared stroke characteristics between patients with and without COVID-19. Methods: This study included all patients hospitalized between March 1, 2020, and April 30, 2020, in Colmar Hospital for ischemic stroke as confirmed by imaging. The characteristics of patients with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection by real-time reverse transcriptase polymerase chain reaction or serology were compared with those without SARS-CoV-2 infection. Result: Among 772 patients, nine COVID-19 patients were compared with 50 patients without COVID-19. The following inflammatory and procoagulant marker levels were significantly higher in the COVID-19 group than those in the control group: C-reactive protein, 57.3 ± 43.4 vs. 15.0 ± 30.6 mg/L, p < 0.001; fibrinogen, 5.89 ± 1.75 vs. 4.03 ± 1.26 g/L, p < 0.001; and D-dimer, 4,833.9 ± 6,549.4 vs. 1,028.6 ± 942.6 ng/ml, p < 0.001. The rates of multifocal cerebral territory involvement (4 vs. 7, p = 0.05), microvascular involvement (4 vs. 6, p = 0.04), and thrombophilia (4 vs. 4, p = 0.014) were significantly higher in the COVID-19 group than in the control group, whereas no significant intergroup differences were found in the stroke mechanisms, i.e., cardio-embolic, atherosclerotic, small vessel disease, and cryptogenic. Conclusion: COVID-19-related stroke is characterized by hypercoagulability and hyperinflammation that may favor strokes via microvascular circulation abnormalities, microthrombus formation, and multifocal lesions.

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network.

BACKGROUND AND OBJECTIVES: To evaluate the efficacy and tolerance of the association rituximab-lenalidomide-ibrutinib (R2I) in relapsed/refractory (R/R) primary CNS lymphoma (PCNSL). METHODS: R/R PCNSL patients treated with R2I were retrospectively selected and analyzed from the French LOC database. RESULTS: Fourteen patients (median age: 63 years, median Karnofsky Performance Status: 75%) received R2I, administered after a median of 2 previous lines of chemotherapy, including autologous stem cell transplantation (ASCT) in 5 cases. The best response was complete response in 4/14 patients and partial response in 4/14 patients, achieved in a median of 2.5 months. Three responder patients received consolidation treatment (WBRT: N = 2, ASCT: N = 1) after R2I, and R2I served as a bridge before CAR-T cell therapy for one patient. R2I was discontinued due to toxicity in 3/14 patients. There were no toxicity-related deaths. DISCUSSION: The R2I combination resulted in a high rate of response of rapid-onset in heavily pretreated patients with poor prognosis, with manageable toxicity, and allowed 3 patients to proceed to consolidation. Although preliminary, these results support the use of R2I for R/R PCNSL failing conventional chemotherapies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that combination of rituximab-lenalidomide-ibrutinib induces a high rate of response in heavily pretreated R/R PCNSL.

Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: An LOC network study.

The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011 and 2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 42/59 (71%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.

High risk of recurrence for grade II meningioma: a 10-year multicenter analysis of prognosis factors.

BACKGROUND: Atypical meningioma is a variant of meningioma with a high risk of recurrence. Gross total resection is the standard of treatment, while no consensus on optimal adjuvant management has been found. METHODS: Between 2008 and 2018, a retrospective search identified 216 grade II meningiomas treated in six centers. Clinical, histological, and therapeutic data were analyzed to determine the prognostic factors of recurrence and survival. RESULTS: In total, 216 patients underwent surgical resection. Among these, 122 patients (56%) underwent gross total resection, and 21% of the patients received adjuvant radiotherapy. Univariate analysis reported subtotal resection, high Ki-67, negative progesterone receptor (PR) and histological grade evolution as unfavorable prognosis factors. According to multivariate analysis, the Ki-67 proliferative index (cut-off value of 17.5%) was the only prognostic factor of recurrence (HR 1.1; 95% CI, 1.0-1.2, P=0.048). Gross total resection improved progression-free survival (PFS) (P=0.03) but without impact on overall survival (OS) (P=0.2). Median PFS and OS times were longer for patients receiving adjuvant radiotherapy than those who did not receive adjuvant radiotherapy. PFS (P=0.3) and OS (P=0.7) were associated with adjuvant RT by trend only. After a median follow-up time of 6.7 years, 99 (46%) patients relapsed. Median progression-free and OS rates were 4.5 (95% CI, 3.5-5.5) and 14.7 years (11.4-NA), respectively. CONCLUSIONS: In this study, Ki-67 proliferative index was significantly associated with recurrence. Gross total resection significantly improved PFS without impacting OS. Adjuvant radiotherapy delayed recurrence and improved OS, but a longer follow-up time is needed to distinguish a statistically significant difference. Large prospective studies are needed to determine postoperative treatment guidelines.

CSF interleukin 6 is a useful marker to distinguish pseudotumoral CNS inflammatory diseases from primary CNS lymphoma.

BACKGROUND: Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS). OBJECTIVE: Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL). METHODS: We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL. RESULTS: In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5-18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5-1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (p = 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (r = 0.56, p = 0.028), but not in the PCNSL group (r = 0.3, p = 0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (p < 0.001). DISCUSSION AND CONCLUSIONS: Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.

Progressive multifocal leukoencephalopathy: MRI findings in HIV-infected patients are closer to rituximab- than natalizumab-associated PML.

OBJECTIVES: To compare brain MRI findings in progressive multifocal leukoencephalopathy (PML) associated to rituximab and natalizumab treatments and HIV infection. MATERIALS AND METHODS: In this retrospective, multicentric study, we analyzed brain MRI exams from 72 patients diagnosed with definite PML: 32 after natalizumab treatment, 20 after rituximab treatment, and 20 HIV patients. We compared T2- or FLAIR-weighted images, diffusion-weighted images, T2*-weighted images, and contrast enhancement features, as well as lesion distribution, especially gray matter involvement. RESULTS: The three PML entities affect U-fibers associated with low signal intensities on T2*-weighted sequences. Natalizumab-associated PML showed a punctuate microcystic appearance in or in the vicinity of the main PML lesions, a potential involvement of the cortex, and contrast enhancement. HIV and rituximab-associated PML showed only mild contrast enhancement, punctuate appearance, and cortical involvement. The CD4/CD8 ratio showed a trend to be higher in the natalizumab group, possibly mirroring a more efficient immune response. CONCLUSION: Imaging features of rituximab-associated PML are different from those of natalizumab-associated PML and are closer to those observed in HIV-associated PML. KEY POINTS: • Nowadays, PML is emerging as a complication of new effective therapies based on monoclonal antibodies. • Natalizumab-associated PML shows more inflammatory signs, a perivascular distribution "the milky way," and more cortex involvement than rituximab- and HIV-associated PML. • MRI differences are probably related to higher levels of immunosuppression in HIV patients and those under rituximab therapy.

Pseudoprogression versus true progression in glioblastoma patients: A multiapproach literature review: Part 1 - Molecular, morphological and clinical features.

With new therapeutic protocols, more patients treated for glioblastoma have experienced a suspicious radiologic image of progression (pseudoprogression) during follow-up. Pseudoprogression should be differentiated from true progression because the disease management is completely different. In the case of pseudoprogression, the follow-up continues, and the patient is considered stable. In the case of true progression, a treatment adjustment is necessary. Presently, a pseudoprogression diagnosis certainly needs to be pathologically confirmed. Some important efforts in the radiological, histopathological, and genomic fields have been made to differentiate pseudoprogression from true progression, and the assessment of response criteria exists but remains limited. The aim of this paper is to highlight clinical and pathological markers to differentiate pseudoprogression from true progression through a literature review.

Late-onset riboflavin transporter deficiency: a treatable mimic of various motor neuropathy aetiologies.

OBJECTIVE: Riboflavin transporter deficiencies (RTDs), involving SLC52A3 and SLC52A2 genes, have recently been related to Brown-Vialetto-Van Laere (BVVL) syndrome, a hereditary paediatric condition associating motor neuropathy (MN) and deafness. BVVL/RTD has rarely been reported in adult patients, but is probably underdiagnosed due to poor knowledge and lack of awareness of this form of disease among neurologists. In this study, we aimed to investigate the phenotype and prognosis of RTD patients with late-onset MN. METHODS: We retrospectively collected clinical, biological and electrophysiological data from all French RTD patients with MN onset after 10 years of age (n=6) and extracted data from 19 other similar RTD patients from the literature. RESULTS: Adult RTD patients with MN had heterogeneous clinical presentations, potentially mimicking amyotrophic lateral sclerosis or distal hereditary motor neuropathy (56%), multinevritis with cranial nerve involvement (16%), Guillain-Barré syndrome (8%) and mixed motor and sensory neuronopathy syndromes (20%, only in SLC52A2 patients). Deafness was often diagnosed before MN (in 44%), but in some patients, onset began only with MN (16%). The pattern of weakness varied widely, and the classic pontobulbar palsy described in BVVL was not constant. Biochemical tests were often normal. The majority of patients improved under riboflavin supplementation (86%). INTERPRETATION: Whereas late-onset RTD may mimic different acquired or genetic causes of motor neuropathies, it is a diagnosis not to be missed since high-dose riboflavin per oral supplementation is often highly efficient.

Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19).

BACKGROUND: Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. PATIENTS AND METHODS: In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and 11th June 2020. The primary end-point was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary end-points. RESULTS: From April 4 to 11th June 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), The Eastern Cooperative Oncology Group Performance Scale (ECOG PS) ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except for cytotoxic chemotherapy in the subgroup of patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment (such as chemotherapy, targeted or immune therapy) interrupted or stopped following diagnosis of COVID-19. CONCLUSIONS: Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis.