In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer’s disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia. SORL1 variants were present in a high proportion of patients with candidate variants (15%, 3/20). We expand the clinical manifestations associated with the SORL1 gene by reporting detailed clinical and neuroimaging findings of six unrelated patients with AD and SORL1 mutations. We also present for the first time a patient with the homozygous truncating variant c.364C>T (p.R122*) in SORL1, who also had severe cerebral amyloid angiopathy. Furthermore, we report neuropathological findings and immunochemistry assays from one patient with the splicing variant c.4519+5G>A in the SORL1 gene, in which AD was confirmed by neuropathological examination. Our results highlight the heterogeneity of clinical presentation and familial dementia background of SORL1-associated AD and suggest that SORL1 might be contributing to AD development as a risk factor gene rather than as a major autosomal dominant gene.
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a life-threatening disorder that often occurs as a paraneoplastic encephalitis and usually begins with neuropsychological or psychiatric symptoms. We report a case of NMDA receptor encephalitis due to an ovarian teratoma, which began with severe and progressive amnesia and behavioral changes, reversed after surgical treatment and plasmapheresis. Using a battery of cognitive tests, its neuropsychological profile before treatment showed a complete alteration of the short and long term memory of both verbal and visual fixation, with clear improvement with cues and with intrusions, and saving other cognitive domains, such as working, episodic and semantic memory, executive, visuospatial, praxical thinking and language functions. These deficits reverted to normalcy with treatment. So, we can conclude that anti-NMDA receptor encephalitis is a rare entity that can be potentially serious depending on early management and diagnosis. We must suspect this entity in children or young people presenting with behavioural disturbances and crisis, with a cognitive pattern of complete alteration in short and long term memory improving with cues, and respecting other cognitive domains.
e18015 Background: PD-L1 is a biomarker of response to anti-PD1 in HNSCC. CA209-7HE trial (NCT04282109) is a randomized, open-label, multicenter, phase II trial including first line R/M HNSCC pts non-eligible for cisplatin-based chemotherapy. Pts were stratified according to Karnofsky performance status, HPV and tissue PD-L1 by Combined Positive Score (CPS). Subjects were randomized to either paclitaxel + nivolumab or paclitaxel + cetuximab. Primary objective was 2-year overall survival. We present the data on centrally determined PD-L1 patterns and its correlation with pt clinical characteristics. Methods: From 176 preliminary samples, only 141 were analyzed. 10 were excluded for not fulfilling quality requirements and 25 belonged to non-eligible pts. 74% (104) were paraffin blocks and 26% (37) tissue slides. 72.3% (102) were primary tumor biopsies, 12.7% (18) local soft tissue relapses, 9.2% (13) lymph node metastases and 5.6% (8) distant metastases. 46.6% (66) were collected from irradiated areas. Hematoxylin-eosin stain confirmed sample representativeness. At least 100 tumor cells/sample was required. Immunohistochemistry for PD-L1 was performed using DAKO PD-L1 IHC 22C3. Means and proportions were dropped for descriptive analyses. Multivariate logistic regresion was used to identify variables associated with higher CPS. Results: Clinical characteristics included 73% (103) males; 77% (108) were either former [56% (78)] or current smokers [21.2% (30)] and clinical stage was recurrent in 48.9% (69), metastatic alone in 29.8% (42) and both recurrent and metastatic in 21.3% (30). Diagnoses included 35.4% (51) oral cavity, 32.3% (45) oropharynx (only 2 pts HPV positive), 16.3% (23) larynx and 15.6% (22) hypopharynx. Mean time to CPS assessment was 5.25 days (CI 95% 4.95 – 5.55). CPS distribution was as follows: 21.7% (31) were CPS < 1, 42.8% (60) were CPS 1-20 and 35.4% (50) were CPS > 20. Multivariate model revealed that oral cavity tumors showed an increased likelihood of CPS > 20 (OR 2.35, 95%CI 1.46 - 3.78; p < 0.001) which was also seen among non-smokers (OR 3.37, 95% CI 1.16 - 9.73; p = 0.02) and pts with recurrent and metastatic disease (OR 2.75, 95% CI 1.03- 7.32; p = 0.04). Oropharyngeal tumors showed lower probability for CPS > 20 (OR 0.35, 95% CI 0.14 - 0.89; p = 0.03). Neither prior irradiation nor origin of the biopsy were associated with any significant variation in CPS. Conclusions: Central assessment of CPS is feasible with no significant treatment delay. HPV negative oropharyngeal tumors were not associated with higher CPS. We also found that oral cavity tumors, non-smokers and pts with recurrent and metastatic disease were independently associated with an increased probability of higher CPS. Future results will elucidate the promising role of combinatorial regimens with immunotherapy in these subpopulations. Clinical trial information: NCT04282109.
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