Biochemical and reperfusion targeting strategies to improve brain protection during prolonged hypothermic circulatory arrest

Abstract Ischaemic cerebral injury follows a well attested sequence of events including three phases, i.e. depolarization, biochemical cascade and reperfusion injury. Glutamate excitotoxicity plays an important role in the development of ischaemic brain injury following prolonged hypothermic circulatory arrest (HCA), and leukocyte infiltration and a cytokine-mediated inflammatory reaction are known to play a pivotal role in the reperfusion phase. The aim of this series of experimental studies was to develop biochemical and reperfusion-related strategies to improve brain protection. We tested the hypotheses that the Na+ channel blocker lamotrigine (I) or the N-Methyl-D-Aspartate-receptor antagonist memantine (III) could improve the cerebral outcome after HCA and studied whether a leukocyte-depletion filter (L-DF; LeukoGuard LG6®, Pall Biomedical, Portsmouth, U.K) could mitigate brain injury (II). The aim of the fourth study was to find out whether lamotrigine combined with the leukocyte-depleting filter can potentiate cerebral protection (IV). A chronic porcine model was used, in which haemodynamic, electrophysiological, metabolic and temperature monitoring were performed for four hours after the instigation of rewarming and S-100β measured up to 20 hours. Cytokines were measured, microdialysis was performed, and daily behavioural assessments were made until death or elective sacrifice on the seventh postoperative day, upon which a histopathological analysis of the brain was carried out. The rate of EEG burst recovery was higher in the lamotrigine-treated animals, the median being 40% of the baseline compared with 17% in the placebo group at 4 hours after the start of rewarming (p = 0.02) and 80% compared with 20% at 4 hours (p = 0.01). Complete behavioural recovery was seen in 5/8 of cases (63%) after lamotrigine administration, compared with 1/8 (13%) in the placebo group (p = 0.02). The median behavioural score among the animals that survived for 7 days was higher in the lamotrigine group (8) than in the controls (7) (p = 0.02). Mortality was 2/10 in the L-DF group and 5/10 in the controls, the median behavioural score on day 7 being higher in the L-DF group (8.5 vs. 3.5 p = 0.04). The median of the total histopathological score was 6.5 in the L-DF group and 15.5 in the control group (p = 0.005). In the memantine group 5/10 animals survived seven days, as compared with 9/10 in the placebo group, and the median behavioural score on day 7 was 3.5 compared with 7.5 in the placebo group (p = 0.39). The median of the total histopathological score was 16 in the memantine group and 14 in the placebo group (p = 0.25). In the LD-F + lamotrigine group 7/8 animals survived for seven days, as compared with 4/8 in the lamotrigine only group and 3/8 among the controls. EEG burst recovery 7 hours after the start of rewarming was highest in the LDF + lamotrigine group, the median being 94% (p = 0.024 vs. controls), compared with 81% in the lamotrigine group and 64% in the control group. The median behavioural score on day 7 was 9 in the LD-F + lamotrigine group (p = 0.004 vs. controls), 4 in the lamotrigine group and 0 in the control group, while the median of total histopathological score was 14 (p = 0.046 vs controls), 14.5 (p = 0.062 vs. controls) and 21, respectively. The control group had the highest intracerebral lactate, glutamate and glycerol levels after HCA. In conclusion, the results indicate that the NA+ channel blocker lamotrigine improves the neurological outcome after a prolonged period of HCA but that the NMDA receptor antagonist memantine does not have this property in the present setting. The leukocyte-depleting filter mitigates brain injury after a prolonged period of HCA, and lamotrigine can potentiate this effect

Thymic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

Abstract Objective: MEN1 is associated with an increased risk of developing tumors in different endocrine organs. Neuroendocrine tumors of the thymus (TNETs) are very rare but often have an aggressive nature. We evaluated patients with MEN1 and TNET in three university hospitals in Finland. Design/Methods: We evaluated patient records of 183 MEN1-patients from three university hospitals between the years 1985–2019 with TNETs. Thymus tumor specimens were classified according to the new WHO 2021 classification of TNET. We collected data on treatments and outcomes of these patients. Results: There were six patients (3.3%) with MEN1 and TNET. Five of them had the same common gene mutation occurring in Finland. They originated from common ancestors encompassing two pairs of brothers from sequential generations. The mean age at presentation of TNET was 44.7 ± 11.9 years. TNET was classified as atypical carcinoid (AC) in five out of six patients. One patient had a largely necrotic main tumor with very few mitoses and another nodule with 25 mitoses per 2 mm², qualifying for the 2021 WHO diagnosis of large cell neuroendocrine carcinoma (LCNEC). In our patients, the 5-year survival of the TNET patients was 62.5% and 10-year survival 31.3%. Conclusion: In this study, TNETs were observed in one large MEN1 founder pedigree, where an anticipation-like earlier disease onset was observed in the most recent generation. TNET in MEN1 patients is an aggressive disease. The prognosis can be better by systematic screening. We also show that LCNEC can be associated with TNET in MEN1 patients