New drugs and therapeutic strategies in pharmacoresistant epilepsy

Epilepsy is a brain disorder characterized by an enduring predisposition to generate recurrent epileptic seizures and by the neurobiologic, cognitive, psychological and social consequences of this condition. Current antiepileptic drugs provide symptomatic relief from seizures, have multiple adverse effects, and fail to control seizures in up to 30% of people. This represents a major unmet clinical need. New anti-seizure treatments for epilepsy are unlikely to bridge this treatment gap. In order to develop such drugs, there is the need to understand the pathological processes occurring in the brain of people exposed to epileptogenic injuries, or with an established diagnosis of epilepsy. In this PhD thesis, I pointed my attention on the role of neuroinflammation in the mechanisms of epileptogenesis. Specific inflammatory molecules and pathways have been shown to significantly contribute to the mechanisms of seizure generation and progression in different experimental models. In particular, I have contributed to demonstrate for the first time that targeting oxidative stress with clinically tested drugs, for a limited time window post-injury, significantly delayed the onset of epilepsy, blocked disease progression and drastically reduced spontaneous seizures and long-term pathological consequences (cell loss, cognitive deficit). This intervention may be considered for patients exposed to potential epileptogenic insults as status epilepticus. Drug-induced reduction of oxidative stress prevented disulfide HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Moreover, my research work provided evidence supporting that monoacylglycerol lipase (MAGL) is a new potential target for drug development in epilepsy, in particular for the treatment of drug-refractory status epilepticus (SE). Inhibition of MAGL by a new potent and selective irreversible inhibitor (CPD-4645) protects mice against refractory SE and its therapeutic effects are potentiated by the ketogenic diet. In conclusion, all these experimental data contribute to better clarify the complex mechanisms underlying the pathophysiology of epilepsy, in order to identify new potential therapeutic targets. However, the major challenge will be represented by the translation of these experimental results into clinically effective human therapies

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders

Laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up

The treatment of ureteral strictures represents a challenge due to the variability of aetiology, site and extension of the stricture; it ranges from an end-to-end anastomosis or reimplantation into the bladder with a Boari flap or Psoas Hitch. Traditionally, these procedures have been done using an open access, but minimally invasive approaches have gained acceptance. The aim of this study is to evaluate the safety and feasibility and perioperative results of minimally invasive surgery for the treatment of ureteral stenosis with a long-term follow-up. Data of 62 laparoscopic (n\uc2 =\uc2 36) and robotic (n\uc2 =\uc2 26) treatments for ureteral stenosis in 9 Italian centers were reviewed. Patients were followed according to the referring center\ue2\u80\u99s protocol. Laparoscopic and robotic approaches were compared. All the procedures were completed successfully without open conversion. Average estimated blood loss in the two groups was 91.2\uc2 \uc2\ub1\uc2 71.9\uc2 cc for the laparoscopic and 47.2\uc2 \uc2\ub1\uc2 32.3\uc2 cc for the robotic, respectively (p\uc2 =\uc2 0.004). Mean days of hospitalization were 5.9\uc2 \uc2\ub1\uc2 2.4 for the laparoscopic group and 7.6\uc2 \uc2\ub1\uc2 3.4 for the robotic group (p\uc2 =\uc2 0.006). No differences were found in terms of operative time and post-operative complications. After a median follow-up of 27\uc2 months, the robotic group yielded 2 stenosis recurrence, instead the laparoscopic group shows no cases of recurrence (p\uc2 =\uc2 0.091). Minimally invasive approach for ureteral stenosis is safe and feasible. Both robotic and pure laparoscopic approaches may offer good results in terms of perioperative outcomes, low incidence of complications and recurrence

Renal cell carcinoma with inferior vena cava involvement: Prognostic effect of tumor thrombus consistency on cancer specific survival: Tumor Thrombus Consistency and Survival

Renal cell carcinoma forming a venous tumor thrombus (VTT) in the inferior vena cava (IVC) has a poor prognosis. Recent investigations have been focused on prognostic markers of survival. Thrombus consistency (TC) has been proposed to be of significant value but yet there are conflicting data. The aim of this study is to test the effect of IVC VTT consistency on cancer specific survival (CSS) in a multi-institutional cohort