Pituitary surgery during Covid-19: a first hand experience and evaluation.

PURPOSE: During the Covid-19 pandemic every hospital has had to change its internal organization. Different institutions have highlighted the risks connected with endoscopic endonasal surgery. The goal of this paper is to illustrate the feasibility of pituitary region surgery during the SARS-CoV-2 pandemic. METHODS: After two negative Covid tests were obtained, three patients with macro GH-secreting tumors, and two patients with micro ACTH-secreting tumors resistant to medical treatment underwent surgery during the pandemic. During the surgery, every patient was treated as if they were positive. RESULTS: Neither operator, nor patient have developed Covid symptoms. The two neurosurgeons performing the operations underwent two Covid swab, which resulted negative. CONCLUSIONS: Pituitary surgery is a high risk non-urgent surgery. However, the method described has so far been effective and is safe for both patients and healthcare providers.

Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?

Glioblastoma Multiforme, the most common and aggressive primary brain tumor, remains incurable despite of the advent of modern surgical and medical treatments. This poor prognosis depends by the recurrence after surgery and intrinsic or acquired resistance to chemotherapy and radiotherapy. Nitric oxide is a small molecule that plays a key roles in glioma pathophysiology. Many researches showing that NO is involved in induction of apoptosis, radiosensitization and chemosensitization. Therefore, NO role, if clarified, may improve the knowledge about this unsolved puzzle called GBM.

Characterization of crumb rubber from end-of-life tyres for paving applications.

Crumb rubber (CR) derived from grinding of end-of-life tyres (ELTs) may be successfully used as a bitumen modifier or as a supplementary component in the production of bituminous mixtures employed for the construction and maintenance of road pavements. However, CRs deriving from different sources and production processes yield effects on performance of corresponding paving mixtures under traffic loading and on gaseous emissions produced during laying on site which may change considerably depending upon their physical and chemical properties. In order to quantitatively assess the possible variability of CR characteristics, 16 samples were taken from 9 Italian and 2 foreign ELT processing plants. Investigation activities included field surveys, during which plants were examined in detail, and laboratory tests, which focused on physical and chemical characterization of CR. Based on the analysis of available technical information and experimental data, it was possible to find relationships between the peculiar characteristics of treatment cycles and corresponding CR properties.

Molecular biology of gliomas: present and future challenges.

Malignant brain tumours are one of the most relevant causes of morbidity and mortality across a wide range of individuals. Malignant glioma is the most common intra axial tumor in the adult. Many researches on this theme brought advances in the knowledge of gliomas biology and pathogenesis and to the development of new agents for targeted molecular therapy. Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors. This Review summarizes these developments analyzing molecular pathology and possible further developments for targeted therapies.

Are acute subdural hematomas possible without head trauma?

Acute subdural hematomas (ASDHs) are rarely reported in the literature. In general, it is due to head trauma, but if the traumatic event is very mild, it is inadequate to explain the ASDH occurrence. Risk factors for the development of spontaneous ASDH include hypertension, vascular abnormalities and deficit of coagulation. We present two cases of ASDH in patients with the coagulation deficit and review of the literature to understand the coagulation factors role and platelet role in the management of ASDHs.

Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.

We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.

Stem cells based therapy in high grade glioma: why the intraventricular route should be preferred?

AIM: Mesenchymal stem cells (MSCs) migrate in response to chemokines and possess extensive tropism for experimental glioma. Antitumor effects have been reported following intracranial and intravenous administration of gene-modified MSCs. Among the different routes for cell transplant, the intraventricular (IV) approach found very little employment in comparison with intraparenchymal, intratumoral and intravenous administration protocols. Nevertheless, IV transplantation offers advantages in terms of cells viability and distribution toward target sites, opening interesting opportunities for its clinical application. METHODS: Using a rat glioma model, we investigated migratory capacity, tumor tropism, distribution and differentiation of MSCs following IV administration. RESULTS: Transplanted MSCs create niches of viable cells in the subventricular zone and can be stimulated to migrate to sites of tumor infiltration. MSCs seemed not to be involved in tumor growth and angiogenesis. CONCLUSION: We speculate that the IV route can be used to achieve a kind of reservoir of self-renewal cells, potentially active against the spread of cancer cells. Further studies are needed to shed light on MSCs distribution close to the ventricular wall, in order to define their lifespan and their capacity to migrate towards new-enhancing foci time after implantation.

Probable REM sleep behaviour disorder and STN-DBS outcome in Parkinson's Disease.

OBJECTIVE: To assess whether the presence of probable REM sleep behaviour disorder (pRBD) influences the long-term outcome of Parkinson's Disease (PD) patients undergoing Subthalamic Nucleus Deep Brain Stimulation (STN-DBS). BACKGROUND: RBD is a parasomnia characterized by loss of muscular atonia and complex motor behaviours during REM sleep, frequently reported in PD patients. Recent evidence suggests that RBD is associated with akinetic rigid disease type and increased frequency of falls. We wondered whether the presence of RBD would also influence the long-term outcome of STN-DBS. METHODS: Forty-one consecutive PD patients treated with bilateral STN-DBS were assessed. The diagnosis of pRBD was based on a clinical interview investigating the occurrence of diagnostic criteria for RBD. The Unified Parkinson's Disease Rating Scale was used to compare the on- and off-medication conditions preoperatively and the on-stimulation/on- and off-medication conditions 1 and 3 years postoperatively. The general linear model for multivariate measures was used to analyse the interaction of pRBD with STN-DBS outcome measures. RESULTS: pRBD was present in 12 out of 41 patients (29%) undergoing STN-DBS. Patients with pRBD had a significantly poorer outcome three years after STN-DBS compared to patients without pRBD, in particular for axial symptoms. CONCLUSIONS: Our findings suggest that the presence of pRBD in PD patients undergoing STN-DBS may be associated with a less favourable outcome and a more prominent development of axial symptoms over time.

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells.

The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1(SFD)), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1(SFD) cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1(SFD) cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation.

A computational model to compare different investment scenarios for mini-stereotactic frame approach to deep brain stimulation surgery.

UNLABELLED: Deep brain stimulation (DBS) alleviates symptoms of many neurological disorders by applying electrical impulses to the brain by means of implanted electrodes, generally put in place using a conventional stereotactic frame. A new image guided disposable mini-stereotactic system has been designed to help shorten and simplify DBS procedures when compared to standard stereotaxy. A small number of studies have been conducted which demonstrate localization accuracies of the system similar to those achievable by the conventional frame. However no data are available to date on the economic impact of this new frame. AIM: The aim of this paper was to develop a computational model to evaluate the investment required to introduce the image guided mini-stereotactic technology for stereotactic DBS neurosurgery. METHODS: A standard DBS patient care pathway was developed and related costs were analyzed. A differential analysis was conducted to capture the impact of introducing the image guided system on the procedure workflow. The analysis was carried out in five Italian neurosurgical centers. RESULTS: A computational model was developed to estimate upfront investments and surgery costs leading to a definition of the best financial option to introduce the new frame. Investments may vary from Euro 1.900 (purchasing of Image Guided [IG] mini-stereotactic frame only) to Euro 158.000.000. Moreover the model demonstrates how the introduction of the IG mini-stereotactic frame doesn't substantially affect the DBS procedure costs.

Management of antiparkinsonian therapy during chronic subthalamic stimulation in Parkinson's disease.

OBJECTIVE: This article reports the detailed analysis of antiparkinsonian drug therapy in 78 consecutive Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: The amount and type of antiparkinsonian drugs--including L-dopa, dopamine receptor agonists, associated drugs such as catechol-O-methyl transferase and monoamine oxidase inhibitors, amantadine and anticholinergics--were quantified before surgery and at two control visits 1 and 3 years following chronic STN stimulation. RESULTS: The L-dopa mean daily dose was reduced by approximately 60% after 1 year and remained stable after 3 years. Apomorphine, bromocriptine, tolcapone and selegiline were withdrawn after STN-DBS. Three years postoperatively, 9 patients (11.5%) no longer required L-dopa and 6 patients (7.7%) completely stopped all dopaminergic medications. More patients were on monotherapy with either L-dopa or dopamine receptor agonist, and fewer patients required combined treatment of dopamine receptor agonist and L-dopa compared with the pre-surgical condition. CONCLUSIONS: Dopaminergic drug treatment is persistently reduced and simplified following chronic STN-DBS for up to 3 years.

Neuro-psychiatric therapy during chronic subthalamic stimulation in Parkinson's disease.

BACKGROUND: Neuro-psychiatric (NP) disturbances are highly prevalent in patients with Parkinson's disease (PD) and contribute to worsen quality of life. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is commonly utilized as surgical treatment for advanced PD with motor complications. The effectiveness of the procedure on motor symptoms is well established whereas the effects of STN-DBS on NP symptoms are less clear. The aim of our study was to analyze the postoperative pharmacological therapy for NP symptoms in a group of STN-DBS treated PD patients. Such therapy provides indirect information about the evolution of underlying NP disturbances during the follow-up in this group of PD patients. METHODS: NP therapy (benzodiazepines, antidepressants, antipsychotics) was assessed in 48 consecutive PD patients treated by STN-DBS, preoperatively and postoperatively after 4 months, 1 year and 3 years. Motor symptoms were evaluated by the Unified PD Rating Scale (UPDRS) and levodopa equivalence daily dose (LEDD) was calculated. Cognitive, mood and anxiety assessments were performed with appropriate rating scales. RESULTS: The number of patients treated with antidepressant drugs gradually increased during the follow-up. The use of antipsychotic drugs was stable until 1 year, with a subsequent increase at 3 years. Benzodiazepines were given to fewer patients immediately after surgery. CONCLUSIONS: Pharmacological treatment supplies further information about NP symptoms in the follow-up of PD patients undergoing STN stimulation.

Influence of basal ganglia on upper limb locomotor synergies. Evidence from deep brain stimulation and L-DOPA treatment in Parkinson's disease.

Clinical evidence of impaired arm swing while walking in patients with Parkinson's disease suggests that basal ganglia and related systems play an important part in the control of upper limb locomotor automatism. To gain more information on this supraspinal influence, we measured arm and thigh kinematics during walking in 10 Parkinson's disease patients, under four conditions: (i) baseline (no treatment), (ii) therapeutic stimulation of the subthalamic nucleus (STN), (iii)L-DOPA medication and (iv) combined STN stimulation and L-DOPA. Ten age-matched controls provided reference data. Under baseline conditions the range of patients' arm motion was severely restricted, with no correlation with the excursion of the thigh. In addition, the arm swing was abnormally coupled in time with oscillation of the ipsilateral thigh. STN stimulation significantly increased the gait speed and improved the spatio-temporal parameters of arm and thigh motion. The kinematic changes as a function of gait speed changes, however, were significantly smaller for the upper than the lower limb, in contrast to healthy controls. Arm motion was also less responsive after L-DOPA. Simultaneous deep brain stimulation and L-DOPA had additive effects on thigh motion, but not on arm motion and arm-thigh coupling. The evidence that locomotor automatisms of the upper and lower limbs display uncorrelated impairment upon dysfunction of the basal ganglia, as well as different susceptibility to electrophysiological and pharmacological interventions, points to the presence of heterogeneously distributed, possibly partially independent, supraspinal control channels, whereby STN and dopaminergic systems have relatively weaker influence on the executive structures involved in the arm swing and preferential action on those for lower limb movements. These findings might be considered in the light of phylogenetic changes in supraspinal control of limb motion related to primate bipedalism.

Antiparkinsonian therapy modifications in PD patients after STN DBS: a retrospective observational analysis.

OBJECTIVE: This study reports a retrospective analysis of 67 consecutive parkinsonian patients to assess changes in antiparkinsonian medications after Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN). METHODS: All antiparkinsonian drugs, including levodopa, dopamine agonists, associated drugs such as COMT and MAO inhibitors, amantadine and anticholinergics, were evaluated pre- and post-operatively at 1 and 3 years follow-up. RESULTS: The levodopa mean daily dose was reduced approximately 60% after 1 year and remained stable after 3 years. Apomorphine, bromocriptine, tolcapone, entacapone and selegiline were withdrawn after STN DBS. Three years post-operatively, 9 patients (13.4%) no longer required levodopa and 6 patients (8.9%) completely stopped all dopaminergic medications. More patients were on monotherapy of either levodopa or dopamine agonist and fewer patients required a combined treatment of dopamine agonist and levodopa, compared to the pre-surgical condition. CONCLUSIONS: STN DBS treated PD patients experience a significant long-term reduction and simplification of the pharmacological treatment.

Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP.

In the acute promyelocytic leukemia cell line, NB4, activation of the CD44 receptor triggers apoptosis. This pathway does not operate in the retinoid-maturation-resistant NB4-LR1 subclone. In this work, we show that the CD44 gene is silenced in these cells. The molecular defect involves DNA methylation of cytosine phosphate guanine (CpG) island and underacetylation of histone H3 at CD44 promoter. The methylating inhibitor 5-aza-CdR and cyclic AMP (cAMP) reverse the CD44 gene silencing. Contrary to 5-aza-CdR, cAMP does not induce DNA demethylation or histone modification at the CD44 promoter, whereas an H3pS10/AcK14 dual modification is observed on a global level. cAMP also induces the expression of c-Jun transcription factor and its recruitment at the CD44 promoter. Chromatin immunoprecipitation assays further show the association of brahma (Brm), a subunit of SWI/SNF chromatin-remodelling complex involved in the crosstalk between transcription and RNA polymerase II (RNA Pol II) processing, as well as the binding of phosphorylated RNA Pol II to the proximal promoter region of CD44. Finally, our study reveals that cAMP re-establishes the CD44-mediated cell death signalling. We propose that one of the actions of cAMP in restoring normal cell phenotype of leukaemia cells may consist in a broad trans-reactivation of silenced genes, despite marked hypermethylation of their promoters, as illustrated here with CD44 re-expression.

A PARP-1/JNK1 cascade participates in the synergistic apoptotic effect of TNFalpha and all-trans retinoic acid in APL cells.

When administrated by isolated limb perfusion, tumor necrosis factor alpha (TNFalpha) is an efficient antitumor agent that improves drug penetration and destroys angiogenic vessels. Moreover, the pronounced potentiation of TNFalpha-induced apoptosis by NF-kappaB inhibitors suggest that these compounds could enhance TNFalpha antitumor efficacy through direct induction of tumor cell apoptosis. Therefore, attempts at amplifying signaling pathways that mediate TNFalpha antitumor effects could help to design combination therapies improving its efficiency. We report that nanomolar concentrations of all-trans retinoic acid (ATRA) amplify TNFalpha-induced apoptosis in APL cells expressing a specific repressor of NF-kappaB activation. This effect is abolished by the pan-caspase inhibitor, Z-VAD-fmk and by caspase-8 and -9 inhibitors. Cell death is accompanied by a drop of mitochondrial potential and by poly (ADP-ribose) polymerase (PARP) activation. Using specific PARP-1 inhibitors and siRNAs, we show that PARP-1 is essential for the synergistic apoptotic effect and c-Jun N-terminal kinase 1 (JNK1) activation triggered by the ATRA/TNFalpha combination. JNK1 siRNAs reduce ATRA/TNFalpha-induced apoptosis, mitochondrial release of cytochrome c and caspase-9 activation. Altogether, these results identify a novel mechanism of PARP-1-induced apoptosis, in which JNK1 provides a link between PARP-1 activation and mitochondrial pathway of caspase-9 activation. This study also suggests that inclusion of nanomolar doses of ATRA could be clinically beneficial in amplifying TNFalpha-induced antitumor signals.

Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus.

OBJECTIVE: To evaluate motor and nonmotor symptoms in patients with Parkinson's disease undergoing bilateral deep brain stimulation of the subthalamic nucleus (STN DBS). METHODS: Thirty-six consecutive patients receiving bilateral STN stimulation implants were evaluated preoperatively as well as 12 and 24 months after surgery. Motor symptoms were assessed through the Unified Parkinson's Disease Rating Scale (UPDRS). Data concerning nonmotor symptoms were collected from items of the UPDRS and 2 additional questions from clinical charts regarding constipation and urological dysfunction. RESULTS: STN DBS was effective in controlling motor symptoms; concerning nonmotor symptoms, sleep quality and constipation improved after surgery as compared to baseline. Salivation, swallowing and sensory complaints were ameliorated to a comparable degree by the medication on state, whether preoperatively or postoperatively. With a lower dose of dopaminergic medication, however, the medication on state appeared to be a much larger percentage of the day postoperatively. No significant variations were detected in intellectual impairment, depression, thought disorders, motivation, falling unrelated to freezing, nausea, orthostatic hypotension and urological dysfunction. CONCLUSIONS: STN DBS effectively controls motor symptoms, while nonmotor features of advanced Parkinson's disease patients are mostly unchanged after surgery, even though some specific aspects, notably sleep complaints and constipation, are ameliorated.

Apathy and verbal fluency in STN-stimulated PD patients. An observational follow-up study.

OBJECTIVE: To evaluate apathy and its relation to verbal fluency tasks in a consecutive series of 19 patients with Parkinson's disease (PD) submitted to deep brain stimulation of the subthalamic nucleus (DBS of STN). METHODS: 19 consecutive PD patients submitted to bilateral DBS of STN were studied for apathy pre-operatively and 17 months after surgery. The PD patients underwent a battery of cognitive tests assessing reasoning, memory and frontal executive functions, including phonemic and categorial fluency tasks. The Beck Depression Inventory (BDI) was used for depression. Apathy was assessed by means of the Apathy Scale (AS). In order to quantify changes among individual patients, the clinical criterion of more or less than 1 SD (standard z-score) was used to register a patient as improved or worsened, respectively. RESULTS: After surgery, apathy scores did not change and mood improved (p < 0.02), while a significant worsening was found in the phonemic fluency (p < 0.001). The percentage of patients with an apathy score above the recommended cut-off value (14) was 42% both before and after DBS of STN. Individual outcomes on the apathy scale (1 SD criterion) evidenced that 53% of the patients remained stable, 16% improved, while 31% worsened. This last percentage reduced to 21% (4/19) when considering only the PD patients with an apathy score > or =14 after surgery. No significant correlation was found between the apathy scores variation and any of the neurological variables considered, and, in particular, no correlation was found between apathy and verbal fluency. CONCLUSIONS: The results of the present study suggest that DBS of STN does not necessarily induce apathy even if individual patients show a moderate post-operative worsening of apathetic symptoms.