The Effects of Tyrosine Kinase Inhibitors (TKIs) in Monotherapy and with Add-on Treatments on Health-related Quality of Life of People with Chronic Myeloid Leukemia: A Systematic Review of Randomized-Controlled Trials.

Background: The era of establishing tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) changed the outcome and the course of this life-threatening malignancy. People suffering from CML have now a better prognosis and a longer life expectancy due to the development of TKIs, even if it requires long-term, often lifelong, treatments that are nonetheless associated with improved Health-related Quality of life (HRQoL). However, data on the effects of TKIs on HRQoL are not always systematic; sometimes the data have been obtained by studies different from RCTs, or without a clear definition of what HRQoL is. The main purpose of this systematic review is to summarize all randomized-controlled trials (RCTs) including HRQoL as main or secondary outcome in patients with CML treated with TKIs or with TKIs plus an add-on treatment. Methods: A systematic review has been conducted by searching the relevant papers in PubMed/Medline and Web of Science with the following keywords: "quality of life" OR "health-related quality of life" OR "QoL" OR "HRQoL" OR "H-QoL" AND "chronic myeloid leukemia". Interval was set from January 2000 to December 2020. Results: 40 papers were identified through the search. Out of them, 7 RCTs were included. All the studies used standardized measures to assess HRQoL, even not always specific for CML. 5 RCTs randomized subjects to 2 or 3 arms to evaluate the effects of TKIs of the first, second and third generation in monotherapy. 2 RCTs randomized subjects to TKI therapy plus an add-on treatment versus TKI therapy as usual. The results of all these trials were examined and discussed. Conclusion: All the included RCTs pointed out significant findings regarding the positive effects of TKIs on HRQoL of people with CML, both when they were used in monotherapy or, notably, with an add-on treatment to enhance TKIs effects.

Incidence and spatial distribution of adult-onset primary malignant and other central nervous system tumors in Southern Sardinia, Italy.

PURPOSE: To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. METHODS: Clinical records of patients > 18 years old who were diagnosed with primary CNS tumors during 2016-2019 in the study area were reviewed. Meningiomas, cranial/paraspinal nerve tumors, lymphomas, and pituitary tumors were excluded. Cases were classified according to the 2016 WHO classification of CNS tumors and to the morphology codes from the International Classification of Diseases-Oncology, third edition. Age-adjusted incidence rates were calculated by the direct method to the 2011-2020 European standard population. Kulldorff's spatial scan statistic was used to identify geographic clusters of patients who shared increased/decreased tendency to develop CNS tumors. RESULTS: CNS tumors were diagnosed in 234 incident patients, but histological diagnosis was available in 222/234 patients (95%) aged 64.3 ± 13.5 years at diagnosis. Crude incidence rate was 7.1 per 100,000 persons-year (95% CI, 6.2-8.1), 6.2 per 100,000 persons-year (95% CI, 5.4-7.0) when age-adjusted. CNS tumors were more frequent in men and after age 40. Glioblastoma accounted for 76% of the total (adjusted rate, 4.7 per 100,000 persons-year; 95% CI, 4.0-5.4). Spatial analysis revealed geographic variations of glioblastoma incidence within the study area. CONCLUSION: Although the distribution of tumor diagnoses in Sardinia reflects expected age and gender-related patterns in western populations, our findings would indicate a slightly higher incidence of glial tumors, glioblastoma in particular, in Sardinia than in other European countries. The identification of spatial clusters of high/low risk will serve as a resource for etiological research.

Principal Component Analysis of the Well-Being at Work and Respect for Human Rights Questionnaire (WWRRR) in the Mediterranean Region.

BACKGROUND: The Well-Being at Work and Respect for human Rights Questionnaire (WWRR) was conceived based on the hypothesis that the perception of respect for users' rights is an essential element of well-being in the workplace in healthcare. The objective of the study is to examine the principal components of the WWRR. METHODS: A random sample representative of a set of professionals working in three different healthcare networks in Tunisia, North-Macedonia, and Italy was enrolled (n=426). Each professional completed a questionnaire on sociodemographic data and the WWRR. The WWRR consists of six items on beliefs about: satisfaction at work, users' satisfaction, organization at work, respect of users' and staff human rights, adequacy of resources. A seventh item assesses the perceived needs of personnel. Correlation between the items was evaluated by analysing the principal components with Varimax rotation and Kaiser normalization (which included all components with an Eigen value> 1). RESULTS: A single factor covered over 50% of the variance, all the items of the questionnaire were closely related and compose a single factor. Tunisia presented some differences regarding the item about the human rights of staff. CONCLUSION: Satisfaction with the respect for the rights of users is strongly correlated with the other factors that are part of the concept of the organizational well-being of health care providers. The WWRR provides a means of measuring this important and often neglected dimension.

The re-organization of functional brain networks in pharmaco-resistant epileptic patients who respond to VNS.

Vagal nerve stimulation (VNS) is a therapeutic add-on treatment for patients with pharmaco-resistant epilepsy. The mechanism of action is still largely unknown. Previous studies have shown that brain network topology during the inter-ictal period in epileptic patients deviates from normal configuration. In the present paper, we investigate the relationship between clinical improvement induced by VNS and alterations in brain network topology. We hypothesize that, as a consequence of the VNS add-on treatment, functional brain network architecture shifts back toward a more efficient configuration in patients responding to VNS. Electroencephalographic (EEG) recordings from ten patients affected by pharmaco-resistant epilepsy were analyzed in the classical EEG frequency bands. The phase lag index (PLI) was used to estimate functional connectivity between EEG channels and the minimum spanning tree (MST) was computed in order to characterize VNS-induced alterations in network topology in a bias-free way. Our results revealed a clear network re-organization, in terms of MST modification, toward a more integrated architecture in patients responding to the VNS. In particular, the results show a significant interaction effect between benefit from VNS (responders/non-responders) and condition (pre/post VNS implantation) in the theta band. This finding suggests that the positive effect induced by VNS add-on treatment in epileptic patients is related to a clear network re-organization and that this network modification can reveal the long debated mechanism of action of VNS. Therefore, MST analysis could be useful in evaluating and monitoring the efficacy of VNS add-on treatment potentially in both epilepsy and psychiatric diseases.

Synovial cysts of the lumbar spine--pathological considerations and surgical strategy.

Symptomatic lumbar synovial cysts (LSCs) are a rare cause of degenerative narrowing of the spinal canal, with thecal sac or nerve root compression. True synovial cysts have a thick wall lined by synovial cells, containing granulation tissue, numerous histiocytes, and giant cells. In contrast, pseudo-cysts lack specialized epithelium, have a collagenous capsule filled with myxoid material, and may be classified into ganglion cysts, originating from periarticular fibrous tissues, and ligamentous cysts, arising from the ligamentum flavum or even from the posterior longitudinal ligament. Here we present the surgical series of the Chair of Neurosurgery at the University of Cagliari (Italy) including a total of 17 LSCs. Surgical technique consisted of facet sparing excision of LSC, achieved by simple hemilaminectomy/laminectomy, and diagnosis was always confirmed by histological specimen examination, which detected the typical synovial epithelium, the intracystic presence of hemosiderin, histiocytes, and calcifications. Further immunohistochemical investigation revealed positive staining for cytokeratin: CK5, CK6, and AE1/AE3. Clinically, our cohort experienced rapid and complete resolution of symptoms, without perioperative complications, or recurrence of cysts or vertebral instability at a median follow up of 28 months, when the MacNab score was generally excellent. A review of the literature, retrieving articles published from 1973, collected a total of 101 articles concerning all the cases of LSC scientifically described to date. Both clinical and histological findings described in our study support the theory of degenerative microtraumatic pathogenesis of synovial cysts.

VNS induced desynchronization in gamma bands correlates with positive clinical outcome in temporal lobe pharmacoresistant epilepsy.

The vagus nerve stimulation (VNS) represents a diffuse non-pharmacological low-risk surgical option for epilepsy treatment. The aim of this study is to investigate the correlation between variations of global EEG synchronization and the clinical outcome in pharmacoresistant epileptic subjects implanted with VNS. Ten subjects affected by pharmacoresistant epilepsy were recruited on the basis of a clear-cut successful or unsuccessful outcome of the VNS add-on treatment. After five years from VNS surgery we examined the EEG in five subjects in each group. The investigation was led with the method of the phase lag index (PLI), which allows for the study of the global rate of synchronicity among the EEG signals before and after VNS implantation. The results of this study show that after five years from VNS surgery, in subjects whose seizures show a significant reduction, the desynchronization in the gamma frequency band is statistically decreased in comparison with patients who failed to show variations in the frequency and characteristics of their seizures. The other frequency bands are unaffected. This finding suggests that long lasting variations in gamma band desynchronization can be a new tool in assessing the efficacy of VNS. The possibility that GABA-mediated VNS-induced effects can also play a role in this result is discussed.

Nonfusion stabilization of the degenerative lumbar spine.

OBJECT: The goal of this study was to assess whether a stable but nonrigid nonfusion implant can stabilize the spine in degenerative diseases and also prevent instability following decompression. Instrumented spondylodesis is a recognized surgical treatment in degenerative disease of the lumbar spine. However, pain can develop at the bone graft donor site and the operative trauma can be very stressful in elderly patients, and it is suspected that there may be increased degenerative changes in the adjacent segments. In 2002, a nonrigid but rotationally stable pedicle screw and rod system was introduced, which could be used without additional fusion (referred to hereafter as the Cosmic system). METHODS: A total of 139 patients with degenerative disease of the lumbar spine underwent spinal stabilization with the Cosmic system without additional spondylodesis. Seventy patients had an additional decompression. The minimum follow-up was 2 years. The perioperative course, the clinical results, and the erect anteroposterior and lateral radiographs were recorded and compared with the preoperative data. The data were obtained from 6 different spine centers in Europe and documented on an Internet platform. RESULTS: The Oswestry Disability Index score improved from 48.9% to 22.5%, and the visual analog scale score decreased from 7.3 to 2.5. Lumbar lordosis did not change, nor did the adjacent disc height. Eleven patients underwent revision, 4 of them for implant failure. Of the 139 patients, 110 assessed the result as excellent, very good, or good; 24 as fair; and 5 as poor. A total of 122 patients would undergo surgery again. There were no significant differences between patients with or without an additional decompression. CONCLUSIONS: The Cosmic system is a stable but nonrigid posterior nonfusion system. Implant complications are low and the clinical outcome is good. Longer follow-up is necessary to confirm the 2-year results.

Cardiovascular modulation during vagus nerve stimulation therapy in patients with refractory epilepsy.

To evaluate the effects of permanent vagal stimulation on cardiovascular system, 10 patients, affected by drug-resistant epilepsy with no primitive cardiovascular pathologies, were assessed prior to VNS surgery. A complete echocardiographic study [conventional and tissue Doppler imaging (TDI)], 24-h blood pressure (BP) monitoring and HRV evaluation were performed. The above mentioned parameters were investigated without any substantial changes to drug treatment during a check-up subsequent to VNS activation [mean: 7.7 months]. The results obtained show that while the anthropometrical data and both conventional and TDI echocardiography were unvaried compared to baseline, BP showed a significant increase of both systodiastolic values. Moreover, a close scrutiny of the most affected period of the BP increase (zenith between 16:31 and 17:30 pm) (systolic BP 114.7 mmHg vs 95.3 mmHg, P < 0.0001; diastolic BP 70.9 mmHg vs 56.9 mmHg, P < 0.001) showed a significant increase of the high frequencies components (HF) (28.4 ± 2.7 vs 36 ± 5.3, P < 0.05) and a significant reduction in low frequency/HF ratio (2.3 ± 0.3 vs 1.7 ± 0.3, P < 0.0001). The present study confirms the intrinsic cardiovascular safety and reliability of VNS procedures on both BP and HF and LF profiles and suggests that a primitive VNS-mediated central impingement on vagal efferents, independently by the antiepileptic mechanism, correlated to an moderate increase of parasympathetic activity, which in turn might play a protective role in seizure-triggered alterations of cardiovascular dynamic.

Involvement of GABA in mirror focus: a case report.

Mirror focus (MF) is a cortical epileptogenic lesion that is posited to develop in the contralateral site to a cortical primary focus (PF) by secondary epileptogenic mechanisms. Previous animal evidence supports the implication of gamma-aminobutyric acid (GABA) in this phenomenon, but this contention has not yet been substantiated by clinical findings. Here we report for the first time clinical evidence suggesting the involvement of GABAergic cortical transmission in MF pathogenesis, in a 37-year-old man affected by a lesional PF in the right frontal lobe and a homotopic MF in the contralateral hemisphere, triggered by hyperventilation. One year after surgical excision of the PF, the electric activity of the MF remained unchanged, but was accompanied by a significant increase in the density of GABA(A)/benzodiazepine receptor binding in the left frontal lobe, as measured by (123)I-Iomazenil SPECT. These results extend previous evidence on the involvement of GABAergic signaling in MF pathophysiology.

Correlation between GABA(A) receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy.

Vagus nerve stimulation (VNS) is an important option for the treatment of drug-resistant epilepsy. Through delivery of a battery-supplied intermittent current, VNS protects against seizure development in a manner that correlates experimentally with electrophysiological modifications. However, the mechanism by which VNS inhibits seizures in humans remains unclear. The impairment of gamma-aminobutyric acid (GABA)-mediated neuronal inhibition associated with epilepsy has suggested that GABA(A) receptors might contribute to the therapeutic efficacy of VNS. We have now applied single photon emission computed tomography (SPECT) with the benzodiazepine receptor inverse agonist [123I]iomazenil to examine cortical GABA(A) receptor density (GRD) before and 1 year after implantation of a VNS device in 10 subjects with drug-resistant partial epilepsy. VNS therapeutic responses resulted significantly correlated with the normalization of GRD. Moreover, a comparable control group, scheduled for a possible VNS implant, failed to show significant GRD variations after 1 year of a stable anti-epileptic treatment. These results suggest that VNS may modulate the cortical excitability of brain areas associated with epileptogenesis and that GABA(A) receptor plasticity contributes to this effect.