Analgesic effectiveness and tolerability of oral oxycodone/naloxone and pregabalin in patients with lung cancer and neuropathic pain. An observational analysis

INTRODUCTION: Cancer-related pain has a severe negative impact on quality of life. Combination analgesic therapy with oxycodone and pregabalin is effective for treating neuropathic cancer pain. We investigated the efficacy and tolerability of a dose-escalation combination therapy with prolonged-release oxycodone/naloxone (OXN-PR) and pregabalin in patients with non-small-cell lung cancer and severe neuropathic pain. METHODS: This was a 4-week, open-label, observational study. Patients were treated with OXN-PR and pregabalin. Average pain intensity ([API] measured on a 0-10 numerical rating scale) and neuropathic pain (Douleur Neuropathique 4) were assessed at study entry and at follow-up visits. The primary endpoint was response to treatment, defined as a reduction of API at T28 ≥30% from baseline. Secondary endpoints included other efficacy measures, as well as patient satisfaction and quality of life (Brief Pain Inventory Short Form), Hospital Anxiety and Depression Scale, and Symptom Distress Scale; bowel function was also assessed. RESULTS: A total of 56 patients were enrolled. API at baseline was 8.0±0.9, and decreased after 4 weeks by 48% (4.2±1.9; P<0.0001 vs baseline); 46 (82.1%) patients responded to treatment. Significant improvements were also reported in number/severity of breakthrough cancer pain episodes (P=0.001), Brief Pain Inventory Short Form (P=0.0002), Symptom Distress Scale (P<0.0001), Hospital Anxiety and Depression Scale depression (P=0.0006) and anxiety (P<0.0001) subscales, and bowel function (P=0.0003). At study end, 37 (66.0%) patients were satisfied/very satisfied with the new analgesic treatment. Combination therapy had a good safety profile. CONCLUSION: OXN-PR and pregabalin were safe and highly effective in a real-world setting of severe neuropathic cancer pain, with a high rate of satisfaction, without interference on bowel function

Business model innovation in SMEs engaging in innovation ecosystems. A decoupling perspective

Digital technologies have been increasingly affecting our day-to-day activities, drastically reshaping markets and society. The diffusion of new digital technologies\u2014such as social media, cloud computing, mobile computing, 3D printing, and big-data analytics \u2013 is posing firms to challenges, creating opportunities to develop radically new business models. However, despite the growing interest towards this issue, the contribute of digitalisation from the perspective of small and medium-sized enterprises (SMEs) is still such an under-investigated topic. SMEs are considered a driving force in most national economies, contributing heavily to employment, innovation and economic growth, but at the same time they often suffer from lack of both financial and human resources. These weaknesses may be compensated by the inflow and outflow of knowledge and capital boosted by technological innovation and participation within innovation ecosystems. The aim of this paper is to understand, through the lens of the institutional theory, how both the relationships established within the ecosystem and the internal organizational capabilities of SMEs impact on business model innovation thanks to the adoption of digital technologies such as Internet of things, big data, and open data. To do so the authors carried out an embedded case study on an Italian Industry 4.0 project which involved several actors (e.g. food SMEs, universities, technology consulting companies, and Piedmont Region). First findings on this ongoing research show that innovation ecosystems could represent a strong driver for developing an innovative business model oriented to value co-creation provided that SMEs already own distinctive dynamic capabilities. Without these capabilities it would be difficult to fully exploit the digital opportunities arising from the relationships among the heterogeneous actors which are part of the project

New antiangiogenics in non-small cell lung cancer treatment: Vargatef™ (BIBF 1120) and beyond

Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named “vascular disrupting agents,” tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances

Heart rate variability analysis during muscle fatigue due to prolonged isometric contraction

Fatigue can be defined as the muscular condition occurring before the inability to perform a task. It can be assessed through the evaluation of the median and mean frequency of the spectrum of the surface electromyography series. Previous studies investigated the relationship between heartbeat dynamics and muscular activity. However, exploitation of such cardiovascular measures to automatically identify muscle fatigue during fatiguing exercises is still missing. To this extent, HRV signals were gathered from 32 subjects during an isometric contraction task, and features defined in the time, frequency and nonlinear domains were investigated. We used surface electromyography to label the occurrence of muscle fatigue. Statistically significant differences were observed by comparing features related to fatigued subjects with the non-fatigued ones. Moreover, a pattern recognition system capable to achieve an average accuracy of 78.24% was implemented. These results confirmed the hypothesis that a relationship between heartbeat dynamics and muscle fatigue might exist

Muscle fatigue assessment through electrodermal activity analysis during isometric contraction

We studied the effects of muscle fatigue on the Autonomic Nervous System (ANS) dynamics. Specifically, we monitored the electrodermal activity (EDA) on 32 healthy subjects performing isometric biceps contraction. As assessed by means of an electromyography (EMG) analysis, 15 subjects showed muscle fatigue and 17 did not. EDA signals were analyzed using the recently proposed cvxEDA model in order to decompose them into their phasic and tonic components and extract effective features to study ANS dynamics. A statistical comparison between the two groups of subjects was performed. Results revealed that relevant phasic EDA features significantly increased in the fatigued group. Moreover, a pattern recognition system was applied to the EDA dataset in order to automatically discriminate between fatigued and non-fatigued subjects. The proposed leave-one-subject-out KNN classifier showed an accuracy of 75.69%. These results suggest the use of EDA as correlate of muscle fatigue, providing integrative information to the standard indices extracted from the EMG signals

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

: Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

sclerostin levels in uremic patients a link between bone and vascular disease

AbstractSclerostin is a marker of low-turnover bone disease in end stage renal disease patients. The aim of this study was to evaluate serum sclerostin in uremic patients, analyzing its behavior during a single hemodialysis session. Twenty-one adult patients on intermittent hemodialysis treatment were enrolled. Acetate Free Bio-filtration (AFB) was the technique employed. Uremic patients were characterized by higher levels of serum sclerostin when compared with values observed in healthy subjects. Sclerostin assessed in pre-dialysis samples was 1.4 ± 1.02 ng/mL, whereas, in post dialysis samples, a reduction of sclerostin values was observed (0.8 ± 0.6 ng/mL; p: 0.008). Sclerostin correlated with parameters of dialysis adequacy, such as creatinine levels and Kt/V values, and it was significantly associated with atherosclerotic disease. Receiver operating characteristics analysis revealed a good diagnostic profile in identifying atherosclerotic disease. Sclerostin, a full dialyzable substance during AFB di..

Comparison between intrasylvian and intracerebral hematoma associated with ruptured middle cerebral artery aneurysms: clinical implications, technical considerations, and outcome evaluation

Background: Subarachnoid hemorrhage (SAH) due to a middle cerebral artery (MCA) aneurysms rupture is often associated with intracerebral (ICH) or intrasylvian hematomas (ISH). Materials and methods: We reviewed 163 patients with ruptured MCA aneurysms associated with pure SAH or SAH+ICH/ISH. Patients were first dichotomized according to the presence of a hematoma (ICH/ISH). Then, we performed a subgroup analysis comparing ICH versus ISH in order to explore their relationship with the most relevant demographic, clinical, and angioarchitectural features. Results: Overall, 85 patients (52%) had a pure SAH, whereas 78 (48%) presented an associated ICH/ISH. No significant differences were observed in demographics and angioarchitectural features between the two groups, but Fisher grading and Hunt-Hess score were higher in patients with hematomas. A good outcome was observed in a higher percentage of patients with pure SAH compared with the others (76% Vs 44%), although mortality rates were comparable. Age, Hunt-Hess and treatment-related complications were the main outcome predictors at multivariate analysis. Patients with ICH appeared clinically worse than those with ISH. We also found that older age, higher Hunt-Hess, larger aneurysms, decompressive craniectomy and treatment-related complications were associated with poor outcome among patients with ISH, but not with ICH, which appeared per se as a more severe clinical condition. Conclusions: Our study confirm that age, Hunt-Hess and treatment-related complications influence the outcome of patients with ruptured MCA aneurysms. However, in the subgroup analysis of patients with SAH associated with ICH or ISH, only the Hunt-Hess at onset appeared as an independent predictor of outcome