Reinforcement learning optimisation for graded metamaterial design using a physical-based constraint on the state representation and action space.

The energy harvesting capability of a graded metamaterial is maximised via reinforcement learning (RL) under realistic excitations at the microscale. The metamaterial consists of a waveguide with a set of beam-like resonators of variable length, with piezoelectric patches, attached to it. The piezo-mechanical system is modelled through equivalent lumped parameters determined via a general impedance analysis. Realistic conditions are mimicked by considering either magnetic loading or random excitations, the latter scenario requiring the enhancement of the harvesting capability for a class of forcing terms with similar but different frequency content. The RL-based optimisation is empowered by using the physical understanding of wave propagation in a such local resonance system to constrain the state representation and the action space. The procedure outcomes are compared against grading rules optimised through genetic algorithms. While genetic algorithms are more effective in the deterministic setting featuring the application of magnetic loading, the proposed RL-based proves superior in the inherently stochastic setting of the random excitation scenario.

Comparison of different second line treatments for metastatic pancreatic cancer: a systematic review and network meta-analysis.

BACKGROUND: In metastatic pancreatic ductal adenocarcinoma (mPDAC), first line treatment options usually include combination regimens of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX or mFOLFIRINOX) or gemcitabine based regimens such as in combination with albumin-bound paclitaxel (GEM + nab-PTX). After progression, multiple regimens including NALIRI + 5-FU and folinic acid, FOLFIRINOX, 5-FU-based oxaliplatin doublets (OFF, FOLFOX, or XELOX), or 5-FU-based monotherapy (FL, capecitabine, or S-1) are considered appropriate by major guidelines. This network meta-analysis (NMA) aimed to compare the efficacy of different treatment strategies tested as second-line regimens for patients with mPDAC after first-line gemcitabine-based systemic treatment. METHODS: Randomized phase II and III clinical trials (RCTs) were included if they were published or presented in English. Trials of interest compared two active systemic treatments as second-line regimens until disease progression or unacceptable toxicity. We performed a Bayesian NMA with published hazard ratios (HRs) and 95%confidence intervals (CIs) to evaluate the comparative effectiveness of different second-line therapies for mPDAC. The main outcomes of interest were overall survival (OS) and progression free survival (PFS), secondary endpoints were grade 3-4 toxicities. We calculated the relative ranking of agents for each outcome as their surface under the cumulative ranking (SUCRA). A higher SUCRA score meant a higher ranking for efficacy outcomes. RESULTS: A NMA of 9 treatments was performed for OS (n = 2521 patients enrolled). Compared with 5-FU + folinic acid both irinotecan or NALIRI + fluoropyrimidines had a trend to better OS (HR = 0.76, 95%CI 0.21-2.75 and HR = 0.74, 95%CI 0.31-1.85). Fluoropyrimidines + folinic acid + oxaliplatin were no better than the combination without oxaliplatin. The analysis of treatment ranking showed that the combination of NALIRI + 5-FU + folinic acid was most likely to yield the highest OS results (SUCRA = 0.7). Furthermore, the NMA results indicated that with the highest SUCRA score (SUCRA = 0.91), NALIRI + 5-FU + folinic acid may be the optimal choice for improved PFS amongst all regimens studied. CONCLUSIONS: According to the NMA results, NALIRI + 5-FU, and folinic acid may represent the best second-line treatment for improved survival outcomes in mPDAC. Further evidence from prospective trials is needed to determine the best treatment option for this group of patients.

Human papillomavirus infection and non-oropharyngeal head and neck cancers: an umbrella review of meta-analysis.

OBJECTIVE: The causative and prognostic roles of human papillomavirus (HPV) in non-oropharyngeal squamous cell carcinoma of the head and neck are uncertain. This umbrella review assessed the strength and quality of evidence and graded the evidence derived from published meta-analyses on this subject. DATA SOURCES: MEDLINE, Embase, and the Cochrane Library were searched. Meta-analyses of observational studies and randomized trials were included. REVIEW METHODS: Evidence of association was graded according to the established criteria: strong, highly suggestive, suggestive, weak, or not significant. RESULTS: 15 meta-analyses were evaluated. The association with HPV was highly suggestive of oral (OR = 2.40, [1.87-3.07], P < 0.00001) and nasopharyngeal cancers (OR = 17.82 [11.20-28.35], P < 0.00001). Improved survival emerged only in hypopharyngeal carcinoma and was confirmed in studies in which only p16 + cancers were considered. CONCLUSION: HPV infection may increase the risk of oral cavity and nasopharyngeal cancer. However, the prognosis was not influenced, except in hypopharyngeal carcinoma.

Gonadal vein leiomyosarcoma, from clinical practice to a literature review: surgical, oncological and histopathologic correlation.

BACKGROUND AND AIM: Vascular leiomyosarcomas are rare and generally originate from the muscular wall of the inferior vena cava. Leiomyosarcomas originating from the wall of the gonadal veins are rare and just about ten cases are described in literature. In the present paper, we have described a case of a LMS originating from the left gonadal vein. METHODS: A 44-year-old woman presented in March 2020 pain symptoms at the level of the left renal lodge. The subsequent CT and the biopsy confirmed the diagnosis of G2 grade LMS. The mass was then removed en bloc from the posterior and inferior pancreatic plane, from the aortic plane and from the retroperitoneal plane, post chemoteraphy. RESULTS: Pathologic report revealed a typical leiomyosarcoma, moderately differentiated G2 with minor dedifferentiated areas of pleomorphic leiomyosarcoma. CONCLUSIONS: The LMSs originating from gonadal veins represent an uncommon oncologic challenge. The radical en bloc excision represents the therapeutic gold standard.

Optimization of an Impact-Based Frequency Up-Converted Piezoelectric Vibration Energy Harvester for Wearable Devices.

This work presents a novel development of the impact-based mechanism for piezoelectric vibration energy harvesters. More precisely, the effect of an impacting mass on a cantilever piezoelectric transducer is studied both in terms of the tip mass value attached to the cantilever and impact position to find an optimal condition for power extraction. At first, the study is carried out by means of parametric analyses at varying tip mass and impact position on a unimorph MEMS cantilever, and a suitable physical interpretation of the associated electromechanical response is given. The effect of multiple impacts is also considered. From the analysis, it emerges that the most effective configuration, in terms of power output, is an impact at the cantilever tip without a tip mass. By changing the value of the tip mass, a sub-optimal impact position along the beam axis can also be identified. Moreover, the effect of a tip mass is deleterious on the power performance, contrary to the well-known case of a resonant energy harvester. A mesoscale prototype with a bimorph transducer is fabricated and tested to validate the computational models. The comparison shows a good agreement between numerical models and the experiments. The proposed approach is promising in the field of consumer electronics, such as wearable devices, in which the impact-based device moves at the frequencies of human movement and is much lower than those of microsystems.

Piezoelectric Energy Harvesting from Low-Frequency Vibrations Based on Magnetic Plucking and Indirect Impacts.

This work proposes a mono-axial piezoelectric energy harvester based on the innovative combination of magnetic plucking and indirect impacts, e.g., impacts happening on the package of the harvester. The harvester exploits a permanent magnet placed on a non-magnetic mass, free to move within a predefined bounded region located in front of a piezoelectric bimorph cantilever equipped with a magnet as the tip mass. When the harvester is subjected to a low-frequency external acceleration, the moving mass induces an abrupt deflection and release of the cantilever by means of magnetic coupling, followed by impacts of the same mass against the harvester package. The combined effect of magnetic plucking and indirect impacts induces a frequency up-conversion. A prototype has been designed, fabricated, fastened to the wrist of a person by means of a wristband, and experimentally tested for different motion levels. By setting the magnets in a repulsive configuration, after 50 s of consecutive impacts induced by shaking, an energy of 253.41 µJ has been stored: this value is seven times higher compared to the case of harvester subjected to indirect impacts only, i.e., without magnetic coupling. This confirms that the combination of magnetic plucking and indirect impacts triggers the effective scavenging of electrical energy even from low-frequency non-periodical mechanical movements, such as human motion, while preserving the reliability of piezoelectric components.

Wearable Ball-Impact Piezoelectric Multi-Converters for Low-Frequency Energy Harvesting from Human Motion.

Multi-converter piezoelectric harvesters based on mono-axial and bi-axial configurations are proposed. The harvesters exploit two and four piezoelectric converters (PCs) and adopt an impinging spherical steel ball to harvest electrical energy from human motion. When the harvester undergoes a shake, a tilt, or a combination of the two, the ball hits one PC, inducing an impact-based frequency-up conversion. Prototypes of the harvesters have been designed, fabricated, fastened to the wrist of a person by means of a wristband and watchband, and experimentally tested for different motion levels. The PCs of the harvesters have been fed to passive diode-based voltage-doubler rectifiers connected in parallel to a storage capacitor, Cs = 220 nF. By employing the mono-axial harvester, after 8.5 s of consecutive impacts induced by rotations of the wrist, a voltage vcs(t) of 40.2 V across the capacitor was obtained, which corresponded to a stored energy of 178 µJ. By employing the bi-axial harvester, the peak instantaneous power provided by the PCs to an optimal resistive load was 1.58 mW, with an average power of 9.65 µW over 0.7 s. The proposed harvesters are suitable to scavenge electrical energy from low-frequency nonperiodical mechanical movements, such as human motion.

A design strategy to match the band gap of periodic and aperiodic metamaterials.

The focus of this paper is on elastic metamaterials characterised by the presence of wide sub-wavelength band gap. In most cases, such mechanical property is strictly connected to the periodic repetition of the unit cell. Nonetheless, the strict periodicity requirement could represent a drawback. In this paper, we present a design strategy for aperiodic elastic metamaterials in order to achieve the same performances as for the periodic counterparts. This is done by exploiting the concept of separation of modes for different building blocks, arranged in aperiodic fashion. A theoretical explanation is provided, as well as numerical simulations; the concept is validated by means of a set of experimental tests on prototypes that are realized via additive manufacturing.

On the Effects of Package on the PMUTs Performances-Multiphysics Model and Frequency Analyses.

This paper deals with a multiphysics numerical modelling via finite element method (FEM) of an air-coupled array piezoelectric micromachined ultrasonic transducers (PMUTs). The proposed numerical model is fully 3D with the following features: the presence of the fabrication induced residual stresses, which determine a geometrically non-linear initial deformed configuration of the diaphragms and a remarkable shift of the fundamental frequency; the multiple coupling between different physics, namely electro-mechanical-coupling for the piezo-electric model, acoustic-structure interaction at the acoustic-structure interface and pressure acoustics in the surrounding air. The model takes into account the complete set of PMUTs belonging to the silicon die in a 4 x 4 array configuration and the protective package, as well. The results have been validated by experimental data, in terms of initial static pre-deflected configuration of the diaphragms and frequency response function of the PMUT. The numerical procedure was applied, to analyze different package configurations of the device, to study the influence of the holes on the acoustic transmission in terms of SPL and propagation pattern and consequently extract a set of design guidelines.

Low frequency 3D ultra-wide vibration attenuation via elastic metamaterial.

The design of innovative metamaterials with robust and reliable performances is attracting increasing interest in the scientific community because of their unique properties and for their unexplored potential. In particular, dynamical properties of periodic structures are widely studied specifically for their bandgap opening characteristic, which enables the design of structures with unprecedented dynamical behaviour. In the present work an ultra-wide three-dimensional bandgap is presented, with extremely low frequency range of operation. Numerical simulations and analytical models are proposed to prove the claimed properties, together with experiments carried out on a prototype built by means of additive manufacturing.

3-D Design and Simulation of a Piezoelectric Micropump.

The objective of this paper is to carefully study the performances of a new piezoelectric micropump that could be used, e.g., for drug delivery or micro-cooling systems. The proposed micropump is characterized by silicon diaphragms, with a piezoelectric actuation at a 60 V input voltage, and by two passive valves for flow input and output. By means of a 3-D Finite Element (FE) model, the fluid dynamic response during different stages of the working cycle is investigated, together with the fluid-structure interaction. The maximum predicted outflow is 1.62 µL min - 1 , obtained at 10 Hz working frequency. The computational model enables the optimization of geometrical features, with the goal to improve the pumping efficiency: The outflow is increased until 2.5 µL min - 1 .

Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis.

Levels of serum lactate dehydrogenase (LDH) are a recognized prognostic factor in malignant melanoma (MM). It is relevant to confirm its prognostic role in patients treated with targeted therapies [BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi)] and immunotherapy (IT). Furthermore, its role as a predictive marker in patients treated with these drugs had still not been investigated. We performed an electronic search for studies reporting information on overall survival (OS) or progression-free survival (PFS) according to LDH levels and on their predictive effect in patients treated with targeted therapies (BRAFi and MEKi) and IT. Data were pooled using hazard ratios (HRs) for OS and HRs for PFS according to a fixed-effect or a random-effect model. For predictive analysys, effect of new agents versus standard therapy was evaluated in LDH high population. A total of 71 publications were retrieved for a total of 16 159 patients. Overall, elevated LDH levels were associated with an HR for OS of 1.72 [95% confidence interval (CI): 1.6-1.85; P<0.0001]. Similarly, HR for PFS was 1.83 (95% CI: 1.53-2.2; P<0.0001). In the LDH elevated subgroup, new agents improved OS significantly (HR: 0.71; 95% CI: 0.62-0.82; P<0.0001) and PFS (HR: 0.63; 95% CI: 0.55-0.72; P<0.0001). In advanced MM treated with IT or BRAFi±MEKi, elevated LDH level at baseline represents a poor prognostic factor. However, patients with increased LDH levels and treated with these drugs gain significant benefits in terms of PFS and OS.

Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis.

INTRODUCTION: Programmed cell death-1 or ligand 1 (PD-(L)1) inhibitors are associated with immune-related adverse events. Conversely, little is known about the incidence of haematological toxicities across published trials. We have performed a systematic review and meta-analysis to evaluate the incidence of immunotherapy-related anaemia, neutropenia and thrombocytopenia among different tumour types, trials phases and anti-PD-(L)1 agents. MATERIAL AND METHODS: A PubMed, Embase and Cochrane library search on 23rd December 2017 and a review of references from relevant articles were done. Studies regarding haematological diseases were excluded. The pooled incidence rates weighted for the individual sample sizes were calculated according to fixed or random effect models. Incidence of all-grade and grade (G) III or higher anaemia were the primary end-points. Neutropenia, febrile neutropenia and thrombocytopenia were secondary end-points. RESULTS: Forty-seven studies of PD-(L)1 inhibitors for a total of 9324 evaluable patients were included in the meta-analysis. The overall incidence of anaemia during PD-(L)1 inhibitor was 9.8% (95% confidence interval [CI], 6-13.6%) for all-grade and 5% (95% CI, 3.3-6.7%) for G3-5 anaemia. The incidence was higher in diseases different from genitourinary, lung and melanoma, with avelumab and in phase II studies. In randomised trials, relative risk of all-grade anaemia for patients receiving anti-PD-(L)1 agents compared with control arms was 0.25 (95% CI, 0.16-0.39; p < 0.001). Incidence of all grades and G3-5 neutropenia and thrombocytopenia were 0.94%, 1.07%, 2.8% and 1.8%, respectively. Febrile neutropenia was 0.45%. CONCLUSIONS: The incidence of PD-(L)1 inhibitor-related anaemia was not negligible. Severe neutropenia, thrombocytopenia and febrile neutropenia were rare. These findings are useful for clinicians and suggest that blood cell count should be checked before every cycle and support should be given when severe toxicity appears.

A systematic review and meta-analysis of second-line therapies for treatment of mesothelioma.

INTRODUCTION: Advanced malignant pleural mesothelioma (MPM) is generally treated with platinum/pemetrexed-based first-line therapy. Once the disease progresses, evidence for the efficacy of palliative treatments is lacking, and platinum re-challenge or single-agent chemotherapy are commonly used. To assess the effects of cytostatic or targeted therapy for treating MPM, we performed a systematic review and meta-analysis. MATERIAL AND METHODS: PubMed, the Cochrane Library, and Embase databases were searched to identify published articles on second-line treatments for recurrent or advanced mesothelioma. Inclusion criteria were publication in the English language, describing clinical trials with 20 or more patients, and evaluability for efficacy and for receiving second-line systemic therapies. Data were pooled using number of events/number of evaluable patients, median overall survival (OS) and progression-free survival (PFS), according to a fixed or random effect model. Pooled median OS was the primary endpoint. RESULTS: A total of 49 eligible studies (n = 3938 patients; range, 12-400) were identified. Median progression-free survival (PFS) was 3.4 months (95%CI 2.87-3.93). Median pooled OS was 7.86 (95%CI 7.01-8.72). The pooled overall response rate (ORR) was 8.63% (95%CI 6-11.26), and the pooled disease control rate (DCR) was 54.8% (95%CI 48.9-60.6). Median pooled OS with platinum- and pemetrexed-based chemotherapy were 7.93 and 7.78 months, respectively. CONCLUSIONS: There remains uncertainty about the ideal second-line agent for MPM. Based on this meta-analysis, palliative chemotherapy or other experimental agents can be considered for patients with MPM who desire further treatment after their disease has progressed, during or after first-line therapy.

Efficacy of ALK inhibitors on NSCLC brain metastases: A systematic review and pooled analysis of 21 studies.

BACKGROUND: Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs. MATERIAL AND METHODS: A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR). RESULTS: A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1-65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3-55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naïve and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%. CONCLUSIONS: Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy.

Different Toxicity of Cetuximab and Panitumumab in Metastatic Colorectal Cancer Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head-to-head comparison. Despite the similar overall toxicity profile, cetuximab and panitumumab retain peculiar safety characteristics that deserve to be deeply investigated. METHODS: We conducted a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms ("cetuximab" or "panitumumab") AND ("colorectal cancer" OR "colorectal carcinoma"). Data of adverse events were aggregated to obtain pooled incidence rates of prespecified adverse events. Incidence of skin toxicities was the primary outcome. A χ2 test was used for comparisons of proportions and an odds ratio (OR) was calculated for comparison. RESULTS: A total of 38 studies were included for analysis. Cetuximab was associated with fewer G3-4 skin toxicities (OR = 0.62, 95% CI 0.53-0.62; p < 0.001), slightly more frequent G3-4 acne-like rash (OR = 1.24, 95% CI 1.04-1.48; p = 0.04), and paronychia (OR 1.36, 95% CI 1.1-1.7), but fewer cases of skin fissures (OR = 0.64, 95% CI 0.44-0.93; p = 0.02) and pruritus (OR = 0.45, 95% CI 0.35-0.58; p < 0.001) than PANI. CONCLUSIONS: In conclusion, this meta-analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events.

3D auxetic single material periodic structure with ultra-wide tunable bandgap.

The design and the combination of innovative metamaterials are attracting increasing interest in the scientific community because of their unique properties that go beyond the ones of natural materials. In particular, auxetic materials and phononic crystals are widely studied for their negative Poisson's ratio and their bandgap opening properties, respectively. In this work, auxeticity and phononic crystals bandgap properties are properly combined to obtain a single phase periodic structure with a tridimensional wide tunable bandgap. When an external tensile load is applied to the structure, the auxetic unit cells change their configurations by exploiting the negative Poisson's ratio and this results in the tuning, either hardening or softening, of the frequencies of the modes limiting the 3D bandgap. Moreover, the expansion of the unit cell in all the directions, due to the auxeticity property, guarantees a fully 3D bandgap tunability of the proposed structure. Numerical simulations and analytical models are proposed to prove the claimed properties. The first experimental evidence of the tunability of a wide 3D bandgap is then shown thanks to the fabrication of a prototype by means of additive manufacturing.

Long-term survival in small cell lung cancer: a case report and review of the literature.

Small cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung cancers. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14-16 months for patients with limited disease and 8-11 months for those with extensive disease, with 20-40% of patients with limited disease and 5% of patients with extensive disease alive at 2 years. This report discusses the case of a long-term SCLC survivor treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs who is alive 7 years after diagnosis, with no evidence of further relapse. In the near future, better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors.

Metabolic syndrome as a peculiar target for management of prostate cancer patients.

An interesting and reciprocal association between the metabolic syndrome and prostate cancer has been identified. Metabolic alterations, such as hyperinsulinemia, increased levels of insulin growth factor-1, and insulin resistance could be on the basis of development and progression of many tumors, including prostate cancer, and changes in body composition, in turn, can represent some side effects of androgen deprivation therapy and novel drugs, such as mammalian target of rapamycin inhibitors. This review evaluates this interrelation between metabolic syndrome and prostate tumor scanning in many clinical and preclinical epidemiological studies and describes possible pathogenetic biological mechanisms. Finally, this article discusses feasible clinical implications for the management, prevention, diagnosis, prognosis, and treatment of patients affected by metabolic syndrome and prostate cancer, with particular attention to the metformin action.