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Background We aimed at appraising real-life efficacy of Crohn’s Disease Exclusion Diet (CDED) coupled with partial enteral nutrition (PEN) in inducing clinical and biochemical remission at disease onset and in patients with loss of response to biologics in a tertiary-level center. We also aimed at identifying early responders to this dietary regimen. Methods We gathered clinical, anthropometric and laboratory data of patients aged less then 18 years of age with a diagnosis of CD, who were consecutively treated with CDED coupled with PEN as main treatment for the induction of remission or in the setting of loss of response to other therapies. We collected data of patients who received CDED plus PEN from April 2019 to June 2022 at diagnosis, at the beginning of the dietary treatment, and at the phase 1. Patients who interrupted diet during follow-up were considered as treatment failures on an intent to treat basis. We compared groups using chi-square, Fisher’s exact test, Mann-Whitney U or related-samples Wilcoxon signed rank tests or McNemar’s test as appropriate. Results 47 patients were retrospectively identified. Table 1. summarizes clinical and biochemical characteristics at diagnosis and at CDED with PEN initiation. 24 (51.1%) patients started CDED as induction therapy at disease onset, whereas 23 (48.9%) of them received CDED with PEN as add-on therapy. 32/47 (68%) patients achieved clinical remission (wPCDAI < 12.5) at the end of phase 1, 16/24 patients (66.7%) who started CDED as induction therapy and 16/23 (69.5%) of those who started CDED as add-on, with no statistically significant difference among the two groups (p=1.00). Laboratory parameters significantly improved in both groups (Figure 1.). There were no statistically significant differences in clinical remission rates between patients with mild-to-moderate and severe disease at the end of phase 1 (25/35 vs 7/12, p=0.481). At disease onset, 14 patients added a concomitant treatment (11 patients added anti-TNF alpha, 3 patients added IMM and one patient added anti-TNF alpha + IMM) after a median time of 4 weeks (IQR: 3-5 weeks). 28 patients had clinical data gathered at week 3. Patients who achieved clinical response at week 3 (a change in wPCDAI > 12.5) were more likely to be in clinical remission at the end of phase 1 (17/20 vs 1/8, p Conclusion CDED with PEN confirmed its efficacy in a real-life setting, both as induction regimen and as add-on therapy, also in patients with clinically severe disease. Early clinical response predicts clinical remission at the end of phase 1, possibly allowing identification of dietary responsive disease. Table 1. Figure 1.

Cardiorespiratory monitoring is recommended for the assessment of symptomatic preterm newborns and infants with a clinical history of Apparent Life-Threatening Events (ALTE). Patients who experience cardiorespiratory events usually have to be moved to specialized centers to perform cardiorespiratory studies. To avoid the transfer of these patients to specialized centers, it has been created a network based on an interchange system where the recordings were uploaded in unspecialized centers (spokes) and downloaded by the Sleep Disorders Breathing (SDB) Center (hub) to be analyzed. From November 2008 to December 2020 cardiorespiratory recordings belonging to 422 patients were collected. This study shows that the inter-hospital network is an efficient system that allows accurate and safe management of infants at risk of apnoea, bradycardia, and hypoxemia also in unspecialized centers, avoiding unnecessary transfers of patients and over – hospitalizations.

Introduction\ud \ud The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC.\ud \ud \ud \ud Methods\ud \ud Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed.\ud \ud \ud \ud Results\ud \ud The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm.\ud \ud \ud \ud In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0–10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2–11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82–1.18]; P = 0.85).\ud \ud \ud \ud Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49–0.98]; P = 0.038), from 7.6 to 9.0 months median OS.\ud \ud \ud \ud With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4–5.3]) and 4.9 months (95%CI:[4.3–5.4]). HR for PFS was 0.97 (95%CI:[0.83–1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS.\ud \ud \ud \ud Conclusion\ud \ud In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

Introduction: The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC. Methods: Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed. Results: The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm. In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0-10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2-11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82-1.18]; P = 0.85). Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a sta-tistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49-0.98]; P = 0.038), from 7.6 to 9.0 months median OS. With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4-5.3]) and 4.9 months (95%CI:[4.3-5.4]). HR for PFS was 0.97 (95%CI:[0.83-1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS. Conclusion: In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

AimThe European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ‐C30) assesses the health‐related quality of life of patients in cancer trials. There are currently no minimally important difference (MID) guidelines for the EORTC QLQ‐C30 for colorectal cancer (CRC). This study aims to estimate MIDs for the EORTC QLQ‐C30 scales in patients with advanced CRC treated with chemotherapy and enrolled in clinical trials.MethodThe data were obtained from three published EORTC trials that treated CRC patients using chemotherapy. Potential anchors were selected from clinical variables based on their correlation with EORTC QLQ‐C30 scales. Anchor‐based MIDs for within‐group change and between‐group change were estimated via the mean change method and linear regression, respectively, and summarized using weighted correlation. Distribution‐based MIDs were also examined.ResultsAnchor‐based MIDs were determined for deterioration in 8 of the 14 EORTC QLQ‐C30 scales and in 9 scales for improvement, and varied by scale, direction of change and anchor. MIDs for improvement (deterioration) ranged from 6 to 18 (−11 to −5) points for within‐group change and 5 to 15 (−10 to −4) for between‐group change. Summarized MIDs (in absolute values) per scale mostly ranged from 5 to 10 points.ConclusionsThese findings have clinical relevance for the interpretation of treatment efficacy and the design of clinical trials by informing sample size requirements.

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB–dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3–4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6–11.0) months in the control arm versus 8.2 (7.5–10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78–1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77–1.35), whereas for those without, HR was 0.90 (95% CI: 0.66–1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases. © 2020 International Association for the Study of Lung Cancer

RF MEMS in low-temperature co-fired ceramics (LTCC) technology have been designed, manufactured and tested for potential utilization in reconfigurable space sub-systems. Specifically, single-pole-single-throw (SPST) and single-pole-double-throw (SPDT) ohmic switch configurations have been studied for wide-band applications. Advantages coming from the measured RF performances and from the integration of RF MEMS by means of the LTCC technology only, to be used also for packaging, are discussed. Furthermore, preliminary on-wafer DC test on a double-pole-double-throw (DPDT) ohmic switch has been done in order to check both the mechanical response and the quality of the ohmic contact (contact resistance).

The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases. In this review, the current knowledge regarding ALK-positive NSCLC, focusing on the biology of the disease and the available therapeutic options are discussed.

Background Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non–small-cell lung cancer (NSCLC). A consensus group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting. Methods A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies’ members. Results 444 responses were analysed (radiation oncologist: 55% [n = 242], pulmonologist: 15% [n = 66], medical oncologist: 14% [n = 64]). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n = 362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% ≤ 3, and 17% ≥ 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that only ≤3 involved organs (excluding primary) should be included. 317 (72%) included mediastinal lymph node involvement in the sOM-d and 22% (n = 70/317) counted mediastinal lymph node as a metastatic site. Most physicians completed sOM staging with brain magnetic resonance imaging (91%, n = 403) and positron emission tomography/computed tomography (98%, n = 437). Pathology proof of metastatic disease was a requirement to define sOM for 315 (71%) physicians. The preferred primary outcome for sOM clinical trials was overall survival (73%, n = 325). Conclusion Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d.

Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life. Unfortunately, the development of different mechanism of resistance, limits the long term efficacy of these agents. The most clear mechanism of resistance is the development of EGFR Thr790Met mutation. Against this new target, different third-generation EGFR-mutant-selective TKIs, such as osimertinib, rociletinib and olmutinib, showed a great activity. In this review, we summarize the scientific evidences about biology, evaluation and treatment on NSCLC with EGFR T790M mutation.

Introduction: Epidermal growth factor receptor (EGFR) mutations are detected in about 10–15% of Caucasian and 30–40% of Asian patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In patients harbouring EGFR mutations, the treatment with different available EGFR tyrosine kinase inhibitors (TKIs) showed to be more effective and safe than platinum-based chemotherapy regimens.Areas covered: The current evidences about the role of afatinib for patients with EGFR-positive NSCLC are reviewed and discussed. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating afatinib in EGFR-positive NSCLC.Expert commentary: Afatinib is the third EGFR TKI approved for the treatment of NSCLC harbouring EGFR mutations, showing high efficacy in this setting of patients.

RF MEMS in Low-Temperature Co-fired Ceramics (LTCC) technology have been designed, manufactured and tested for potential utilization in reconfigurable space sub-systems. Specifically, single-pole-single-throw (SPST) and single-pole-double-throw (SPDT) ohmic switch configurations have been studied for wide-band applications. Advantages coming from the measured RF performances and from the integration of RF MEMS by means of the LTCC technology only, to be used also for packaging, are discussed.

Lung cancer represent the leading cause of cancer related-death worldwide. Although cytotoxic chemotherapy and targeted agents improved survival, the median overall survival for patients with metastatic disease remains poor. Docetaxel is still the corner stone of the second-line treatment, although associated with an unfavourable safety profile. Recent advances in the understanding of cancer immune escape system lead to the development of novel immunotherapies agent that can restore patient's immune response to cancer cells. Unlike vaccines, immune checkpoints inhibitors have shown promising results in non-small cell lung cancer patients. Especially, nivolumab and pembrolizumab, monoclonal antibodies against PD-1, provides as single agent therapy in chemotherapy refractory patients objective response rates ranging from 15%-25%, the majority of which arose quickly and were ongoing 1 year after starting treatment. Furthermore, the toxicity profile differs from that of cytotoxic chemotherapy and is much better tolerated. PD-L1 expression is a promising biomarker for selection and stratification of patients, although its prognostic and predictive role remains to be defined. Several trials are currently ongoing to define the role of immune checkpoint inhibitors in the treatment of patients with non-small cell lung cancer, their combination with cytotoxic chemotherapy or targeted agents and the efficacy and safety of double blockage of PD-1/PD-L1 and CTLA4. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating immune checkpoint inhibitors and NSCLC, considering the measured outcomes as progression free survival (PFS), overall survival (OS), and the overall response rate (ORR).

The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) changed dramatically the history of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Several randomized prospective trials confirmed the superiority of these target agents about survival and response rate when comparing with platinum-based chemotherapy. Knowledge about EGFR mutations increased gradually during the development of target agents and different clinical trials. EGFR mutations cannot be considered all equal, but different entities should be considered in our clinical practice: exon 19 deletions, exon 21 mutation (L858R) and uncommon mutation (exon 20, exon 18 and double mutation). Nowadays, we dispose of three different EGFR TKIs (afatinib, erlotinib and gefitinib) approved for the treatment for first-line treatment of patients di NSCLC carrying EGFR, that was compared only by indirect analysis, producing data not always clear and convincing. This research highlight is an overview of data about EGFR TKIs in first-line setting, focusing on differences about exon 19 deletions and L585R mutation in patients treated with different TKIs. In addition, we report the preliminary results of the first head-to-head randomized clinical trial between two different EGFR TKIs, the LUX-Lung 7 (LL7) that compared afatinib and gefitinib showing interesting results.

Two different topologies of radio frequency micro-electro-mechanical system (RF MEMS) series ohmic switches (cantilever and clamped–clamped beams) in coplanar waveguide (CPW) configuration have been characterized by means of DC, environmental, and RF measurements. In particular, on-wafer checks have been followed by RF test after vibration, thermal shocks, and temperature cycles. The devices have been manufactured on high resistivity silicon substrates, as building blocks to be implemented in different single-pole 4-throw (SP4 T), double-pole double-throw (DPDT) configurations, and then integrated in Low Temperature Co-fired Ceramics (LTCC) technology for the realization of large-order Clos 3D networks.

Objective: To assess computed tomography with volume rendering (CT-VR) as a tool to evaluate parenchymal hyperinflation before and after bronchoscopic lung volume reduction (BLVR) in patients with advanced stage emphysema. Materials and methods: Between March 2006 and October 2007, we have prospectively studied pre- and postoperatively by spiral multislice CTscan and functional tests seven patients (six male, one female; age range 51—77 years, mean 64) with advanced stage heterogeneous emphysema who underwent BLVRusing the Emphasys one-way valves (Emphasys, Redwood City, CA, USA). CT parameters considered were: the volume of the ‘target’ lobe and of the entire treated lung, the diameters (antero-posterior and cranio-caudal) of the treated hemithorax and the emphysematous parenchyma rate with respect to the normal parenchyma rate of the treated lobe. Lung parenchyma has been classified as emphysematous if the density was in the 1024/900 Hounsfield units (HU) range and as normal if the density was in the 900/200 HU range. Preoperative radiological data were compared with postoperative data and plotted against spirometric data observed 1 month after treatment. Results: Overall, 24 valves have been implanted in the 7 patients. Valves have been placed in the right upper lobe in two patients, in the left upper lobe in four and in both the left upper lobe and the right lower lobe in one. Volume reduction as a proportion of the ‘target’ lobe and of the entire lung has been observed in all patients with significant differences between mean preoperative and postoperative values [p = 0.016 (target lobe); p = 0.031 (lung)]. Lobar volume reduction ranged between 1.3% and 53.7% of preoperative values. Volume reduction of the entire lung ranged between 3.1% and 16.8%. Thoracic diameters decreased in all patients after treatment with significant mean differences [p = 0.007 (antero-posterior); p = 0.004 (cranio-caudal)]. FEV1 increased in six of seven patients with significant mean differences (p = 0.025). The higher volume reduction rate has been observed in the three patients showing the better FEV1 improvement. Emphysematous lung parenchyma rate decreased postoperatively in six of seven patients with mean differences being not significant (p = 0.17).Conclusions:CT-VR is an excellent tool to confirm the efficacy of BLVR in reducingparenchymal hyperinflation. Functional advantages are proportional to the volume reduction as measured by CT-VR. # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.