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It is well-known that when a single-degree-of-freedom (sdof) system is excited by a continuous motion of the foundation, the force transmissibility, relating the force transmitted to the foundation to the applied force, equals the displacement transmissibility. Recent developments in the generalization of the transmissibility to multiple-degree-of-freedom (mdof) systems have shown that similar simple and direct relations between both types of transmissibility do not appear naturally from the definitions, as happens in the sdof case. In this paper, the authors present their studies on the conditions under which it is possible to establish a relation between force transmissibility and displacement transmissibility for mdof systems. As far as the authors are aware, such a relation is not currently found in the literature, which is justified by being based on recent developments in the transmissibility concept for mdof systems. Indeed, it does not appear naturally, but the authors observed that the needed link is present when the displacement transmissibility is obtained between the same coordinates where the applied and reaction forces are considered in the force transmissibility case; this implies that the boundary conditions are not exactly the same and instead follow some rules. This work presents a formal derivation of the explicit relation between the force and displacement transmissibilities for mdof systems, and discusses its potential and limitations. The authors show that it is possible to obtain the displacement transmissibility from measured forces, and the force transmissibility from measured displacements, opening new perspectives, for example, in the identification of applied or transmitted forces. With this novel relation, it becomes possible, for example, to estimate the force transmissibility matrix with the structure off its supports, in free boundary conditions, and without measuring the forces. As far as force identification is concerned, this novel approach significantly decreases the computational effort when compared to conventional approaches, as it requires only local information of the sets of coordinates involved. Numerical simulations and experimental examples are presented and discussed, to illustrate the proposed developments. [ABSTRACT FROM AUTHOR]

One of the main objectives of Acoustic Emission (AE) monitoring is to identify approaching critical stage of damage in the structure before it fails. State-of-the-art AE analysis is done on the features in both the time and frequency domains. Many features such as centroid frequency, duration, rise-time, count and energy are dependent on acquisition settings; threshold and timing parameters. Incorrect acquisition settings may result in inaccurate classification of the AE source. This work proposes a new feature in the time domain signal based on 2nd order Renyi’s entropy, which proves to be efficient in identifying different stages of damage. Renyi’s entropy is a measure of uncertainty or randomness of the signals and is directly derived from the distribution of signal amplitude. Therefore, it is independent of threshold and timing parameters. The validity of the proposed parameter is investigated by performing AE monitoring during fatigue endurance test of 316L stainless steel. Digital Image Correlation (DIC) and global strain monitoring was carried out to relate material damage with AE activity. The result shows Renyi’s entropy to be an effective measure to identify critical stages of damage in the material.

Background: Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes., Methods: Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes., Results: In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation., Conclusions: Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients., (© The Author(s) 2024. Published by Oxford University Press.)

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism., (© 2024. The Author(s).)

Introduction: We aimed to determine if advanced BRAF-mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected., Methods: Between 2008 and 2021, 182 patients with BRAF-mutant advanced NSCLC (BRAF V600E, n = 70; BRAF non-V600E, n = 112) were retrospectively identified from 18 centers in Spain. Patients received chemotherapy (n = 147), immunotherapy (n = 69), targeted therapy (n = 42), and immunotherapy + chemotherapy (n = 26)., Results: Incidence rate of TEE was 26.4 % (95%CI: 19.9 %-32.9 %). A total of 72 TEE were documented among 48 patients, as 18 patients (37.5 %) developed more than one event. Median time to TEE onset was 2 months, 69 % of TEE occurred in the peridiagnostic period (+/- 90 days from cancer diagnosis), and in 16 pts. (33 %) TEE was the form of lung cancer presentation. Although most TEE were only venous (82 %; PE, n = 33; DVT, n = 16), arterial events were reported in 31 % and occurred earlier, or TEE presented in atypical locations (13.9 %). TEE were related to high hospitalization rate (59 %), recurrence (23 %), and mortality (10.4 %) despite appropriate anticoagulant/antiaggregant treatment. Median OS in patients without-TEE was 19.4 months (95%CI: 4.6-34.1), and significantly shorter in patients with arterial-TEE vs venous-TEE vs both of them: 9.9 months (95%CI: 0-23.5) vs 41.7 months (95%CI: 11.3-72.2 m) vs 2.7 months (95%CI: 2.1-3.3), p = 0.001. Neither clinical or molecular features (BRAF V600E/non-V600E), nor cancer treatment was associated to TEE occurrence. Khorana score underperformed to predict thrombosis at cancer diagnosis, as only 19.2 % of patients were classified as high-risk., Conclusions: Thrombotic events represent a new clinical feature of BRAF-mutant lung cancer. Patients with almost a 30 % incidence of TEE should be offered systematic anticoagulation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: Immune Checkpoint Inhibitors (ICI) can be associated with thrombotic events, both venous and arterial (VTE/AT). However, there is a paucity of information regarding patients in routine clinical practice., Methods/patients: Retrospective, multicenter study promoted by the Thrombosis and Cancer Section of the Spanish Society of Medical Oncology (SEOM). Patients with melanoma and lung cancer who initiated ICI between 01/01/2015 and 31/12/2019 were recruited. Minimum follow-up was 6 months (unless it was not possible because of death). The primary objective was to calculate the incidence of ICI-associated VTE/AT and the secondary objectives included to analyze its impact on survival and to identify predictor variables for VTE/AT., Results: 665 patients with lung cancer were enrolled. The incidence of VTE/AT during follow-up was 8.4%. Median overall survival (OS) was lower in the VTE/AT group (12 months 95% CI 4.84-19.16 vs. 19 months 95% CI 16.11-21.9; p = 0.0049). Neutrophil/lymphocyte ratio (NLR) and anemia upon initiation of IT, as well as a history of thrombosis between cancer diagnosis and the start of ICI, were predictive variables for developing of VTE/AT (p < 0.05). 291 patients with melanoma were enrolled. There was a 5.8% incidence rate of VTE/AT during follow-up. Median OS was lower in the VTE/AT group (10 months 95% CI 0.0-20.27 vs. 29 months 95% CI 19.58-36.42; p = 0.034). NLR and lactate dehydrogenase (LDH) at the beginning of ICI were predictor variables for VTE/AT (p < 0.05)., Conclusions: ICI increases the risk of VTE/AT in patients with lung cancer and melanoma, which impact OS., (© 2022. The Author(s).)

Introduction: Patients with cancer (PC) are at high risk of acquiring COVID-19 and can develop more serious complications. Deeper understanding of vaccines immunogenicity in this population is crucial for adequately planning vaccines programs. The ONCOVac study aimed to comprehensively assess the immunogenicity of mRNA-1273 vaccine in terms of humoral and cellular response., Methods: We conducted a prospective, single-center study including patients with solid tumours treated with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), immunotherapy (IT) or chemotherapy (CT). Patients were enrolled previously to vaccination with mRNA-1273. We also involved health care workers (HCW) to serve as a control group. We took blood samples before first dose administration (BL), after first dose (1D), and after second dose (2D). The primary objective was to compare the rate and magnitude of T cell response after second dose whereas safety and humoral response were defined as secondary objectives. We also collected patient reported outcomes after both the first and second vaccine dose and a six-month follow-up period to diagnose incident COVID-19 cases was planned., Results: The rate of specific anti-S serologic positivity (anti-S IgG cut-off point at 7,14 BAU/mL) was significantly higher in HCW compared to PC after 1D (100% versus 83.8%; p = 0.04), but similar after 2D (100% versus 95.8%; p = 0.5). This difference after 1D was driven by PC treated with CT (100% versus 64.5%; p = 0.001). Cellular response after 2D was significantly lower in PC than in HCW for both CD4+ (91.7% versus 59.7%; p = 0.001) and CD8+ (94.4% versus 55.6%; p < 0.001) T cells. We found a difference on pre-existing CD4+ T cell response in HCW comparing to PC (36% and 17%, p = 0.03); without difference in pre-existing CD8+ T cell response (31% and 23%, p = 0.5). After excluding patients with pre-existing T cell response, PC achieved even lower CD4+ (50.9% versus 95.5%, p < 0.001) and CD8+ (45.5% versus 95.5%, p < 0.001) T cell response compared with HCW. Regarding safety, PC reported notably more adverse events than HCW (96.6% versus 69.2%, p < 0.001)., Conclusion: We demonstrated that PC showed a similar humoral response but a lower T cell response following two doses of mRNA-1273 vaccination. Further studies are needed to complement our results and determine the implication of low T cell response on clinical protection of PC against COVID-19., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alfonso Cortes declares the payment for presentations/speaker bureaus/manuscript-writing/educational events from GSK, AstraZeneca, Roche, MSD and Eisai. Alfonso Cortes declares consulting fees from Clovis, Lilly, Pfizer, GSK, Ferrer and Roche. Alfonso Cortes has received research grants from Pfizer. Alfonso Cortes declares support for attending meetings from Roche, Daiichi and Pfzer. Alfonso Cortes is co-founder of ONCARE. Jose Luis Casado and Federico Longo have not conflict of interest to declare. Juan José Serrano declares speaker bureau from Pierre-Fabre and travel/accomodation/expenses from Novartis. Cristina Saavedra declares travel/accomodation/expenses from Lilly and Pfizer. Hector Velasco, Alejandro Vallejo and Adrian San Miguel have not conflict of interest to declare. Jesus Chamorro and Diana Rosero have not conflict of interest to declare. María Fernandez, María Gion and Noelia Martinez have not conflict of interest to declare. Ainara Soria has not conflict of interest to declare. Teresa Alonso declares: Scientific Consultancy Role (speaker and advisory role) and travel grant from IPSEN, Pfizer, Bayer, Sanofi, Janssen, Astellas, Adacap, Eisai, Lilly, Novartis, BMS, Roche. Teresa Alonso declares the participation in Clinical trials from Roche, BMS, MSD, Pfizer, Novartis, IPSEN, Exelixis, Astrazeneca-Medimmune, Janssen, Lilly, Eisai, Astellas. Teresa Alonso declares research support from Roche, Pfizer, IPSEN. Iñigo Martinez and Yolanda Lage have not conflict of interest to declare. Elena López declares to receive advisory/consultancy honorarium from AstraZeneca, Pfizer, Roche, Novartis. Elena López has received speaker bureau/expert testimony honorarium from Roche, Novartis , Eisai, Astra Zeneca; and has received travel/accommodation/expenses from Roche, Novartis. María Eugenia Olmedo has not conflict of interest to declare. Pablo Reguera has not conflict of interest to declare. Pablo Gajate declares travel and educational support from BMS, MSD, Pfizer, Ipsen, Sanofi-Genzyne, Roche and Jansen. Pablo Gajate declares advisor and delivered lectures for BMS, MSD, Merck Serono, Pfizer, Ipsen, Roche, Adacap, Eisai, Sanofi-Genzyme, Novartis and Jansen. Javier Molina declares consultant, advisory or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, and BMS. Javier Molina has received research grants from Pfizer, IPSEN and Roche. Eva Guerra declares: advisory/consultancy honorarium from AstraZeneca-MSD, Clovis Oncology, GSK-Tesaro, PharmaMar, Roche. Eva Guerra has received speaker bureau/expert testimony honorarium from AstraZeneca, PharmaMar, Roche, GSK; and has received travel/accommodation/expenses from Roche, TESARO, and Baxter. Raquel Fuentes, Beatriz Romero and Mario J Rodriguez-Dominguez have not conflict of interest. Alfredo Carrato has not conflict of interest to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET , NTRK fusions, c-MET alterations, and activating mutations in KRAS , BRAF , and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes., Competing Interests: Conflict-of-interest statement: Xabier Mielgo-Rubio declares the following conflicts of interest: Advisory role; Boehringer-Ingelheim, AstraZeneca, Bristol Myers Squibb. Speakers’ bureau; Roche, AstraZeneca, Bristol Myers Squibb, MSD, Abbott. Research funding; Bristol Myers Squibb. Luis Cabezón-Gutiérrez received speaker or consulting fees from Angelini, Grunenthal, Kyowa Kirin, Mundipharma, Pfizer, Roche, Rovi, Leo Pharma, Merck Serono, Ipsen Pharma, Lilly, Amgen, Boehringer Ingelheim, and AstraZeneca; The remaining authors declare no conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies., Competing Interests: PG declares personal financial interests as advisor for AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol, Gilead, Guardant Health, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Rovi, Sysmex and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corral de la Fuente, Olmedo Garcia, Gomez Rueda, Lage and Garrido.)

Supercritical fluid extraction was applied to the determination of naturally contaminated polycyclic aromatic hydrocarbons (PAHs) in bird tissue by liquid chromatography with fluorescence detection (LC-FL). Recoveries (> 90%) and relative standard deviations (< or = 7.7%) were satisfactory. The levels of 10 PAHs were analyzed in 6 classes of tissues (heart, liver, intestine, muscle, lung, and kidney) of 10 buzzards and 2 tawny owls, predatory birds from the Galicia (northwest Spain). The PAHs found most abundantly were pyrene, fluoranthene, benzo[a]anthracene, and anthracene. Chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[ghi]perylene, and indeno[1,2,3-cd]pyrene were not detected. Intestine, kidney, and lung were more polluted than other tissues.