Advances in Immunotherapy for Malignant Pleural Mesothelioma: From Emerging Strategies to Translational Insights.

MPM stands as a rare malignancy necessitating improved therapeutic strategies due to its limited treatment choices and unfavorable prognosis. The advent of immune checkpoint inhibitors has heralded a paradigm shift in the therapeutic landscape of MPM, offering promising avenues across diverse clinical scenarios. In the context of advanced stages of the disease, Immune check-point inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-as-sociated protein 4 (CTLA-4), have exhibited encouraging potential in clinical trials, particularly manifesting efficacy among patients exhibiting disease progression following chemotherapy regimens. Innovative combination regimens, exemplified by the concurrent administration of nivolumab and ipilimumab, have demonstrated marked improvement in survival and patient's benefits. A deeper comprehension of the intricate genetic underpinnings of MPM, encompassing key mutations such as cyclin-dependent kinase inhibitor 2A (CDKN2A), neurofibromin 2 (NF2), and BRCA1-associated protein 1 (BAP1) mutations, has elucidated novel avenues for targeted therapeutic interventions. This review accentuates the transformative capacity of immunotherapy in revolutionizing the therapeutic outlook for MPM, thereby potentially translating into augmented survival rates and offering glimpses of new approaches on the horizon. Despite the persisting challenges, the synergistic crossroads of interdisciplinary research and collaborative clinical endeavors portend a hopeful landscape for MPM treatment.

El mesotelioma pleural maligno (MPM) es una neoplasia poco frecuente que requiere una mejora de las estrategias terapéuticas debido a sus limitadas opciones de tratamiento y a su pronóstico desfavorable. La llegada de los inhibidores de los puntos de control inmunitario ha supuesto un cambio de paradigma en el panorama terapéutico del MPM, ofreciendo vías prometedoras en diversos escenarios clínicos. En el contexto de los estadios avanzados de la enfermedad, los inhibidores de puntos de control inmunitario dirigidos contra la proteína de muerte celular programada 1 (PD-1) y la proteína 4 asociada a los linfocitos T citotóxicos (CTLA-4) han mostrado un potencial alentador en los ensayos clínicos, sobre todo por su eficacia en los pacientes con progresión de la enfermedad tras los regímenes de quimioterapia. Los regímenes combinados innovadores, ejemplificados por la administración concurrente de nivolumab e ipilimumab, han demostrado una mejora significativa de la supervivencia y de los beneficios para los pacientes. Una comprensión más profunda de los complejos fundamentos genéticos del MPM, que abarca mutaciones clave como el inhibidor de la cinasa dependiente de ciclina 2A (CDKN2A), la neurofibromina 2 (NF2) y las mutaciones de la proteína 1 asociada a BRCA1 (BAP1), ha dilucidado nuevas vías para el desarrollo de intervenciones terapéuticas dirigidas. Esta revisión acentúa la capacidad transformadora de la inmunoterapia para revolucionar las perspectivas terapéuticas en el MPM, lo que podría traducirse en un aumento de las tasas de supervivencia y ofrecer nuevos enfoques terapéuticos en el horizonte próximo. A pesar de los retos persistentes, el cruce sinérgico de la investigación interdisciplinar y los esfuerzos clínicos de colaboración auguran un panorama esperanzador en el tratamiento de los MPM.

Biological treatments in childhood asthma.

PURPOSE OF REVIEW: The aim is to update the information currently available for the use of biologics in severe asthma in children, in order to facilitate their prescription as far as possible. RECENT FINDINGS: The appearance of biologics for the treatment of severe asthma has meant a revolutionary change in the therapeutic approach to this disease. Currently, five biologics have been approved for severe asthma in children and/or adolescents by the regulatory agencies: omalizumab, mepolizumab, benralizumab, dupilumab and tezepelumab. But despite their positive results in terms of efficacy, there are still relevant points of debate that should induce caution when selecting the most appropriate biologic in a child with severe asthma. Indeed, safety is essential and, for several of the existing treatments, the availability of medium-term to long-term data in this regard is scarce. SUMMARY: The use of biologics can facilitate the therapeutic paradigm shift from pleiotropic treatments to personalized medicine. However, the choice of the most appropriate biologics remains a pending issue. On the other hand, to the extent that several of the biologics have been available for a relatively short time, the most robust evidence in terms of efficacy and safety in children is that of omalizumab.

Multidisciplinary approach for locally advanced non-small cell lung cancer (NSCLC): 2023 expert consensus of the Spanish Lung Cancer Group GECP.

INTRODUCTION: Recent advances in the treatment of locally advanced NSCLC have led to changes in the standard of care for this disease. For the selection of the best approach strategy for each patient, it is necessary the homogenization of diagnostic and therapeutic interventions, as well as the promotion of the evaluation of patients by a multidisciplinary oncology team. OBJECTIVE: Development of an expert consensus document with suggestions for the approach and treatment of locally advanced NSCLC leaded by Spanish Lung Cancer Group GECP. METHODS: Between March and July 2023, a panel of 28 experts was formed. Using a mixed technique (Delphi/nominal group) under the guidance of a coordinating group, consensus was reached in 4 phases: 1. Literature review and definition of discussion topics 2. First round of voting 3. Communicating the results and second round of voting 4. Definition of conclusions in nominal group meeting. Responses were consolidated using medians and interquartile ranges. The threshold for agreement was defined as 85% of the votes. RESULTS: New and controversial situations regarding the diagnosis and management of locally advanced NSCLC were analyzed and reconciled based on evidence and clinical experience. Discussion issues included: molecular diagnosis and biomarkers, radiologic and surgical diagnosis, mediastinal staging, role of the multidisciplinary thoracic committee, neoadjuvant treatment indications, evaluation of response to neoadjuvant treatment, postoperative evaluation, and follow-up. CONCLUSIONS: Consensus clinical suggestions were generated on the most relevant scenarios such as diagnosis, staging and treatment of locally advanced lung cancer, which will serve to support decision-making in daily practice.

[Questions and Answers in Lung Cancer]. / Preguntas y respuestas en cáncer de pulmón.

Over the past 2 decades, scientific evidence has strongly supported the use of low-radiation dose chest computed tomography (CT) as a screening technique for lung cancer. This approach has resulted in a significant reduction in mortality rates by enabling the detection of early-stage lung cancer amenable to potentially curative treatments. Regarding diagnosis, there are also novel methods under study, such as liquid biopsy, identification of the pulmonary microbiome, and the use of artificial intelligence techniques, which will play a key role in the near future. At present, there is a growing trend towards less invasive surgical procedures, such as segmentectomy, as an alternative to lobectomy. This procedure is based on 2 recent clinical trials conducted on peripheral tumors measuring less than 2 cm. Although these approaches have demonstrated comparable survival rates, there remains controversy due to uncertainties surrounding recurrence rates and functional capacity preservation. With regard to adjuvant therapy, immunotherapy, either as a monotherapy or in conjunction with chemotherapy, has shown encouraging results in resectable stages of locally advanced lung cancer, demonstrating complete pathologic responses and improved overall survival.After surgery treatment, despite the lack of solid evidence for long-term follow-up of these patients, clinical practice recommends periodic CT scans during the early years.In conclusion, there have been significant advances in lung cancer that have improved diagnostic techniques using new technologies and screening programs. Furthermore, the treatment of lung cancer is increasingly personalized, resulting in an improvement in the survival of patients.

Outcomes of Surgery for Metachronous Second Primary Non-small Cell Lung Cancer.

OBJECTIVE: The optimal surgical approach for second primary metachronous lung cancer (MPLC) remains unclear. Our aim is to evaluate the morbidity and prognostic value based on the extent of surgical resection in MPLC. METHODS: Retrospective study of 84 patients with a history of anatomical resection for lung cancer and MPLC surgically treated between January 2010 and December 2020. RESULTS: The interval between the initial primary tumor and the second was 50.38±32.89 months. The second resection was contralateral in 43 patients (51.2%) and ipsilateral in 41 (48.8%). Thirty-six patients (42.9%) underwent a second anatomical resection, and in 48 patients (57.1%), it was non-anatomical. Postoperative complications were observed in 29 patients (34.5%) after the second lung resection. According to the Clavien-Dindo classification, 95.2% were mild (Clavien-Dindo I-II), and a single patient died (1.2%) in the postoperative period (Grade V). Prolonged air leak (p=0.037), postoperative arrhythmias (p=0.019) and hospital stay showed significant differences depending on the extent of surgery in ipsilateral resections. The main histological type was adenocarcinoma (47.6%) and the median tumor size was 17.74±11.74mm. The overall survival was 58.07 months (95% CI 49.29-66.85) for patients undergoing anatomical resection and 50.97 months (95% CI 43.31-58.63) for non-anatomical without significant differences (p=0.144). The disease-free survival after the second surgery was 53.75 months (95% CI 45.28-62.23) for anatomical resection and 41.34 months (95% CI 33.04-49.65) for non-anatomical group. CONCLUSION: Second anatomical resections provide good long-term outcomes and have been shown to provide better disease-free survival compared to non-anatomical resections in properly selected patients.

Epidemiological impacts of attenuated African swine fever virus circulating in wild boar populations.

African swine fever virus (ASFV) genotype II has been present in wild boar in the European Union since 2014. Control measures have reduced the incidence of the ASF, but highly virulent as well as attenuated ASFV strains continue to circulate. We present the intraherd epidemiological parameters of low and highly virulent ASFV in wild boar from experimental data, and for the first time, evaluate the impact of attenuated strain circulation through unique deterministic compartmental model simulations under various potential scenarios and hypotheses. Using an estimated PCR infectious threshold of TPCR = 36.4, we obtained several transmission parameters, like an Rx (experimental intraherd R0) value of 4.5. We also introduce two novel epidemiological parameters: infectious power and resistance power, which indicate the ability of animals to transmit the infection and the reduction in infectiousness after successive exposures to varying virulence strains, respectively. The presence of ASFV attenuated strains results in 4-17% of animals either remaining in a carrier state or becoming susceptible again when exposed to highly virulent ASFV for more than two years. The timing between exposures to viruses of different virulence also influences the percentage of animals that die or remain susceptible. The findings of this study can be utilized in epidemiological modelling and provide insight into important risk situations that should be considered for surveillance and future potential ASF vaccination strategies in wild boar.

Disentangling the role of virus infectiousness and awareness-based human behavior during the early phase of the COVID-19 pandemic in the European Union.

In this work, we manage to disentangle the role of virus infectiousness and awareness-based human behavior in the COVID-19 pandemic. Using Bayesian inference, we quantify the uncertainty of a state-space model whose propagator is based on an unusual SEIR-type model since it incorporates the effective population fraction as a parameter. Within the Markov Chain Monte Carlo (MCMC) algorithm, Unscented Kalman Filter (UKF) may be used to evaluate the likelihood approximately. UKF is a suitable strategy in many cases, but it is not well-suited to deal with non-negativity restrictions on the state variables. To overcome this difficulty, we modify the UKF, conveniently truncating Gaussian distributions, which allows us to deal with such restrictions. We use official infection notification records to analyze the first 22 weeks of infection spread in each of the 27 countries of the European Union (EU). It is known that such records are the primary source of information to assess the early evolution of the pandemic and, at the same time, usually suffer underreporting and backlogs. Our model explicitly accounts for uncertainty in the dynamic model parameters, the dynamic model adequacy, and the infection observation process. We argue that this modeling paradigm allows us to disentangle the role of the contact rate, the effective population fraction, and the infection observation probability across time and space with an imperfect first principles model. Our findings agree with phylogenetic evidence showing little variability in the contact rate, or virus infectiousness, across EU countries during the early phase of the pandemic, highlighting the advantage of incorporating the effective population fraction into pandemic modeling for heterogeneity in both human behavior and reporting. Finally, to evaluate the consistency of our data assimilation method, we performed a forecast that adequately fits the actual data. Statement of significance: Data-driven and model-based epidemiological studies aimed at learning the number of people infected early during a pandemic should explicitly consider the behavior-induced effective population effect. Indeed, the non-isolated, or effective, fraction of the population during the early phase of the pandemic is time-varying, and first-principles modeling with quantified uncertainty is imperative for an adequate analysis across time and space. We argue that, although good inference results may be obtained using the classical SEIR type model, the model posed in this work has allowed us to disentangle the role of virus infectiousness and awareness-based human behavior during the early phase of the COVID-19 pandemic in the European Union from official infection notification records.

Cost-effectiveness of omalizumab for the treatment of severe pediatric allergic asthma-Results of a real-life study in Spain.

BACKGROUND: Severe pediatric allergic asthma (SPAA) induces a huge economic burden in terms of direct, indirect, and intangible costs. The use of omalizumab for the treatment of these patients has produced a significant improvement in several clinical outcomes, but at the same time, the cost for the management of the disease has also increased. The aim of this report was to evaluate whether the use of omalizumab is cost-effective. METHODS: A sample of 426 children with SPAA from the ANCHORS (Asthma iN CHildren: Omalizumab in Real-life in Spain) study was used to calculate the incremental cost-effectiveness ratio (ICER) for the avoidance of moderate-to-severe exacerbations (MSE) and also for the improvement in childhood Asthma Control Test (c-ACT) or the Asthma Control Questionnaire (ACQ5). We retrospectively collected data on health encounters and drug consumption before and up to 6 years after the beginning of the treatment with omalizumab. RESULTS: The ICER per avoided MSE was €2107 after 1 year, and it consistently decreased to €656 in those followed up to 6 years. Similarly, the ICER for the minimally important difference in control tests showed a decrease from €2059 to €380 per each 0.5 points of improvement in ACQ5 and from €3141 to €2322 per each 3 points improvement in c-ACT, at years 1 and 6, respectively. CONCLUSION: The use of OMZ is a cost-effective option for most children with uncontrolled SPAA, especially those who have frequent exacerbations; the costs are progressively reduced in successive years of treatment.

Higher plasma levels of thymosin-α1 are associated with a lower waning of humoral response after COVID-19 vaccination: an eight months follow-up study in a nursing home.

BACKGROUND: Older people achieve lower levels of antibody titers than younger populations after Covid-19 vaccination and show a marked waning humoral immunity over time, likely due to the senescence of the immune system. Nevertheless, age-related predictive factors of the waning humoral immune response to the vaccine have been scarcely explored. In a cohort of residents and healthcare workers from a nursing home that had received two doses of the BNT162b2 vaccine, we measured specific anti-S antibodies one (T1), four (T4), and eight (T8) months after receiving the second dose. Thymic-related functional markers, including thymic output, relative telomere length, and plasma thymosin-α1 levels, as well as immune cellular subsets, and biochemical and inflammatory biomarkers, were determined at T1, and tested for their associations with the magnitude of the vaccine response (T1) and the durability of such response both, at the short- (T1-T4) and the long-term (T1-T8). We aimed to identify age-related factors potentially associated with the magnitude and persistence of specific anti-S immunoglobulin G (IgG)-antibodies after COVID-19 vaccination in older people. RESULTS: Participants (100% men, n = 98), were subdivided into three groups: young (< 50 years-old), middle-age (50-65 years-old), and older (≥65 years-old). Older participants achieved lower antibody titers at T1 and experienced higher decreases in both the short- and long-term. In the entire cohort, while the magnitude of the initial response was mainly associated with the levels of homocysteine [ß (95% CI); - 0.155 (- 0.241 to - 0.068); p = 0.001], the durability of such response at both, the short-term and the long-term were predicted by the levels of thymosin-α1 [- 0.168 (- 0.305 to - 0.031); p = 0.017, and - 0.123 (- 0.212 to - 0.034); p = 0.008, respectively]. CONCLUSIONS: Higher plasma levels of thymosin-α1 were associated with a lower waning of anti-S IgG antibodies along the time. Our results suggest that plasma levels of thymosin-α1 could be used as a biomarker for predicting the durability of the responses after COVID-19 vaccination, possibly allowing to personalize the administration of vaccine boosters.

Factors associated with the humoral response after three doses of COVID-19 vaccination in kidney transplant recipients.

Introduction: Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients. Methods: To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response. Results: Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses. Discussion: In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.

Presbycusis and balance disorders in the elderly. Bibliographical review of ethiopathogenic aspects, consequences on quality of life and positive effects of its treatment.

At this time, we still do not have adequate knowledge and awareness of the consequences of hearing loss in the elderly on quality of life. Similarly, there is also insufficient information on the relationship of presbycusis and balance disorders with other comorbidities. Such knowledge can contribute to improve both prevention and treatment of these pathologies, to reduce their impact on other areas such as cognition or autonomy, as well as to have more accurate information on the economic impact they generate in society and in the health system. Therefore, with this review article we aim to update the information on the type of hearing loss and balance disorders in people over 55 years of age, and their associated factors; to analyze the impact on the quality of life of these people and the one which can be generated at a personal and population level (both sociological and economic) if an early intervention in these patients is pursued.

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Background: Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. Methods: In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. Results: We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Conclusions: Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

Spanish Society of Thoracic Surgery (SECT) consensus document. Long-term follow-up for operated patients with lung cancer.

The most effective treatment for lung cancer is complete lung resection, although recurrences reach up to 10% and the appearance of second neoplasms, up to 6%. Therefore, the follow-up of these patients will be essential for the early detection and treatment of these events; however there is no definition of the form, time and cadence of these follow-ups. In this consensus document, we try to define them based on the available scientific evidence. A critical review of the literature is carried out (meta-analysis, systematic reviews, reviews, consensus recommendations of scientific societies, randomized controlled studies, non-randomized controlled studies, observational studies and case series studies) and communications to the main congresses on oncology and thoracic surgery in Spanish, English and French. The evidences found are classified following the GRADE system. It is defined according to the existing evidence that the patient resected for lung cancer should be followed up, as well as that this follow-up should be close during the first years and with CT (not being necessary to follow up with PET-CT, biomarkers or bronchoscopy). Cessation of smoking is also recommended in this follow-up.

Impact of neoadjuvant therapy on postoperative complications in non-small-cell lung cancer patients subjected to anatomic lung resection.

OBJECTIVE: To study the impact of neoadjuvant therapies on postoperative complications and mortality among non-small-cell lung cancer (NSCLC) patients subjected to anatomic lung resection and included in the Spanish cohort of the video-assisted thoracic surgery (GE-VATS) multicenter database. METHODS: The study included a total of 3085 patients from 33 centers between December 2016 and March 2018. We performed a comparative analysis of the complications and mortality in patients who received neoadjuvant therapies (n = 263) versus those who did not (n = 2822). A propensity score-matched analysis was used to adjust for potential confounders. Association between exposure in two groups and outcomes were estimated by logistic regression weighted by inverse of probability of receiving the treatment that actually received. RESULTS: In the unadjusted analysis, the chemotherapy (CT) and chemoradiotherapy (CRT) group presented a higher frequency of ICU readmissions, reinterventions, empyema, cardiovascular complications, a greater frequency of atrial fibrillation, and an increased need for blood product transfusions. In the adjusted group, CT and CRT patients had a higher rate of cardiovascular complications (CT p = 0.002; OR 2.29; 95% CI 1.34-3.94 and CRT p = 0.001; OR 2.90; 95% CI 1.52-5-52), arrhythmias (CT p = 0.013; OR 2.23; 95% CI 1.18-4.20 and CRT p = 0.046; OR 2.22; 95% CI 1.01-4.90) and transfussions (CT p = 0.042; OR 2.95; 95% CI 1.04-8.35 and CRT p < 0.001; OR 7.74; 95% CI 3.01-19-92). CONCLUSIONS: Based on our series, neoadjuvant CT and CRT were associated with a higher rate of cardiovascular complications, arrhythmias and transfussions in patients with NSCLC subjected to anatomic lung resection.