Non-small cell lung cancer: an update on emerging EGFR-targeted therapies.

INTRODUCTION: Current research in EGFR-mutated NSCLC focuses on the management of drug resistance and uncommon mutations, as well as on the opportunity to extend targeted therapies' field of action to earlier stages of disease. AREAS COVERED: We conducted a review analyzing literature from the PubMed database with the aim to describe the current state of art in the management of EGFR-mutated NSCLC, but also to explore new strategies under investigation. To this purpose, we collected recruiting phase II-III trials registered on Clinicaltrials.govand conducted on EGFR-mutated NSCLC both in early and advanced stage. EXPERT OPINION: With this review, we want to provide an exhaustive overview of current and new potential treatments in EGFR-mutated NSCLC, with emphasis on the most promising newly investigated strategies, such as association therapies in the first-line setting involving EGFR-TKIs and chemotherapy (FLAURA2) or drugs targeting different driver pathways (MARIPOSA). We also aimed at unearthing challenges to achieve in this field, specifically the need to fully exploit already available compounds while developing new ones, the management of new emerging toxicities and the necessity to improve our biological understanding of the disease to design trials with a solid scientific rationale and to allow treatment personalization such in case of uncommon mutations.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Parenchymal lung abnormalities following hospitalisation for COVID-19 and viral pneumonitis: a systematic review and meta-analysis.

INTRODUCTION: Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis. METHODS: Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression. RESULTS: Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (-0.036; 95% CI -0.068 to -0.004; p=0.029), associations with fibrotic sequelae did not reach significance (-0.021; 95% CI -0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864). DISCUSSION: Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity. PROSPERO REGISTRATION NUMBER: CRD42020183139.

Three-Month FVC Change: A Trial Endpoint for Idiopathic Pulmonary Fibrosis Based on Individual Participant Data Meta-analysis.

Rationale: Novel therapies for idiopathic pulmonary fibrosis (IPF) are in development, but there remains uncertainty about the optimal trial endpoint. An earlier endpoint would enable assessment of a greater number of therapies in adaptive trial designs. Objectives: To determine whether short-term changes in FVC, DlCO, and six-minute-walk distance could act as surrogate endpoints to accelerate early-phase trials in IPF. Methods: Individual participant data (IPD) from IPF clinical trials were included in a two-step random-effects meta-analysis to determine whether baseline or 3-month changes in FVC, DlCO, and 6-minute-walk distance were associated with mortality or disease progression in placebo arms. Three-month and 12-month FVC decline endpoints were compared with treatment arm data from antifibrotic studies by meta-regression. Measurements and Main Results: IPD were available from 12 placebo cohorts totaling 1,819 participants, with baseline and 3-month changes in all physiological variables independently associated with poorer outcomes. Treatment data were available from six cohorts with 1,684 participants. For each 2.5% relative decline in FVC over 3 months, there was an associated 15% (adjusted hazard ratio, 1.15; 95% confidence interval [CI], 1.06-1.24; I2 = 59.4%) and 20% (adjusted hazard ratio, 1.20; 95% CI, 1.12-1.28; I2 = 18.0%) increased risk for mortality in untreated and treated individuals, respectively. An FVC change treatment effect was observed between treatment and placebo arms at 3 months (difference in FVC change of 42.9 ml; 95% CI, 24.0-61.8 ml; P < 0.001). Conclusions: IPD meta-analysis demonstrated that 3-month changes in physiological variables, particularly FVC, were associated with mortality among individuals with IPF. FVC change over 3 months may hold potential as a surrogate endpoint in IPF adaptive trials.

3-T magnetic resonance-guided high-intensity focused ultrasound (3 T-MR-HIFU) for the treatment of pain from bone metastases of solid tumors.

INTRODUCTION: Bone metastases (BM) are still the main cause of morbidity and mortality in cancer patients, not only because of their complications, defined as skeletal-related events (SREs), but also because of the negative impact bone pain has on quality of life (QoL) and survival, especially when opioid analgesics and locoregional treatments fail. MATERIALS AND METHODS: A single-center prospective study was carried out on 12 patients with symptomatic BM treated with MRI-guided focused ultrasound (MR-HIFU). The primary endpoint was the effectiveness of MR-HIFU in reducing current and breakthrough cancer pain (BTCP) scores. The main secondary aims were the evaluation of circulating markers at different time-points and their relation to pain and procedure efficacy. Other secondary objectives included temporal evolution of pain response, evaluation of QoL, and side effects of the treatment. Descriptive statistics were used to evaluate primary and secondary endpoints. Questionnaires on pain and QoL completed at baseline and at 30 days were compared using appropriate statistical tests with exploratory intent. RESULTS: MR-HIFU was successfully completed in all 12 patients enrolled between September 2015 and December 2018. On day 30, 6 (50.0%) patients showed a complete response of current pain and 6 a partial response, while 5 (41.7%) obtained a complete BTCP response. A partial response of BM evaluated by MD Anderson criteria was obtained in 9 (81.8%) patients. Only one patient progressed in the target lesion after MR-HIFU. No treatment-related adverse events were recorded. Bone turnover markers CTX/RANK-L (P) do not demonstrate any significant change with the pain or BM response. CONCLUSION: In our patients, targeted therapy of painful BM with MRI-guided focused ultrasound ablation was safe and showed encouraging early-onset and functional results.

Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19.

BACKGROUND: There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19. METHODS: Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality. RESULTS: 71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I2=0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I2=98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I2=76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI -0.07 to 0.80, I2=93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent. CONCLUSION: Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings. PROSPERO REGISTRATION NUMBER: CRD42020176375.

Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.

OBJECTIVE: To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. STUDY DESIGN: Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. RESULTS: Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P < .001) with no statistically significant differences between groups. Rescue surfactant use (19 [33.9%] vs 17 [29.8%]), bronchopulmonary dysplasia (31 [55.4%] and 32 [56.1%]), and mortality at day 28 (4 [7.1%] and 3 [5.3%]) were similar in the CHF5633 and poractant alfa groups, respectively. In 2 (3.4%) and 1 (1.7%) neonates, adverse drug reactions were reported in CHF5633 and poractant alfa groups, respectively. No immunogenicity was detected. CONCLUSIONS: Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02452476.

Ten-year experience of the multidisciplinary Osteoncology Center.

PURPOSE: Bone metastases (BMs) are responsible for high morbidity in patients. A multidisciplinary approach involving a team of specialists offers an effective therapeutic strategy based on disease characteristics, medical history, and performance status. We evaluated the impact of our 10-year multidisciplinary experience on the management of patients with BM. METHODS: We retrospectively analyzed 2194 medical reports of 1628 patients referred to our Osteoncology Center from 2005 to 2015. Cases were discussed weekly by a multidisciplinary team. RESULTS: Eight hundred thirty-eight (38.2%) of the 2194 visits were requested because of a risk of complications from BM. Antiblastic treatment and bone-targeted therapy were modified in 709 (66.3%) and 309 (31%) of cases, respectively. Radiotherapy was scheduled in 220 (20%) of the 1099 patients for whom information was recorded. Patients completed the Brief Pain Inventory (BPI) during their first visit, 1296 (59.1%) reporting pain (median intensity 4), and 537 (41.4%) experiencing a level that interfered substantially with daily activities. New ortheses and/or antalgic therapy was prescribed accordingly. After 7 days, 208 (16%) patients were re-evaluated and a new BPI administered. A significant improvement in the worst (p < 0.0001) and current pain (p = 0.03) was seen, together with a favorable impact on daily activities (p = 0.02). Two thousand fifty-one patients completed an anonymous questionnaire on the quality of the service, the majority (69.4%) expressing high satisfaction. CONCLUSIONS: Our 10-year osteoncology experience confirms the importance of a multidisciplinary approach to optimize BM management. Further evaluations are needed in relation to quality of life, outcome, and costs.

Association between physical activity and functional and cognitive status in nonagenarians: results from the Mugello study.

This study aimed at assessing daily physical activity and its relationship with functional and cognitive status in nonagenarians. Cross-sectional study. 167 nonagenarians (124 women and 43 men, mean age 92 years ± 3) who participated in the Mugello study. Participants underwent daily step count through the SenseWear armband, which was considered as an indicator of physical activity. Other main variables were: handgrip strength, gait speed, depression, cognitive status and quality of life. The median value of steps per day was 883 and 658 in women and men, respectively, with a participant, in the women group, showing values up to 10,000. After adjusting for potential confounders, physical activity remained a significant positive correlate of handgrip strength (r = 0.4), gait speed (r = 0.8), and cognitive status (r = 0.6 and 0.8, respectively for raw scores and for scores adjusted for age and education). On the contrary, physical activity remained a significant negative correlate of depression (r = 0.5). Our results provide quantitative information on daily physical activity and show a significant relationship between daily physical activity and functional and cognitive status in nonagenarians.

Five-country manikin study found that neonatologists preferred using the LISAcath rather than the Angiocath for less invasive surfactant administration.

AIM: Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting. METHODS: This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well-recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10-item questionnaire. RESULTS: The responses to nine of 10 questions showed that 67-95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two-thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath. CONCLUSION: Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin.

Is Less Invasive Surfactant Administration Necessary or "Only" Helpful or Just a Fashion?

In the 1990s, the most relevant pillars in the treatment of neonatal respiratory distress syndrome (RDS) have been improvements in ventilation strategies, the introduction of exogenous surfactant replacement therapy, and the use of antenatal steroids. Lately, in addition to the standard INSURE (INtubation-SURfactant administration-Extubation) method to administer surfactant, a new technique has been gaining increasing popularity. It is the so-called less invasive surfactant administration (LISA) method, which has shown promising results in preventing bronchopulmonary dysplasia development and in reducing mortality in preterm neonates. The rationale behind this technique is to avoid positive pressure ventilation and the endotracheal tube, being surfactant delivered through a thin catheter while the neonate is maintained on continuous positive airway pressure. Given the paucity of large-scale randomized trials on LISA method to prove its effects on short- and long-term outcomes, some questions still remain unanswered. Then, uncertainty regarding the feasibility of this maneuver needs to be better clarified before gaining wide acceptance in routine clinical practice. In our report, we aim at hypothesizing the main mechanisms behind the efficacy of LISA, considering it as a single maneuver in a comprehensive approach for RDS management in the delivery room.

Single bone metastasis from adenocarcinoma of the lacrimal gland: a case report.

Malignant tumors of the lacrimal gland are rare, and single bone metastases from lacrimal gland carcinoma are an exceptional event. We present the case of a 71-year-old man with a history of lumbar pain and left exophthalmos. Surgical resection of the lacrimal lesion and a bone biopsy gave a final histopathological diagnosis of primary ductal adenocarcinoma of the lacrimal gland with bone metastasis. The pathological tissue from both procedures was positive for androgen receptor expression. The patient underwent embolization and radiotherapy in association with total androgen blockade. After 20 months, the patient is still asymptomatic and has maintained the partial response at L1 with no progression to other sites. Our patient would appear to have a better prognosis and the disease a more indolent clinical course than the other cases of ductal adenocarcinoma of the lacrimal gland reported in the literature.

Appropriateness of Mini-Invasive Approaches for Nausea and Vomiting Refractory to Medical Therapy in Palliative Care Setting: A Case Report.

Introduction: Nausea and vomiting are frequent multifactorial symptoms in oncological patients. These manifestations, mainly affecting the advanced disease stages, may lead to existential, psychological, and physical suffering, with a negative impact on the quality of life (QoL) of the individual and his family. The medical approach makes use of a wide range of drugs, with different antiemetic potency and various mechanisms of action, taking into account the etiology and the patient's response to the different therapeutic strategies. In recent years, in addition to pharmacological treatments, some endoscopic procedures have been integrated into clinical practice as promising palliative approaches. Case Presentation: Herein, we describe and discuss a case of a 64-year-old female affected by advanced stage pancreatic adenocarcinoma, in which different techniques - both medical and endoscopic - have been used to approach a refractory symptomatology with a negative impact on the patient's QoL. In the context of a multidisciplinary approach in primary palliative care, a tailored intervention encompassing invasive methods for palliative purposes, may be considered adequate and appropriate when the prognostic expectation and the physical functionality indices allow it. Conclusion: Minimally invasive palliative interventions should be offered to patients with advanced cancer when symptoms become refractory to standard medical therapies, as part of the holistic approach in modern treatments. Therefore, the integration of an early palliative approach into the patient's therapeutic path becomes essential for the management of all the individual's needs.

Mycophenolate and azathioprine efficacy in interstitial lung disease: a systematic review and meta-analysis.

OBJECTIVES: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD. DESIGN: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded. DATA SYNTHESIS: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design. RESULTS: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I2=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence. CONCLUSIONS: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD. PROSPERO REGISTRATION NUMBER: CRD42023423223.

ERS International Congress 2023: highlights from the Interstitial Lung Diseases Assembly.

This article summarises a selection of scientific highlights in the field of interstitial lung diseases (ILDs) presented at the International Congress of the European Respiratory Society in 2023. Translational and clinical studies focused on the whole spectrum of ILDs, from (ultra)rare ILDs to sarcoidosis, ILDs associated with connective tissue disease and idiopathic pulmonary fibrosis. The main topics of the 2023 Congress presentations were improving the diagnostic process of ILDs, better prediction of disease course and investigation of novel treatment options.

Add-on therapy for pulmonary fibrosis, a forthcoming era with implications for practice: the BI 101550 and RELIEF trials.

The therapeutic landscape for idiopathic pulmonary fibrosis (IPF) and progressive fibrosing interstitial lung disease (PFILD) is increasingly complex, with add-on antifibrotic options now in clinical trials, or available for patients progressing on first-line therapy in both conditions. Here, we review two recent trials of potential add-on therapeutic options, the BI 101550 and RELIEF trials. BI 101550 was a phase 2 randomised control trial (RCT) of a novel phosphodiesterase-4 inhibitor in patients with IPF, with a primary end-point of change in forced vital capacity (ΔFVC) (in mL) at 12 weeks. The RELIEF trial was a phase 2 RCT in patients with PFILD, with a primary end-point of ΔFVC (absolute % predicted) over 48 weeks. Whilst the BI 101550 and RELIEF trials showed positive results in their primary end-points, the strengths and weaknesses of both trials are discussed with importance for their interpretation and clinical impact. We review current clinical practice in IPF and PFILD and place the BI101550 and RELIEF trial results in context, highlighting advances and problems with antifibrotic therapies. Commentary on: Richeldi L, et al. Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N Engl J Med 2022; 386: 2178-2187.Behr J, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med 2021; 9: 476-486.