Development and validation of a computed tomography-based immune ecosystem diversity index as an imaging biomarker in non-small cell lung cancer.

OBJECTIVES: To date, there are no data on the noninvasive surrogate of intratumoural immune status that could be prognostic of survival outcomes in non-small cell lung cancer (NSCLC). We aimed to develop and validate the immune ecosystem diversity index (iEDI), an imaging biomarker, to indicate the intratumoural immune status in NSCLC. We further investigated the clinical relevance of the biomarker for survival prediction. METHODS: In this retrospective study, two independent NSCLC cohorts (Resec1, n = 149; Resec2, n = 97) were included to develop and validate the iEDI to classify the intratumoural immune status. Paraffin-embedded resected specimens in Resec1 and Resec2 were stained by immunohistochemistry, and the density percentiles of CD3+, CD4+, and CD8+ T cells to all cells were quantified to estimate intratumoural immune status. Then, EDI features were extracted using preoperative computed tomography to develop an imaging biomarker, called iEDI, to determine the immune status. The prognostic value of iEDI was investigated on NSCLC patients receiving surgical resection (Resec1; Resec2; internal cohort Resec3, n = 419; external cohort Resec4, n = 96; and TCIA cohort Resec5, n = 55). RESULTS: iEDI successfully classified immune status in Resec1 (AUC 0.771, 95% confidence interval [CI] 0.759-0.783; and 0.770 through internal validation) and Resec2 (0.669, 0.647-0.691). Patients with higher iEDI-score had longer overall survival (OS) in Resec3 (unadjusted hazard ratio 0.335, 95%CI 0.206-0.546, p < 0.001), Resec4 (0.199, 0.040-1.000, p < 0.001), and TCIA (0.303, 0.098-0.944, p = 0.001). CONCLUSIONS: iEDI is a non-invasive surrogate of intratumoural immune status and prognostic of OS for NSCLC patients receiving surgical resection. KEY POINTS: • Decoding tumour immune microenvironment enables advanced biomarkers identification. • Immune ecosystem diversity index characterises intratumoural immune status noninvasively. • Immune ecosystem diversity index is prognostic for NSCLC patients.

Robotic-Assisted Lobectomy Favors Early Lung Recovery versus Limited Thoracotomy.

BACKGROUND: Postoperative pulmonary recovery after lobectomy has showed early benefits for the video-assisted thoracoscopic surgery and sparing open techniques over nonsparing techniques. Robotic-assisted procedures offer benefits in term of clinical outcomes, but their advantages on pulmonary recovery and quality of life have not yet been distinctly prospectively studied. METHODS: Eighty-six patients undergoing lobectomy over a period of 29 months were prospectively studied for their pulmonary function recovery and pain score level during the in-hospital stay and at 1, 2, and 6 months. Quality of life was evaluated at 2 and 6 months. Forty-five patients were operated by posterolateral limited thoracotomy and 41 patients by robotic approach. The postoperative analgesia protocol differed for the two groups, being lighter for the robotic group. RESULTS: The pulmonary tests were not significantly different during the in-hospital stay. At 1 month, the forced expiratory volume in 1 second, forced vital capacity, vital capacity, and maximal expiratory pressure were significantly better for the robotic group (p = 0.05, 0.04, 0.05, and 0.02, respectively). There was no significant difference left at 2 and 6 months. Pain intensity was equivalent during the in-hospital stay but was significantly lower for the robotic group at 1 month (p = 0.02). At 2 and 6 months, pain and quality of life were comparable. CONCLUSION: Robotic technique can offer similar pulmonary and pain recovery during the in-hospital stay with a lighter analgesia protocol. It clearly favors the early term recovery compared with the open limited technique. The objective and subjective functional recovery becomes equivalent at 2 and 6 months.

Usefulness of surgical lung biopsies after cryobiopsies when pathological results are inconclusive or show a pattern suggestive of a nonspecific interstitial pneumonia.

BACKGROUND: Although increasing data supports the use of transbronchial lung cryobiopsies (TBLCs) for the diagnosis of diffuse parenchymal lung diseases (DPLDs), its role as an alternative to surgical lung biopsy (SLB) is still under debate. The aim of this study was to assess the benefit of additional SLBs performed in selected patients after TBLCs. METHOD: We conducted a multicentric Belgian prospective trial in which SLBs were performed after TBLCs when the pathological diagnosis was uncertain or if a nonspecific interstitial pneumonia (NSIP) pattern was observed hypothesizing that SLB could provide additional information and that a co-existent UIP pattern could be missed. RESULTS: Eighty-one patients with TBLCs performed for a DPLD were included in the study between April 2015 and December 2019. A specific histological diagnosis was obtained in 52 patients (64%) whereas no pathological diagnosis following TBLCs was obtained in 13 patients (16%) and a pattern suggestive of a NSIP was observed in 16 patients (20%). Fourteen out of these 29 patients had SLBs after TBLCs. SLBs showed a UIP pattern in 11 (79%), a pattern suggestive of a hypersensitivity pneumonitis in two (14%) and a NSIP pattern in one patient (7%). Among the 16 patients with pathological NSIP following TBLCs, six underwent a SLBs showing a UIP in five and confirming a NSIP in one patient only. A retrospective pathological analysis of patients having both procedures showed a lower diagnostic confidence and agreement among pathologists for TBLCs compared to SLBs. Major factors underlying the added value of SLBs were the bigger size of the sample as well as the subpleural localization of the biopsies. CONCLUSIONS: TBLCs are useful in the setting of DPLDs with a good diagnostic yield. However, our study suggests that SLB provides critical additional information in case TBLCs are inconclusive or show a pattern suggestive of a NSIP, questioning the accuracy of TBLC to adequately identify this histological pattern.

Pain, Quality of Life, and Clinical Outcomes after Robotic Lobectomy.

Background To evaluate pulmonary function, pain, and quality of life at midterm after robotic lobectomy performed in a single institution. Methods Sixty-five consecutive patients underwent robotic thoracic surgery over 32 months using a complete four-arm portal technique. Sixty-one patients underwent lobectomies predominantly for stage I non-small cell lung cancer. Pulmonary function tests were repeated at midterm follow-up. Pain and quality of life were evaluated during the follow-up on a subgroup of 39 patients, excluding the learning period. Results At a mean of 7-month follow-up, there was no significant difference in preoperative and midterm postoperative pulmonary function. A total of 62.5% of the patients reported a variable intensity of discomfort or pain at the surgical site, with a mean pain intensity score of 2.1 ± 1.4. Mean pain interference score were weak (1.8 ± 1.9), with patients with moderate pain reporting significantly higher pain interference scores than those with mild pain (p = 0.0025). Only one patient suffered from neuropathic-like pain. Quality of life was globally favorable and related to the pain level, with a significant interference on the physical component. Conclusion Robotic lobectomy does not appear to have an impact on midterm pulmonary function. Persistent postoperative pain is mild, nonneuropathic-like, with weak interference on daily activities. Quality of life is satisfactory but related to the pain level.

Validation of the French version of the Leicester Cough Questionnaire in chronic obstructive pulmonary disease.

Cough is one of the three major symptoms reported by chronic obstructive pulmonary disease (COPD) patients. The Leicester Cough Questionnaire (LCQ) is a questionnaire exploring the impact of cough, but it does not exist in French. The aim of this study was to develop a French version of LCQ and to assess its psychometrics properties. A forward-backward translation process was used to develop the French version of the LCQ. COPD patients completed LCQ and Cough and Sputum Assessment Questionnaire (CASA-Q) to determine concurrent validity, content validity and internal consistency. Two weeks later, the LCQ was repeated to evaluate the reproducibility. Seventy-four COPD patients were recruited. The concurrent validity showed highly significant correlations between all scores of LCQ and CASA-Q (p < 0.001). The content validity was good with domain total scores correlations ranging from 0.918 to 0.953. The LCQ domains and total scores showed a very good internal consistency with Cronbach's α coefficients ranging between 0.802 and 0.917. The test-retest reliability was high in COPD patients with no change in cough. In conclusion, The French version of the LCQ is a valid and reliable instrument to measure health status in COPD patients.

A breath of not so fresh air .

Despite being widely used as a recreational drug, "poppers" lack a legal framework for their delivery. Their composition may vary largely. This report describes a case of severe bronchiolitis following amyl nitrite mixture inhalation. https://bit.ly/3p3S7LM.

Dyspnea could be accurately assessed by a caregiver in hospitalized patients with respiratory diseases: Interrater reliability and agreement study.

BACKGROUND: The perception of dyspnea is a subjective feeling typically self-assessed by the patient. However, the assessment by a caregiver is sometimes required. OBJECTIVES: The primary aim was to compare patient self-assessment and caregiver assessment of dyspnea (interrater reliability) using the modified Borg and visual analog scale (VAS) in hospitalized patients. The secondary aim was to compare dyspnea assessment between the two scales for patients and caregiver (inter-instrument reliability). METHODS: Self-assessment of dyspnea intensity of hospitalized patients with respiratory diseases was compared with caregiver's assessment. Dyspnea intensity was measured using two scales, the modified Borg scale (0-10 scale) and the 10 cm VAS. Mean difference and 95% confidence interval (CI) between assessors (i.e. patient versus caregiver) were calculated for each scale. Inter- and intra-rater reliability was calculated using intraclass correlation coefficients (ICCs). RESULTS: A total of 254 patients were recruited. The mean differences between patient and caregiver ratings were 0.31 (95% CI: 0.09, 0.53) for the modified Borg scale and 0.36 (95% CI: 0.06, 0.65) for the VAS scale. Interrater reliability was good for both scales with ICC of 0.79 (95% CI: 0.73, 0.84) for VAS and 0.82 (95% CI: 0.77, 0.86) for the modified Borg scale. The mean differences in scores between scales were 0.93 (95% CI 0.69, 1.17) for patients' ratings and 0.88 (95% CI 0.72, 1.04) for caregiver's rating. The inter-instrument reliability was moderate to good and similar for both assessors. CONCLUSION: Dyspnea can be accurately estimated by caregivers when patients with lung diseases cannot self-report. Scores on the VAS to rate dyspnea were higher than the scores on the Borg scale.

Real-World Treatment Patterns, Epidermal Growth Factor Receptor (EGFR) Testing and Outcomes in EGFR-Mutated Advanced Non-small Cell Lung Cancer Patients in Belgium: Results from the REVEAL Study.

BACKGROUND: Treatment of patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) continues to evolve expeditiously. OBJECTIVES: This retrospective study investigated real-world treatment patterns and EGFR mutation testing in patients with EGFRm advanced NSCLC in Belgium. METHODS: Data were extracted from medical records of adults diagnosed with EGFRm locally advanced/metastatic NSCLC between 1 September 2015 and 31 December 2017. Patients were followed retrospectively from diagnosis until 1 September 2018, end of clinical activity or death. Data on demographics, patient outcomes and disease characteristics, treatment patterns and EGFR mutation testing at diagnosis and progression were analyzed descriptively. RESULTS: A total of 141 patients were enrolled. At diagnosis, median age was 69 years, 63.1% were female, 88.7% had metastatic disease, 94.3% had adenocarcinoma histology, 76.6% had ECOG 0/1, 70.9% had common EGFR mutations and 29.1% had only rare mutations. In first line, 73.8% of patients received first/second-generation EGFR-tyrosine kinase inhibitors (1G/2G EGFR-TKIs), while 21.9% received other systemic treatments. Among 61 patients progressing on and discontinuing a first 1G/2G EGFR-TKI, 45 (73.8%) received subsequent systemic treatment while 16 (26.2%) did not; 20 (32.8%) received osimertinib. Among 65 patients progressing on a first 1G/2G EGFR-TKI, 47 (72.3%) were tested for T790M, of whom 25 (53.2%) were positive. CONCLUSION: These real-world data from Belgium show that a substantial fraction of patients with EGFRm NSCLC do not receive 1G/2G EGFR-TKIs in first line and do not receive subsequent systemic treatment after progression on 1G/2G EGFR-TKIs. Only a third receive osimertinib upon progression on 1G/2G EGFR-TKIs. These observations should be considered in first-line treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03761901-December 3, 2018.

Real-life prevalence of progressive fibrosing interstitial lung diseases.

The concept of progressive fibrosing interstitial lung disease (PF-ILD) has recently emerged. However, real-life proportion of PF-ILDs outside IPF is still hard to evaluate. Therefore, we sought to estimate the proportion of PF-ILD in our ILD cohort. We also determined the proportion of ILD subtypes within PF-ILD and investigated factors associated with PF-ILDs. Finally, we quantified interobserver agreement between radiologists for the assessment of fibrosis. We reviewed the files of ILD patients discussed in multidisciplinary discussion between January 1st 2017 and December 31st 2019. Clinical data, pulmonary function tests (PFTs) and high-resolution computed tomography (HRCTs) were centrally reviewed. Fibrosis was defined as the presence of traction bronchiectasis, reticulations with/out honeycombing. Progression was defined as a relative forced vital capacity (FVC) decline of ≥ 10% in ≤ 24 months or 5% < FVC decline < 10% and progression of fibrosis on HRCT in ≤ 24 months. 464 consecutive ILD patients were included. 105 had a diagnosis of IPF (23%). Most frequent non-IPF ILD were connective tissue disease (CTD)-associated ILD (22%), hypersensitivity pneumonitis (13%), unclassifiable ILD (10%) and sarcoidosis (8%). Features of fibrosis were common (82% of CTD-ILD, 81% of HP, 95% of uILD). After review of HRCTs and PFTs, 68 patients (19% of non-IPF ILD) had a PF-ILD according to our criteria. Interobserver agreement for fibrosis between radiologists was excellent (Cohen's kappa 0.86). The main diagnosis among PF-ILD were CTD-ILD (36%), HP (22%) and uILD (20%). PF-ILD patients were significantly older than non-F-ILD (P = 0.0005). PF-ILDs represent about 20% of ILDs outside IPF. This provides an estimation of the proportion of patients who might benefit from antifibrotics. Interobserver agreement between radiologists for the diagnosis of fibrotic ILD is excellent.

Real life safety and effectiveness of nivolumab in older patients with non-small cell lung cancer: Results from the Belgian compassionate use program.

OBJECTIVES: To compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS). METHODS: We performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged ≥70 years and < 70 years and between ECOG-PS 0/1 and ≥ 2. RESULTS: A total of 324 patients with NSCLC were included. There was no significant difference between older (≥70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1;7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p = 0,638). Patients with an ECOG-PS ≥2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0-1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p = 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p < 0.001 respectively). No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p = 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p = 0.009) but no difference in grade 3/4 AEs was observed (p = 0.406) compared to ECOG-PS ≥2. CONCLUSION: This real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status.

Multidisciplinary management of interstitial lung diseases: A real-life study.

BACKGROUND: The guidelines on idiopathic pulmonary fibrosis (IPF) diagnosis established the crucial role of multidisciplinary discussion (MDD) in the diagnosis of interstitial lung diseases (ILD). However, real-life evaluation of MDD remains scarce. Our aim was to study the impact of a well-structured MDD on etiological assessment, diagnosis, and management of ILD. METHODS: We collected and analysed all relevant data on patients concerning diagnosis and treatment before and after MDD during the year 2017. RESULTS: One hundred fifty patients were included in the analysis. MDD had a significant impact on management: 42% of diagnoses were revised and the number of unclassifiable ILD was significantly reduced. Lung biopsy was performed in 26 patients (12 cryobiopsies and 14 surgical biopsies). The most prevalent diagnoses were connective-tissue disease associated ILD (32%), idiopathic pulmonary fibrosis (23%), hypersensitivity pneumonitis (13%) and granulomatous ILD (7%). MDD led to a change or initiation of treatment in 55% of cases. Nine patients were evaluated for transplantation, 23 patients were screened for academic or sponsored clinical trials and an 8-fold increase in rehabilitation inclusion was observed. CONCLUSION: Our results confirm the benefits of MDD on ILD management and diagnosis. MDD also facilitates access to non-pharmacological therapies and clinical trials.

Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

OBJECTIVES: To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function. METHODS: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function. RESULTS: Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs. CONCLUSIONS: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.

A Multicenter Study to Assess EGFR Mutational Status in Plasma: Focus on an Optimized Workflow for Liquid Biopsy in a Clinical Setting.

A multicenter study was performed to determine an optimal workflow for liquid biopsy in a clinical setting. In total, 549 plasma samples from 234 non-small cell lung cancer (NSCLC) patients were collected. Epidermal Growth Factor Receptor (EGFR) circulating cell-free tumor DNA (ctDNA) mutational analysis was performed using digital droplet PCR (ddPCR). The influence of (pre-) analytical variables on ctDNA analysis was investigated. Sensitivity of ctDNA analysis was influenced by an interplay between increased plasma volume (p < 0.001) and short transit time (p = 0.018). Multistep, high-speed centrifugation both increased plasma generation (p < 0.001) and reduced genomic DNA (gDNA) contamination. Longer transit time increased the risk of hemolysis (p < 0.001) and low temperatures were shown to have a negative effect. Metastatic sites were found to be strongly associated with ctDNA detection (p < 0.001), as well as allele frequency (p = 0.034). Activating mutations were detected in a higher concentration and allele frequency compared to the T790M mutation (p = 0.003, and p = 0.002, respectively). Optimization of (pre-) analytical variables is key to successful ctDNA analysis. Sufficient plasma volumes without hemolysis or gDNA contamination can be achieved by using multistep, high-speed centrifugation, coupled with short transit time and temperature regulation. Metastatic site location influenced ctDNA detection. Finally, ctDNA levels might have further value in detecting resistance mechanisms.

Influence of Different Kinds of Music on Walking in Children.

PURPOSE: The aim of this study was to evaluate the effect of different kinds of music on submaximal performance and exercise tolerance in healthy children by means of the 6-minute walking test (6MWT) and to explore the influence of gender. DESIGN: Cross-over study. METHOD: Ninety-seven children performed 6MWT in four conditions (without music, with their preferred music, with slow and with fast music). Distance, cardio-respiratory parameters, perceived exertion rate, and amount of dyspnea were measured. FINDINGS: Walked distance depended on the kind of music (p = .022). To listen to fast music promoted a longer distance when compared with slow music. Walked distance was not influenced by gender (p = .721) and there was no interaction between music and gender for walked distances (p = .069). The other parameters were not modified by music and gender. CONCLUSION: Music influences submaximal performances without modifying exercise tolerance in healthy children. CLINICAL RELEVANCE: Music does modify submaximal performance in children.

Role of Transbronchial Lung Cryobiopsies in Diffuse Parenchymal Lung Diseases: Interest of a Sequential Approach.

Background. Transbronchial lung cryobiopsies (TBLCs) are a promising diagnostic tool in the setting of diffuse parenchymal lung diseases (DPLDs). However, no comparison with surgical lung biopsy (SLB) in the same patient is available. Methods. The diagnostic yield and safety data of TBLCs, as well as the result of SLB performed after TBLCs, were analysed in a multicentric Belgian study. A SLB was performed after TBLCs in absence of a definite pathological diagnosis or if a NSIP pattern was observed without related condition identified following multidisciplinary discussion. Results. Between April 2015 and November 2016, 30 patients were included. Frequent complications included pneumothorax (20%) and bleeding (severe 7%, moderate 33%, and mild 53%). There was no mortality. The overall diagnostic yield was 80%. A SLB was performed in six patients (three without definite histological pattern and three with an NSIP). The surgical biopsy changed the pathological diagnosis into a UIP pattern in five patients and confirmed a NSIP pattern in one patient. Conclusion. TBLCs are useful in the diagnostic work-up of DPLDs avoiding a SLB in 80% of the patients. However, surgical biopsies, performed as a second step after TBLCs because of an indefinite diagnosis or a NSIP pattern, provide additional information supporting the interest of a sequential approach in these patients.

A distância entre o domicílio e o centro de reabilitação não influencia a adesão ao programa de reabilitação pulmonar: um estudo retrospectivo / Distance from home to rehabilitation center did not influence adherence to pulmonary rehabilitation program: a retrospective study

Background: Adherence to treatment is critical when dealing with chronic diseases. One of the difficulties in maintain long-term adherence is the distance from home to rehabilitation center. Objective: To determine the influence of the distance from subjects' residence to rehabilitation center on adherence of a 12-week pulmonary rehabilitation program in chronic respiratory disease. Methods: This retrospective study analyzed patients' medical records with chronic respiratory diseases from a pulmonary rehabilitation center. Driving distance between patients' home and rehabilitation center was calculated with Google maps. The home-rehabilitation center distances were classified in three levels: up to 10, 10-30 and more than 30 km. Results: 280 medical records from patients with chronic pulmonary diseases with medical indication to follow the pulmonary rehabilitation program were found and 148 medical records were included in our study. Out of them, the majority (n = 93) had chronic obstructive pulmonary disease (COPD). Seventy percent of patients lived up to 10 km, 24% lived between 10 and 30 km and 6% lived more than 30 km. No difference in adherence was found comparing the three groups based on the distance from home to rehabilitation center. Conclusion: In this study, distance between home and rehabilitation center did not influence adherence to pulmonary rehabilitation program. (AU)