Introduction Primary spontaneous pneumothorax (PSP) patients are probably exposed to a high burden of radiation. Reference values for chest x-ray and high-resolution computed tomography (HRCT) are 0.04 mSv resp. 3.6 mSv These patients are usually young and radiation exposure can be harmful. Aim and objectives The aim of this study is to analyze the amount of radiation exposure in PSP patients during the first event and subsequent episodes. Methods Patients with PSP were retrospectively analyzed for the number of chest x-rays and chest CT scans related to the diagnosis and treatment of the pneumothorax in an academic (Leiden University Medical Center) and a teaching hospital (Alrijne) in the Netherlands. The number of imaging studies was counted for the first episode and all subsequent episodes of ipsilateral and contralateral recurrence. Results From January 2015 till December 2022 the medical files of 257 primary spontaneous pneumothorax patients were analyzed, 142 patients in the academic center and 115 in the teaching hospital. An average number of 20 chest x-rays were performed per patient in the academic center and 16 in the teaching hospital. In the academic center half of these patients received one or more chest CT scans. In the teaching hospital one or more chest CT were performed in 42 percent of all pneumothorax patients. Conclusions These findings suggest that the current procedure results in high radiation exposure in PSP patients. Aims to reduce recurrence by smoking cessation, pleurodesis in cases at high risk for recurrence (such as Birt-Hogg-Dubé patients and patients with extensive blebs and bullae) 1,2, as well as other techniques to monitor the efficacy of chest tube drainage such as ultrasound need to be evaluated 3-4. In addition the use of low-dose CT (0.6mSv) needs to be evaluated at the time of diagnosis to evaluate the risk of recurrence at the earliest possible stage. References 1. Ann Am Thorac Soc 2017 May;14(5):706-713 2. Ann Thorac Surg 2013;95:249-56 3. Critical Care 2013; 17(5): R208 4.Chest 2011;140:859-66

Lymph node micrometastases could be one of the reasons for the high recurrence rate after complete surgical resection in stage I–IIIA non‐small cell lung cancer (NSCLC). The standard evaluation of a single haematoxylin and eosin (H&E) slide of a paraffin‐embedded section of a lymph node is insufficient for the detection of micrometastases, and there is a need for additional histopathological evaluation. The association of lymph node micrometastases with survival remains as yet unresolved. The aim of this systematic review and meta‐analysis is to investigate if lymph node micrometastases and isolated tumour cells in patients with stage I–IIIA NSCLC, detected with multiple sectioning and/or immunohistochemistry (IHC) and/or reverse transcriptase polymerase chain reaction (RT‐PCR), are associated with overall survival (OS) and disease‐free survival (DFS) after surgical resection. We performed a meta‐analysis of time‐to‐event outcomes based on 15 articles using ancillary techniques to detect micrometastases. We extracted the OS and DFS every 3–6 months after surgery, for patients with and without occult lymph node micrometastasis, from the survival curves published in each article. These data were used to reconstruct OS and DFS for ‘micrometastasis’ and ‘no micrometastasis’ groups. Based on all included studies that used IHC, serial sectioning, or RT‐PCR, we found a 5‐year OS of 55% (micrometastasis) vs. 75% (no micrometastasis), and a 5‐year DFS of 53% (micrometastasis) vs. 75% (no micrometastasis). Patients with stage I–IIIA NSCLC with lymph node micrometastases detected by ancillary histopathological and molecular techniques have a significantly poorer OS and DFS compared to patients without lymph node micrometastases.

Supplementary Data from Color Fluorescence Ratio for Detection of Bronchial Dysplasia and Carcinoma In situ

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

Introduction: Investigation to diagnose Birt-Hogg-Dubé (BHD) syndrome in spontaneous pneumothorax (SP) patients is no routine despite that the prevalence of BHD may be as high as 5-10 percent1. The lifetime risk in BHD patients for renal cell cancer is high (up to 35%)2 and may therefore justify screening for BHD in SP patients. Furthermore, for each affected SP patient 3-4 affected family members were found. Aim and objectives: The aim of this study is to establish the prevalence of Birt-Hogg-Dubé syndrome in patients presenting with a ‘primary’ SP. The second aim of the study is to detect other abnormalities likely related to the SP. In this study a total of 350 patient will be included from 11 hospitals in the Netherlands. Methods: Patients with a primary SP are tested for the existence of BHD through FLCN mutation testing and low dose CT Thorax. In addition a questionnaire at start, 1 and 4 years is performed. We present the first results of screening for FLCN mutation after SP. Results: From September 2020 till December 2021 106 spontaneous pneumothorax patients were included and analyzed in this study. 7 (6-7%) patients were found to carry a FLCN mutation. Conclusions: These early findings suggest that the prevalence of BHD in SP patients might be as high as 6-7 percent. As the lifetime risk in BHD patients for renal cell cancer is high, and through each affected person asymptomatic family members may be found, this justifies screening for BHD in SP patients. References 1. Ren, H.Z. et al. Clin Genet 2008; 74: 178-1832. 2. Schmidt, L.S. et al. Semin Oncol. 2016; 43: 566–574

Background Birt-Hogg-Dubé syndrome (BHD) is an inherited disease caused by pathogenic variants in the FLCN gene. One of the characteristics is the increased risk for spontaneous pneumothorax, likely due to the presence of pulmonary cysts mainly distributed under the carina. Due to variable expression and lack of awareness, BHD is likely to be underdiagnosed . We aimed to examine the prevalence of BHD in patients presenting with an apparent primary spontaneous pneumothorax and to evaluate the contribution of chest CT in establishing the diagnosis. Methods Patients who presented with apparent primary spontaneous pneumothorax between 2004 and 2017 in a large Dutch teaching hospital were enrolled in this quantitative cross-sectional study. A questionnaire was sent to eligible patients. Patients who completed the questionnaire and consented to further participation were invited to visit the hospital for genetic testing and low dose, volumetric chest CT. Results Genetic testing was performed in 88 patients with apparent primary spontaneous pneumothorax. Three patients were found to have a pathogenic variant in the FLCN gene (3.4%). No variants of unknown significance were detected. Pulmonary cysts were detected in 14 out of 83 participants with an available chest CT, six had more than one cyst. All three patients with BHD had multiple pulmonary cysts. Conclusions Based on previous literature and the present study, we believe that performing a chest CT in every patient presenting with primary spontaneous pneumothorax is justified. Subsequent genetic testing of the FLCN gene should be considered when multiple pulmonary cysts are present. Trial registration The study was registered at clinicaltrials.gov with reference NCT02916992. Summary at a glance Three out of 88 patients with an apparent primary spontaneous pneumothorax were diagnosed with Birt-Hogg-Dubé syndrome in this study and all three had multiple pulmonary cysts. We believe that performing a chest CT in every patient with an apparent primary spontaneous pneumothorax is justified to identify underlying diseases.

The TNM staging system is currently guiding our multidisciplinary team (MDT) meetings and the process of clinical decision making for patients with NSCLC. The combination of tumor (T), nodes (N), and metastases (M) is used to define the stage of disease. Owing to the extensive work of the International Association for the Study of Lung Cancer, a prognosis might be precisely predicted in relation to stage, taking into account that prognosis will be determined by the treatment options available at the time the databases were filled with cases.1International Association for the Study of Lung CancerInternational Association for the Study of Lung Cancer (IASLC) Staging Project.https://www.iaslc.org/research-education/research-committees-projects/staging-and-prognostic-factors-committeeDate accessed: May 10, 2022Google Scholar Figure 1 illustrates the current staging algorithm according to the guidelines of the European Society of Thoracic Surgeons and the European Society for Medical Oncology and the respective sensitivity and negative predictive value of the different staging procedures. Recent advances in imaging techniques (i.e., qualitative improvements in computed tomography [CT] and positron emission tomography [PET]) and invasive and noninvasive staging procedures contribute to a more accurate T, N, and M staging, and today's large real-world data sets may give us the opportunity to predict prognosis even more accurately. Currently, in the eighth version of the TNM system, there are 11 options for the T stage, five options for the N stage, and four options for the M stage.2Goldstraw P. Chansky K. Crowley J. et al.The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.J Thorac Oncol. 2016; 11: 39-51Abstract Full Text Full Text PDF PubMed Scopus (2487) Google Scholar The more detailed options in every new version of the TNM system to define the T, N, and M stages make it possible to predict prognosis even more accurately for a patient. Nevertheless, the more detailed subdivision of the T, N, and M comes at a risk of high rates of inaccurate clinical staging. During the time that the seventh version of the TNM system was used, agreement between clinical TNM stage and pathologic TNM stage was only 53% in The Netherlands in daily clinical practice in a cohort of 5449 patients.3Heineman D.J. Ten Berge M.G. Daniels J.M. et al.The quality of staging non-small cell lung cancer in the Netherlands: data from the Dutch Lung Surgery Audit.Ann Thorac Surg. 2016; 102: 1622-1629Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,4Heineman D.J. Hoeijmakers F. Beck N. et al.Impact of health care organization on surgical lung cancer care.Lung Cancer. 2019; 135: 181-187Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In other countries, similar numbers were found.4Heineman D.J. Hoeijmakers F. Beck N. et al.Impact of health care organization on surgical lung cancer care.Lung Cancer. 2019; 135: 181-187Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,5Jakobsen E. Green A. Oesterlind K. Rasmussen T.R. Iachina M. Palshof T. Nationwide quality improvement in lung cancer care: the role of the Danish Lung Cancer Group and Registry.J Thorac Oncol. 2013; 8: 1238-1247Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar A more detailed classification (such as the eighth version of the TNM system) might reduce agreement even further. One may argue whether a small inaccuracy in tumor size is relevant for the treatment plan, but an inaccuracy in the N stage certainly may have large consequences for a patient with respect to the treatment plan. It is not known whether understaging or overstaging influences overall long-term survival, but it certainly influences treatment decisions. In addition, high levels of interobserver variation were found when locally advanced NSCLC was clinically staged by different MDTs.6Hoeijmakers F. Heineman D.J. Daniels J.M. et al.Variation between multidisciplinary tumor boards in clinical staging and treatment recommendations for patients with locally advanced non-small cell lung cancer.Chest. 2020; 158: 2675-2687Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Tumor size is still measured manually, N stage on the basis of imaging has considerable false positives and negatives, and dedicated (nuclear) imaging experts are not always involved. It is hoped that, new techniques, for example, total body PET-CT and artificial intelligence, can reduce inaccuracy and interobserver variation in the future. Nevertheless, for our current era, a staging system on the basis of the prognosis of patients with lung cancer, with a low accuracy and a high level of interobserver variation and outcomes affected by therapeutic possibilities of the past, is not very suitable for making treatment decisions. Figure 2 illustrates the TNM system and how the different stages are composed of the T, N, and M. The color coding in the figure indicates whether it is obvious which treatment options are available for a stage or whether (a combination of) multiple treatment options are available for a certain stage and differentiating information is not supplied by the TNM system. For stages I and II, the MDT will usually propose radical local therapy as initial treatment (e.g., surgery or radiotherapy). Nevertheless, with new options for local therapy, for example, stereotactic irradiation or introduction of minimally invasive sublobar resections,7Saji H. Okada M. Tsuboi M. et al.Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.Lancet. 2022; 399: 1607-1617Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar treatment options are increasing. The MDT will make a decision on the basis of patient characteristics outside the TNM system, for example, performance status, pulmonary function, and patient preferences. Unfortunately, multiple attempts to acquire level I evidence for the optimal treatment for operable stage I NSCLC have failed in the past owing to problems with trial accrual, and this remains a topic of debate. Especially stage III illustrates why the TNM system does not support the MDT in making treatment decisions, although patients share a similar prognosis. Stage III, but also the subgroups stage IIIA and IIIB, comprises a very heterogeneous group of patients, and the amount of treatment strategies is numerous, occasionally even for patients in the same subgroup.8Remon J. Soria J.C. Peters S. ESMO Guidelines CommitteeElectronic address: [email protected] Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy.Ann Oncol. 2021; 32: 1637-1642Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Furthermore, there is a lack of clear evidence for treatment of stage IIIA-N2 disease, expressed by different recommendations in national guidelines worldwide.9Putora P.M. Leskow P. McDonald F. Batchelor T. Evison M. International guidelines on stage III N2 nonsmall cell lung cancer: surgery or radiotherapy?.ERJ Open Res. 2020; 6: 00159-2019Crossref PubMed Scopus (28) Google Scholar Trials addressing new multimodality treatment regimens usually include all patients with resectable or irresectable stage III (or all IIIA or IIIB) and not just a specific subgroup (e.g., only IIIA-N2 disease), which will add to the lack of clarity. It is likely that the extremes within IIIA (T1aN2 versus T4N0) may have a different biological behavior and have different optimal treatment regimens. In the past, the prognosis of these tumors was similar with the available treatment options, but modern therapy may have a considerable impact on treatment decisions and outcome. Left upper lobe NSCLC with (biopsy-proven) involvement of lymph node stations N5 or N6 also represents a specific group of patients. They are staged as having N2 disease; however, they behave as having N1 disease (and upfront surgery seems a good treatment option).10Patterson G.A. Piazza D. Pearson F.G. et al.Significance of metastatic disease in subaortic lymph nodes.Ann Thorac Surg. 1987; 43: 155-159Abstract Full Text PDF PubMed Scopus (160) Google Scholar In addition to morphologic tumor characteristics as expressed in the TNM system, an increasing number of evidence on the basis of prognostic biological factors may play an important role in clinical care and treatment decisions. The extended tumor profile, including histopathologic, molecular, and genetic features, provides us with possible targets for innovative treatments.11Brierley J. Gospodarowicz M. O'Sullivan B. The principles of cancer staging.Ecancermedicalscience. 2016; 10: ed61Crossref Scopus (31) Google Scholar Recently, knowledge of some of these features has become available. An example is the publication of the light-microscopic subclassification of adenocarcinoma resulting in a refinement of that large subgroup within the combined description of NSCLC.12Travis W.D. Brambilla E. Burke A.P. Marx A. Nicholson A.G. Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart.J Thorac Oncol. 2015; 10: 1240-1242Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar Shortly after this, the role of retinoblastoma gene in the neuroendocrine subgroup was highlighted.13Derks J.L. Leblay N. Lantuejoul S. Dingemans A.C. Speel E.M. Fernandez-Cuesta L. New insights into the molecular characteristics of pulmonary carcinoids and large cell neuroendocrine carcinomas, and the impact on their clinical management.J Thorac Oncol. 2018; 13: 752-766Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar In 2020, the first targeted therapy, osimertinib, was approved for adjuvant use in patients with resected stages IB to IIIA NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations.14Wu Y.L. John T. Grohe C. et al.Postoperative chemotherapy use and outcomes from ADAURA: osimertinib as adjuvant therapy for resected EGFR-mutated NSCLC.J Thorac Oncol. 2022; 17: 423-433Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar The value of osimertinib and other targeted therapies in the neoadjuvant setting is currently investigated. The recently published CheckMate 816 trial included patients with resectable stages IB to IIIA and randomized between a regimen with neoadjuvant nivolumab with platinum-doublet chemotherapy or chemotherapy alone before resection.15Forde P.M. Spicer J. Lu S. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (335) Google Scholar Patients receiving nivolumab had a significantly longer event-free interval and higher rate of pathologic complete response. Long-term follow-up for patients treated with neoadjuvant immunotherapy and resection is not yet available, but it is expected that prognosis of patients with NSCLC will be improved significantly, as was proven in patients with irresectable stage III disease.16Spigel D.R. Faivre-Finn C. Gray J.E. et al.Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.J Clin Oncol. 2022; 40: 1301-1311Crossref PubMed Scopus (201) Google Scholar When these results are available, it will be important to update the TNM system with these features not only to give patients a better prediction of their prognosis but also to guide MDTs in making treatment decisions. With the introduction of novel neoadjuvant regimens on the basis of tumor biology, histologic analysis of tumor cells and prediction of tumor response to targeted therapy by new PET ligands will become increasingly important before start of treatment. MDTs will increasingly analyze tumor biology in the coming years before starting treatment, to choose a patient-tailored strategy that suits best for every specific situation. In patients in whom this is impossible owing to small size or location of the tumor, there might be a preference for initial surgical treatment (preferably minimally invasive and parenchymal sparing) to obtain a full pathologic diagnosis. In case of future disease recurrence, new biopsies are usually preferred because of the possibility of tumor heterogeneity. As was stated before, correct clinical staging is complex and preferably comprises multiple staging procedures, such as a (PET-)CT scan, histologic biopsy, brain magnetic resonance imaging, endobronchial ultrasound or esophageal ultrasound with ultrasound bronchoscope, and (video)mediastinoscopy. In a study on patient preferences regarding mediastinal nodal staging, the most important attribute regarding patients was the duration of the staging period, followed by the risk of a futile surgical lung resection (defined as having unforeseen N2 after surgery). Nevertheless, there was a strong dichotomy among patients always or never willing to undergo confirmatory mediastinoscopy.17Bousema J.E. Hoeijmakers F. Dijkgraaf M.G.W. et al.Patients' preferences regarding invasive mediastinal nodal staging of resectable lung cancer.Patient Prefer Adherence. 2021; 15: 2185-2196Crossref Scopus (1) Google Scholar This strengthens the idea that a correct TNM, something that is hard to achieve because of all the aforementioned arguments, is not necessarily the focus for most patients. If obtaining the correct clinical stage consists of invasive procedures with the risk of a complication, and delays the start of treatment, this will not correspond with the priorities of some patients. Therefore, it is important to use shared decision making before using these procedures by explaining risks and benefits of all possible scenarios to the patient. The TNM system is a very valuable system to categorize patients, predict their prognosis, and facilitate communication between medical physicians. Nevertheless, recent developments in treatment of patients with lung cancer and improved understanding of tumor biology have made this system less useful in daily practice to guide treatment decisions. In the newest era, MDTs make treatment decisions combining morphologic and biological features, patient factors, and shared decision making, to optimize patient-tailored treatments. Ideally, a new system should be developed that takes all these factors into account. Fieke Hoeijmakers: Conceptualization, Project administration, Visualization, Writing—original draft. Wilhelmina H. Schreurs: Conceptualization, Supervision, Validation, Writing—review and editing. Emile F. I. Comans, José S. A. Belderbos: Validation, Writing—review and editing. Pieter E. Postmus: Conceptualization, Validation, Writing—review and editing. Rob A. E. M. Tollenaar: Conceptualization, Supervision, Writing—review and editing. David J. Heineman: Conceptualization, Supervision, Validation, Writing—original draft, Writing—review and editing.

"Natural Course of Cysts in Birt-Hogg-Dubé Syndrome." American Journal of Respiratory and Critical Care Medicine, 205(12), pp. 1474–1475

Background: Lung cancer is one kind of malignant tumor with a high risk for morbidity and mortality compared to other solid organ malignancies. Brain metastases occur in 30-55% of non-small cell lung cancer (NSCLC) patients. Prognosis of NSCLC patients with brain metastases is very poor. Our previous study showed that cell adhesion molecule 2 (CADM2) could regulate the development of brain metastasis in NSCLC cells. Therefore, the objective of the study is to evaluate the effect of CADM2 on the prognosis of NSCLC patients with brain metastases. Methods: The expression of CADM2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in the tissue of the primary tumor. Patients were followed up and overall survival (OS) was calculated. The relationships between CADM2 and clinicopathological features were analyzed using the chi-square test. Kaplan-Meier analysis was carried out to demonstrate the influence of CADM2 on the OS of patients. Univariate and multivariate Cox analyses were used to determine the prognosis of NSCLC patients with brain metastases. Results: A total of 139 NSCLC patients with brain metastases from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University, treated between January 2015 and December 2017 were evaluated retrospectively. The expression level of CADM2 in patients ranged from 1 to 17.2677, with a median of 6.0772. Chi-square analysis showed that CADM2 gene expression level was not significantly associated with gender, age, tumor location, histological subtype, tumor T stage, extracranial metastasis, or smoking status. However, CADM2 expression was notably associated with risk for lymph node metastasis. The results of the Kaplan-Meier analysis showed that high expression [CADM2 messenger RNA (mRNA) >= 6.0772] of CADM2 was markedly associated with poor prognosis. Univariate and multivariate Cox analyses demonstrated that CADM2 was an independent risk factor for survival in NSCLC patients with brain metastases (P<0.05). Conclusions: CADM2 expression is up-regulated and closely associated with disease progression and poor prognosis in NSCLC patients with brain metastases. CADM2 expression warrants special consideration given its potential prognostic significance that might help inform clinical decision making.

Background: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients. In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped. Methods: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status. Findings: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P<0.001; 15.4%; P<0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients. Interpretation: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role. (C) 2021 The Author(s). Published by Elsevier Ltd.

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab -paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC. Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab -paclitaxel 100 mg/m 2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred. Conclusions: The nab -paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted. Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326). EudraCT number: 2014-001105-41

Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important—and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendations for optimal molecular diagnostics in the post-EGFR tyrosine kinase inhibitor (TKI) resistance setting. Methods: We compared molecular workup strategies from three hospitals of 161 first- or second-generation EGFR TKI–treated cases and 159 osimertinib-treated cases. Laboratories used combinations of DNA next-generation sequencing (NGS), RNA NGS, in situ hybridization (ISH), and immunohistochemistry (IHC). Results: Resistance mechanisms were identified in 72 first-generation TKI cases (51%) and 85 osimertinib cases (57%). RNA NGS, when performed, revealed fusions or exon-skipping events in 4% of early TKI cases and 10% of osimertinib cases. Of the 30 MET and HER2 amplifications, 10 were exclusively detected by ISH or IHC, and not detected by DNA NGS, mostly owing to low tumor cell percentage (<30%) and possibly tumor heterogeneity. Conclusions: Our real-world data support a method for molecular diagnostics, consisting of a parallel combination of DNA NGS, RNA NGS, MET ISH, and either HER2 ISH or IHC. Combining RNA and DNA isolation into one step limits dropout rates. In case of financial or tissue limitations, a sequential approach is justifiable, in which RNA NGS is only performed in case no resistance mechanisms are identified. Yet, this is suboptimal as—although rare—multiple acquired resistance mechanisms may occur.

Immunohistochemical programmed death‐ligand 1 (PD‐L1) staining to predict responsiveness to immunotherapy in patients with advanced non‐small cell lung cancer (NSCLC) has several drawbacks: a robust gold standard is lacking, and there is substantial interobserver and intraobserver variance, with up to 20% discordance around cutoff points. The aim of this study was to develop a new deep learning‐based PD‐L1 tumour proportion score (TPS) algorithm, trained and validated on a routine diagnostic dataset of digitised PD‐L1 (22C3, laboratory‐developed test)‐stained samples.

IntroductionAccess to targeted therapies for lung cancer depends on the accurate identification of patients’ biomarkers through molecular testing. The International Association for the Study of Lung Cancer (IASLC) conducted an international survey to evaluate perceptions on current practice and barriers to implementation of molecular testing.MethodsWe distributed the survey to IASLC members and other health care professionals around the world. The survey included a seven-question introduction for all respondents, who then answered according to one of three tracks: (1) requesting tests and treating patients, (2) performing and interpreting assays, or (3) tissue acquisition. Barriers to implementing molecular testing were provided in free-response fields. The chi-square test was used for regional comparisons.ResultsA total of 2537 respondents from 102 countries participated. Most respondents who test and treat patients believe that less than 50% of patients with lung cancer in their country receive molecular testing, but reported higher rates within their own practice. Although many results varied by region, the five most frequent barriers cited in all regions were cost, quality and standards, access, awareness, and turnaround time. Many respondents expressed dissatisfaction with the current state of molecular testing for lung cancer, including 41% of those performing and interpreting assays. Issues identified included trouble understanding results (37%) and the quality of the samples (23% reported >10% rejection rate). Despite concerns regarding the quality of testing, 47% in the performing and interpreting track stated there is no policy or strategy to improve quality in their country. In addition, 33% of respondents who request tests and treat patients were unaware of the most recent College of American Pathologists, IASLC, and Association for Molecular Pathology guidelines for molecular testing.ConclusionsAdoption of molecular testing for lung cancer is relatively low across the world. Barriers include cost, access, quality, turnaround time, and lack of awareness.

IntroductionFrequently, patients with locally advanced or metastatic NSCLC are screened for mutations and fusions. In most laboratories, molecular workup includes a multitude of tests: immunohistochemistry (ALK, ROS1, and programmed death-ligand 1 testing), DNA sequencing, in situ hybridization for fusion, and amplification detection. With the fast-emerging new drugs targeting specific fusions and exon-skipping events, this procedure harbors a growing risk of tissue exhaustion.MethodsIn this study, we evaluated the benefit of anchored, multiplexed, polymerase chain reaction-based targeted RNA sequencing (RNA next-generation sequencing [NGS]) in the identification of gene fusions and exon-skipping events in patients, in which no pathogenic driver mutation was found by DNA-based targeted cancer hotspot NGS (DNA NGS). We analyzed a cohort of stage IV NSCLC cases from both in-house and referral hospitals, consisting 38.5% cytology samples and 61.5% microdissected histology samples, mostly core needle biopsies. We compared molecular findings in a parallel workup (DNA NGS and RNA NGS, cohort 1, n = 198) with a sequential workup (DNA NGS followed by RNA NGS in selected cases, cohort 2, n = 192). We hypothesized the sequential workup to be the more efficient procedure.ResultsIn both cohorts, a maximum of one oncogenic driver mutation was found per case. This is in concordance with large, whole-genome databases and suggests that it is safe to omit RNA NGS when a clear oncogenic driver is identified in DNA NGS. In addition, this reduced the number of necessary RNA NGS to only 53% of all cases. The tumors of never smokers, however, were enriched for fusions and exon-skipping events (32% versus 4% in former and current smokers, p = 0.00), and therefore benefited more often from the shorter median turnaround time of the parallel approach (15 d versus only 9 d in the parallel workup).ConclusionsWe conclude that sequentially combining DNA NGS and RNA NGS is the most efficient strategy for mutation and fusion detection in smoking-associated NSCLC, whereas for never smokers we recommend a parallel approach. This approach was shown to be feasible on small tissue samples including for cytology tests, can drastically reduce the complexity and cost of molecular workup, and also provides flexibility in the constantly evolving landscape of actionable targets in NSCLC.

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel +/- durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

OBJECTIVES:The tumor-stroma ratio (TSR) is based on the relative amount of stroma in the primary tumor and has proven to be an independent prognostic factor in various solid tumors. The prognosis of patients and adjuvant treatment decision making in lung squamous cell carcinomas (SqCC) is based on the TNM classification. Currently, no other prognostic biomarkers are available. In this study we evaluated the prognostic value of the TSR in lung SqCC. MATERIAL AND METHODS:Patients undergoing lung surgery because of lung SqCC between 2000 and 2018 at the Leiden University Medical Center were included. The TSR was scored on hematoxylin & eosin stained tissue sections. Based on the amount of tumor-stroma, two groups were defined: ≤50% was classified as a stroma-low tumor and >50% as stroma-high. The prognostic value of the TSR was determined with survival analysis. RESULTS:A total of 174 stage I-III patients were included. Of them, 79 (45%) were stroma-low and 95 (55%) stroma-high. Separately analyzed for tumor stages, the TSR showed to be an independent prognostic biomarker in stage II (n = 68) for 5-year overall survival (HR=3.0; 95% CI, 1.1-8.6; p = 0.035) and 5-year disease free survival (DFS) (HR=3.6; 95% CI, 1.3-9.9; p = 0.014). Patients with a stroma-high tumor had a worse 5-year DFS in the whole cohort (HR 1.6; 95% CI, 1.0-2.4; p = 0.048), but no independent prognostic value was found. CONCLUSION:In stage II lung SqCC patients, stroma-low tumors have a better prognosis compared to stroma-high tumors. Moreover, adjuvant chemotherapy could be spared for these stroma-low patients.

BACKGROUND:The therapeutic landscape for non-small-cell lung cancer (NSCLC) patients that have common epidermal growth factor receptor (EGFR) mutations has changed radically in the last decade. The availability of these treatment options has an economic impact, therefore a budget impact analysis was performed.METHODS:A budget impact analysis was conducted from a Dutch healthcare perspective over a 5-year time horizon in EGFR-mutant NSCLC patients receiving first-line afatinib (Gilotrif®) versus first-line osimertinib (Tagrisso®), followed by subsequent treatments. A decision analysis model was constructed in Excel. Scenario analyses and one-way sensitivity analysis were used to test the models' robustness.RESULTS:Sequential treatment with afatinib versus first-line treatment with osimertinib showed mean total time on treatment (ToT) of 29.1 months versus 24.7 months, quality-adjusted life months (QALMs) of 20.2 versus 17.4 with mean cost of €108,166 per patient versus €143,251 per patient, respectively. The 5-year total budget impact was €110.4 million for the afatinib sequence versus €158.6 million for the osimertinib sequence, leading to total incremental cost savings of €48.15 million.CONCLUSIONS:First-line afatinib treatment in patients with EGFR-mutant NSCLC had a lower financial impact on the Dutch healthcare budget with a higher mean ToT and QALM compared to osimertinib sequential treatment.

BackgroundA partial response according to the Response Evaluation Criteria in Solid Tumors includes a wide range of changes in tumor size. This study evaluated whether further specification of tumor reduction based on the depth of response (DpR) would provide a more precise association with outcomes for patients with non–small cell lung cancer (NSCLC) treated with first‐line platinum‐based chemotherapy.MethodsA retrospective analysis was performed for the randomized phase 3 CA031 trial in patients with NSCLC treated with carboplatin in combination with nab‐paclitaxel or solvent‐based paclitaxel. Quartiles according to the maximum tumor reduction from the baseline were defined (quartile 1 [Q1], >0% to 25%; quartile 2 [Q2], >25% to 50%; quartile 3 [Q3], >50% to 75%; and quartile 4 [Q4], >75%) and were compared with those patients with no tumor reduction (NTR). The primary objective was to evaluate the association between DpR and overall survival (OS).ResultsOf the 1052 patients enrolled in the CA031 trial, 959 (91%) were evaluable, and they included 365 (38.1%) who were classified as Q1, 327 (34.1%) who were classified as Q2, 131 (13.7%) who were classified as Q3, and 34 (3.5%) who were classified as Q4; 102 had NTR (10.6%). The median OS values for patients in the NTR, Q1, Q2, Q3, and Q4 groups were 4.8, 10.4, 14.5, 19.3, and 23.5 months, respectively. The maximum DpR on treatment was an independent predictor of improved OS in comparison with patients with NTR; the hazard ratio decreased from 0.43 in Q1 to 0.16 in Q4.ConclusionsDpR was strongly associated with OS in patients with NSCLC receiving first‐line platinum‐based therapy. Additional studies may help to define the role of DpR in solid tumors.