Showing papers by "Andrew G. Nicholson published in 2022"
TL;DR: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise and additional research into pirfenidone was recommended.
Abstract: Background This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results 1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.
282 citations
TL;DR: In this paper , the authors reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation.
46 citations
TL;DR: In this article , the authors proposed a 2019 WHO Classification of Tumors of the Pleura and Pericardium (P2P) for mesothelioma and pericardial tumors.
41 citations
TL;DR: This statement delineates the syndrome of CPFE and highlights research priorities, and offers a research definition and classification criteria and proposes that studies on CPFE include a comprehensive description of radiologic and, when available, pathological patterns.
Abstract: Background: The presence of emphysema is relatively common in patients with fibrotic interstitial lung disease. This has been designated combined pulmonary fibrosis and emphysema (CPFE). The lack of consensus over definitions and diagnostic criteria has limited CPFE research. Goals: The objectives of this task force were to review the terminology, definition, characteristics, pathophysiology, and research priorities of CPFE and to explore whether CPFE is a syndrome. Methods: This research statement was developed by a committee including 19 pulmonologists, 5 radiologists, 3 pathologists, 2 methodologists, and 2 patient representatives. The final document was supported by a focused systematic review that identified and summarized all recent publications related to CPFE. Results: This task force identified that patients with CPFE are predominantly male, with a history of smoking, severe dyspnea, relatively preserved airflow rates and lung volumes on spirometry, severely impaired DlCO, exertional hypoxemia, frequent pulmonary hypertension, and a dismal prognosis. The committee proposes to identify CPFE as a syndrome, given the clustering of pulmonary fibrosis and emphysema, shared pathogenetic pathways, unique considerations related to disease progression, increased risk of complications (pulmonary hypertension, lung cancer, and/or mortality), and implications for clinical trial design. There are varying features of interstitial lung disease and emphysema in CPFE. The committee offers a research definition and classification criteria and proposes that studies on CPFE include a comprehensive description of radiologic and, when available, pathological patterns, including some recently described patterns such as smoking-related interstitial fibrosis. Conclusions: This statement delineates the syndrome of CPFE and highlights research priorities.
22 citations
TL;DR: In this paper , the authors show that human lung tissues harbor a resident Vδ1 γδ T cell population and demonstrate that Vβ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues.
Abstract: Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA-CD27- effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.
21 citations
Peer Review•
TL;DR: The most recent edition of the World Health Organization (WHO) classification of thymic epithelial tumors (including thymomas, carcinomas, and neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to list established and new tumor entities and subtypes as discussed by the authors .
Abstract: This overview of the fi fth edition of the WHO classi fi cation of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exempli fi ed by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the fi ndings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1 high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classi fi cation of thymic NETs that may fi t into the classi fi cation scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fi fth edition of the WHO classi fi cation of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.
18 citations
TL;DR: The fifth edition of the Thoracic Tumor Blue Book was published in April 2021 as mentioned in this paper , which includes a large volume of new published data and updates especially in the epidemiology, histopathology, immunohistochemistry, and molecular pathology, and diagnostics of thoracic tumors have been incorporated into this new edition.
18 citations
TL;DR: A review of multidisciplinary perspectives in diagnosis and management of thymic carcinoma can be found in this article , where the authors present a review of the most recent advances in diagnostic imaging, surgical approaches, systemic therapies, and radiation therapy techniques.
10 citations
TL;DR: In this paper , the authors suggest a pragmatic approach on how to apply existing guidelines to distinguish idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP).
7 citations
TL;DR: Downstream analyses suggested that PCSK6 protein may serve as prognostic biomarker in IPF and potential therapeutic target, and four novel variants associated with IPF survival, including one in PCSK 6 that reached genome-wide significance.
Abstract: Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. Novel therapies and prognostic biomarkers are needed. Objective: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Main Results: After quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma and negatively correlated with survival. Peripheral blood PCSK6 gene expression and plasma concentration were associated with reduced transplant-free survival. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein may serve as prognostic biomarker in IPF and potential therapeutic target.
6 citations
TL;DR: The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024 as discussed by the authors .
TL;DR: The National Lung Cancer Audit (NLCA) as mentioned in this paper is a data set that monitors lung cancer care and outcomes, by embedding routine data collection, feeding results back to hospitals, and driving quality improvement.
TL;DR: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.
Abstract: OBJECTIVES
Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making.
RATIONALE
To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study.
METHODS
CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years.
MEASUREMENTS AND MAIN RESULTS
CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts.
CONCLUSIONS
CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.
TL;DR: In this article , a Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and noninvasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes.
TL;DR: In insights into the association between morphological and molecular heterogeneity in LUAD are revealed, key features of tumor evolutionary tendencies are described and the utility of detailed tumor morphological assessment integrated with molecular characterization and ctDNA detection is demonstrated.
Abstract:
Background: Lung adenocarcinoma (LUAD) is a morphologically and genetically diverse disease. The prognostic impact of LUAD histological patterns have been described, such as solid growth pattern and poor outcomes, though their underlying biology is poorly understood. Furthermore, the genomic characteristics and evolutionary constraints in relation to the inter- and intra- tumoral variance of histological patterns in primary and metastatic disease are unknown.
Methods: Pathological classification of 246 patients with LUAD from the TRACERx 421 cohort was performed at the whole tumor (diagnostic samples) and multi-regional sample level (matched for tumor whole exome sequencing and RNA sequencing). Circulating tumor DNA (ctDNA) data was also integrated to determine the relationship between pathological subtypes and ctDNA detection.
Results: Chromosomal instability, characterized by fraction of the genome affected by subclonal copy number alterations was significantly correlated with proportion of high-grade patterns, namely solid, cribriform and micropapillary (Spearman’s Rho 0.27, p<0.001). Analysis of somatic copy number alterations (SCNAs) and driver mutation profiles showed that specific SCNAs were associated with a predominant growth pattern, such as 3q arm gains in predominantly cribriform and solid pattern tumors. Multiregional analysis of tumors with mixed patterns showed higher grade regions to be associated with a higher frequency of LOH and expression of proliferation-related pathway genes, suggesting intra-tumoral sequential evolution from low to high grade growth patterns. No recurrent subclonal mutations or SCNAs were found to associate with progression from low to high grade patterns. The growth pattern in metastatic tumors tended to show similar or a higher-grade pattern compared with primary tumor regions harboring metastasizing clones (seeding regions). The growth pattern of the seeding regions in the primary tumor was not necessarily higher grade compared with their non-seeding counterparts. Finally, the proportion of solid pattern in the primary tumor and the presence of necrosis were found to be strongly associated with pre-operative ctDNA detection, while histological ‘spread through air spaces’ (STAS) was identified in 92% (12/13) of pre-operative ctDNA-negative tumors that subsequently were associated with recurrence. Patients with both pre-operative detectable ctDNA and STAS had a particularly poor prognosis.
Conclusion: These data reveal insights into the association between morphological and molecular heterogeneity in LUAD, describe key features of tumor evolutionary tendencies and demonstrate the utility of detailed tumor morphological assessment integrated with molecular characterization and ctDNA detection.
Citation Format: Takahiro Karasaki, David A. Moore, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Maise Al Bakir, Thomas B. Watkins, Oriol Pich, Alexander M. Frankell, Emilia Lim, Mark S. Hill, Kristiana Grigoriadis, Carlos Martinez-Ruiz, James R. Black, Clare Puttick, Dhruva Biswas, Ariana Huebner, Michelle Dietzen, Emma Colliver, Claudia Lee, Nnenna Kanu, Sadegh Mohammad Saghafinia, Francisco Gimeno Valiente, Christopher Abbosh, Crispin T. Hiley, Simone Zaccaria, Nicolai J. Birkbak, Allan Hackshaw, TRACERx Consortium, Teresa Marafioti, Roberto Salgado, John Le Quesne, Andrew G. Nicholson, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani. Evolutionary characterisation of lung adenocarcinoma pathological subtypes in TRACERx [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6091.
TL;DR: Two neonates requiring extracorporeal membrane oxygenation for undiagnosed recalcitrant pulmonary hypertension are presented, highlighting the clinical and ethical dilemmas in management of very rare diseases.
Abstract: We present two neonates requiring extracorporeal membrane oxygenation for undiagnosed recalcitrant pulmonary hypertension, highlighting the clinical and ethical dilemmas in management of very rare diseases.
TL;DR: In this paper , the authors reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography, and demonstrate how changes to the ECM in IPF directly influence KRT-5+ cell behaviour and function contributing to remodelling events in the fibroic niche.
Abstract: Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry-based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.
TL;DR: Substantial changes in the 2021 WHO Classification of Tumors of the Pleura and Pericardium mesothelioma can be diagnosed in small biopsies having both epithelioid and sarcomatoid components even if the amount of one component is less than 10% as discussed by the authors .
Abstract: Substantial changes in the 2021 WHO Classi fi cation of Tumors of the Pleura and Pericardium mesothelioma can be diagnosed in small biopsies having both epithelioid and sarcomatoid components even if the amount of one component is less than 10%; and (9) the most frequently altered genes in diffuse pleural mesothelioma include BAP1 , CDKN2A , NF2 , TP53 , SETD2 , and SETDB1 . (cid:2) 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
TL;DR: The PATHways survey as mentioned in this paper aimed to capture pathologists' perspectives on current diagnostic pathways, the increasing role of molecular diagnostic tests, and improvement opportunities for optimising pathways to ensure equitable and timely access.
Abstract: Background: The PATHways survey aimed to capture pathologists’ perspectives on current diagnostic pathways, the increasing role of molecular diagnostic tests, and improvement opportunities for optimising pathways to ensure equitable and timely access. Here we report the results for breast cancer (BC) testing.