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Biomedicines
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Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches
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Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 November 2025) | Viewed by 8002

Special Issue Editor

Dr. Yanyun Gao

E-Mail Website
Guest Editor
Bern University Hospital, University of Bern, Bern, Switzerland
Interests: thoracic malignancy; chemotherapy resistance; target therapy; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Among thoracic malignancies, lung cancer is the most frequent and deadly cancer type worldwide, including non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Esophageal cancer is also involved in thoracic oncology, and occurs more often in Asian populations. Pleural mesothelioma (PM) is a rare but very aggressive thoracic malignancy, originating from mesothelium tissues covering the lung (pleura), usually associated with exposure to asbestos. To treat thoracic malignancies, many promising drugs have been approved, with clear improvements in terms of outcomes, new immunotherapeutic drugs, new combinations, and new targeted drugs, based on pathological understanding. The results of tumor biology and translational studies for these cancers are worth spreading throughout the scientific community. Moreover, the intrinsic and acquired resistance mechanisms to these new strategies need to be explored.

In this collection, we aim to include original articles and reviews on histological, molecular, and biological mechanisms, as well as novel treatments of thoracic malignancies, including NSCLC, SCLC, oesophageal cancer, and pleural mesothelioma. We also welcome articles on promising study models for these cancers (organoids, tissue slices, and mouse models). 

Dr. Yanyun Gao
Guest Editor

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Keywords

  • thoracic malignancies
  • lung cancer
  • esophageal cancer
  • pleural mesothelioma (PM)
  • molecular subtypes
  • drug resistance
  • target therapy
  • biomarkers
  • immunotherapy
  • preclinical models

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Published Papers (6 papers)

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Research

Jump to: Review

14 pages, 403 KB  
Article
PIK3CA Alterations in NSCLC: Clinical Characteristics of a “Neglected” Population of Oncogene-Addicted Patients
by Sabrina Rossi, Arianna Pagliaro, Silvia Masini, Giovanna Finocchiaro, Luca Toschi, Emilio Bria, Vitale Antonio, Stefani Alessio, Alessandro Inno, Stefania Gori, Ettore D’Argento and Armando Santoro
Biomedicines 2026, 14(2), 362; https://doi.org/10.3390/biomedicines14020362 - 4 Feb 2026
Viewed by 877
Abstract
Background/Objectives: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (PIK3CA) are identified in approximately 2–4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize [...] Read more.
Background/Objectives: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (PIK3CA) are identified in approximately 2–4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize the clinical and molecular features, as well as outcomes, of patients with PIK3CA-altered NSCLC across different disease stages. Methods: We conducted a retrospective multicenter analysis of 62 patients with histologically confirmed early-stage or advanced NSCLC-harboring PIK3CA alterations (mutations and/or gene amplifications) treated between 2015 and 2022 at three Italian institutions. Demographic, clinical, pathological, and molecular variables were systematically collected and analyzed. Results: PIK3CA mutations accounted for the majority of alterations (90.3%), while amplifications represented 9.7%. The most frequent mutations involved exon 9 (66.1%), predominantly E545K and E542K, followed by exon 20 (16.1%). Most patients were current or former smokers, and concomitant oncogenic alterations were detected in 59.7% of cases, most commonly KRAS mutations. A history of prior malignancy was reported in 24.6% of cases. In the metastatic setting, adenocarcinoma histology was associated with significantly longer overall survival (OS) compared with non-adenocarcinoma histologies (18.4 vs. 5.5 months; p = 0.02). Patients with PD-L1–negative tumors demonstrated a numerically longer OS than those with PD-L1–positive tumors; however, this difference did not reach statistical significance (19.1 vs. 5.4 months; p = 0.05). No statistically significant survival differences were observed according to specific PIK3CA mutation subtypes or treatment strategies. Conclusions: PIK3CA-altered NSCLC represents a molecularly heterogeneous and clinically understudied subgroup, frequently characterized by co-occurring oncogenic alterations. In this study, no definitive prognostic or predictive role for PIK3CA alterations could be established. Nevertheless, these findings provide a descriptive real-world characterization of this molecular subset and support the need for validation in larger, prospectively designed, molecularly stratified studies. Full article
(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)
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16 pages, 1097 KB  
Article
The Role of Antifibrotic Therapy in Pulmonary Fibrosis and Lung Cancer: A Multicenter Retrospective Analysis
by Francesco Rocco Bertuccio, Nicola Baio, Fabio Perrotta, Donato Lacedonia, Vito D’Agnano, Andrea Bianco, Giulia Scioscia, Pasquale Tondo, Maria Pia Foschino Barbaro, Chandra Bortolotto, Angelo Guido Corsico and Giulia Maria Stella
Biomedicines 2025, 13(9), 2310; https://doi.org/10.3390/biomedicines13092310 - 21 Sep 2025
Cited by 2 | Viewed by 1527
Abstract
Background: Patients with fibrotic interstitial lung disease (ILD) are at increased risk of lung cancer, yet the impact of antifibrotic therapy on oncologic outcomes remains unclear. Objective: This study aimed to explore associations between antifibrotic therapy and overall survival (OS) and acute [...] Read more.
Background: Patients with fibrotic interstitial lung disease (ILD) are at increased risk of lung cancer, yet the impact of antifibrotic therapy on oncologic outcomes remains unclear. Objective: This study aimed to explore associations between antifibrotic therapy and overall survival (OS) and acute exacerbations of ILD (AE-ILD) in patients with fibrotic ILD who develop lung cancer. Methods: We retrospectively analyzed 61 patients from multiple Italian centers: 35 received antifibrotic therapy (pirfenidone or nintedanib) and 26 did not. Outcomes included OS from cancer diagnosis and post-treatment AE-ILD. Results: Mean OS was 17.9 months in the antifibrotic group and 33.2 months in the non-antifibrotic group; no adjusted survival analyses were possible due to missing censoring data, and these descriptive values should not be overinterpreted. AE-ILD occurred in 11.4% of antifibrotic-treated patients and 11.5% of those without antifibrotics. PD-L1 expression was detected in 24.1% vs. 21.8% of tumors in the two groups, and autoantibody positivity was observed in 22.8% vs. 30.7%, respectively, reflecting differences in ILD subtypes. Conclusions: In this heterogeneous real-world cohort, antifibrotic therapy was not associated with increased AE-ILD risk, and descriptive OS comparisons showed no clear survival advantage. These exploratory findings warrant confirmation in larger, prospective studies. Full article
(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)
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14 pages, 1088 KB  
Article
Combined Serum IL-6 and CYFRA 21-1 as Potential Biomarkers for Radon-Associated Lung Cancer Risk: A Pilot Study
by Narongchai Autsavapromporn, Aphidet Duangya, Pitchayaponne Klunklin, Imjai Chitapanarux, Chutima Kranrod, Churdsak Jaikang, Tawachai Monum and Shinji Tokonami
Biomedicines 2025, 13(9), 2145; https://doi.org/10.3390/biomedicines13092145 - 3 Sep 2025
Cited by 2 | Viewed by 1679
Abstract
Background: Radon, a naturally occurring radioactive gas, is increasingly recognized as a major risk factor for lung cancer (LC), especially among non-smokers. The objective of this study was to identify serum biomarkers for the early detection of LC in individuals at high [...] Read more.
Background: Radon, a naturally occurring radioactive gas, is increasingly recognized as a major risk factor for lung cancer (LC), especially among non-smokers. The objective of this study was to identify serum biomarkers for the early detection of LC in individuals at high risk due to prolonged residential radon exposure in Chiang Mai, Thailand, and to assess whether the use of single or combined biomarkers improves the sensitivity and specificity of detection. Methods: A total of 15 LC patients and 30 healthy controls (HC) were enrolled. The HC group was further stratified into two subgroups: low radon (LR, n = 15) and high radon (HR, n = 15) exposure. All participants were non-smokers or former smokers. Serum levels of cytokeratin 19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA), interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor-alpha (TGF-alpha), and indoleamine 2,3-dioxygenase-1 (IDO-1) were measured using the Milliplex® Kit on a Luminex® Multiplexing Instrument (MAGPIX® System). Results: Serum CEA, IL-6 and IL-8 levels were significantly higher in LC patients compared to the HC group (p < 0.05). Among analyzed biomarkers, only IL-8 was significantly elevated in LC patients compared to the HR group (p = 0.04). Notably, CYFRA 21-1 was the only biomarker that significantly differed between LR and HR groups (p = 0.004). The diagnostic potential of these biomarkers was evaluated using receiver operating characteristic (ROC) analysis. Individually, IL-6 showed the highest discriminative ability for differentiating LC patients from both HC and HR groups, with high specificity but moderate sensitivity. Combining IL-6 and IL-8 improved specificity and increased the area under the ROC curve (AUC), though it did not enhance sensitivity for distinguishing LC from HC. For distinguishing LC from HR individuals, IL-6 and CYFRA 21-1 exhibited strong diagnostic performance. Their combination significantly improved diagnostic accuracy, yielding the highest AUC, sensitivity, and specificity. In contrast, CEA, IL-8, TGF-alpha, and IDO-1 demonstrated limited diagnostic utility. Conclusions: Based on the available literature, this is the first study to evaluate the combined use of IL-6 and CYFRA 21-1 as potential biomarkers for LC screening in individuals with high residential radon exposure. Our findings highlight their utility, particularly in combination, for improving diagnostic accuracy in this high-risk population. Full article
(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)
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12 pages, 1295 KB  
Article
Non-Specific Pleuritis After Medical Thoracoscopy: The Portrait of an Open Issue and Practical Hints for Its Management
by Matteo Daverio, Mariaenrica Tinè, Umberto Semenzato, Roberta Prevedello, Matteo Dalla Libera, Elisabetta Cocconcelli, Elisabetta Balestro, Marco Damin, Paolo Spagnolo and Davide Biondini
Biomedicines 2025, 13(8), 1934; https://doi.org/10.3390/biomedicines13081934 - 8 Aug 2025
Cited by 1 | Viewed by 1166
Abstract
Background/Objectives: Up to one third of pleural biopsies performed during medical thoracoscopy (MT) are labelled as non-specific pleuritis (NSP). The histological diagnosis of NSP has long been worrisome for pulmonologists, with the potential to evolve into a life-threatening condition. The aim of this [...] Read more.
Background/Objectives: Up to one third of pleural biopsies performed during medical thoracoscopy (MT) are labelled as non-specific pleuritis (NSP). The histological diagnosis of NSP has long been worrisome for pulmonologists, with the potential to evolve into a life-threatening condition. The aim of this study was to identify clinical and biological predictors for patients with a diagnosis of NSP to guide clinical decisions. Methods: Baseline, procedural and follow-up data of NSP patients were retrospectively analysed to identify potential outcome predictors. Results: Of the 272 patients who underwent MT, 192 (71%) were diagnosed with malignancies, 9 (3%) with benign diseases and 71 (26%) with NSP. At follow-up, 17% were diagnosed with malignant disease and 21% with a benign condition and 62% remained idiopathic. A thoracoscopist’s evaluation of the pleural appearance reported a PPV of 28% and an NPV of 91% to predict malignancy. Patients with a subsequent diagnosis of malignancy tended to have a higher volume of fluid drained than those with persistently idiopathic NSP [2.7 litres (L) vs. 1.6 L p = 0.06]. A lymphocytic pleural effusion was more common in the malignant and idiopathic groups (63% and 60%, respectively) than the benign group (16%; p = 0.06 and p = 0.01). The three groups had a similar rate of effusion recurrence. Overall survival was higher in patients with idiopathic pleural effusion than in those with malignant (p = 0.04) or benign disease (p = 0.008). Conclusions: NSP diagnosis hides a malignancy in one in five cases, underlying the importance of closely following up these patients. The volume of drained pleural fluid, cell count and thoracoscopist’s impression may guide clinicians in the challenging management of patients with NSP. Full article
(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)
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Review

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16 pages, 10104 KB  
Review
En-Bloc Resection of Stage T4 Non-Small Cell Lung Cancer with Direct Spinal Invasion: Technical Considerations and Comprehensive Literature Review
by Wei-Ting Lee, Ke-Cheng Chen, Ching-Yao Yang, Yu-Cheng Yeh, Yen-Heng Lin, Yu-Cheng Huang, Jo-Yu Chen, Jin-Shing Chen and Fon-Yih Tsuang
Biomedicines 2026, 14(3), 733; https://doi.org/10.3390/biomedicines14030733 - 23 Mar 2026
Viewed by 848
Abstract
Historically, stage T4 non-small cell lung cancer (NSCLC) with direct spinal invasion was considered a definitive surgical contraindication due to the perceived inability to achieve negative margins without catastrophic morbidity. This paradigm has shifted through the advancement of specialized surgical techniques, which facilitate [...] Read more.
Historically, stage T4 non-small cell lung cancer (NSCLC) with direct spinal invasion was considered a definitive surgical contraindication due to the perceived inability to achieve negative margins without catastrophic morbidity. This paradigm has shifted through the advancement of specialized surgical techniques, which facilitate radical en-bloc resection in highly selected candidates by adhering to the en-bloc concept. This concept mandates the retrieval of the tumor and invaded vertebral segments as a single, contiguous unit to prevent intralesional transgression and local recurrence. Achieving microscopic negative margins (R0) stands as the most critical prognostic factor, as radical resection offers a significantly improved potential for long-term survival. Technical success requires a meticulously planned multidisciplinary approach encompassing varied surgical corridors—ranging from combined anterior–posterior windows to single-stage posterior-only approaches—tailored to the tumor’s anatomical level. Furthermore, preoperative hemostatic optimization using dual-energy computed tomography (DECT) for vascular assessment and transarterial embolization (TAE) has become indispensable for managing the hypervascularity of the invaded vertebral bone. This review synthesizes these evolving strategies, illustrated by a case of a 74-year-old male with stage T4 NSCLC where an R0 resection was achieved through a two-stage approach integrating uniportal video-assisted thoracoscopic surgery (VATS). Ultimately, en-bloc management provides a feasible and potential surgical strategy toward long-term survival for localized, spine-invasive lung cancer within a multidisciplinary treatment framework. Full article
(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)
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20 pages, 2788 KB  
Review
Turning Fluids into Data for Precision Oncology: A Multidisciplinary Tumor Board Approach to Malignant Pleural Effusions
by Domenico Damiani, Ilaria Girolami, Esther Hanspeter, Christine Mian, Christine Schwienbacher, Johanna Köhl, Stefania Kinspergher, Giovanni Zambello, Francesco Zaraca, Giovanni Negri, Patrizia Pernter, Mohsen Farsad, Sara Gusella and Georgia Levidou
Biomedicines 2026, 14(3), 673; https://doi.org/10.3390/biomedicines14030673 - 16 Mar 2026
Viewed by 908
Abstract
Background: Malignant pleural effusion (MPE) represents a frequent and clinically challenging manifestation of advanced malignancy, particularly in metastatic non-small cell lung cancer (NSCLC). Its management requires integration of diagnostic imaging, symptom-directed therapeutic strategies, and, increasingly, molecular profiling technologies. Recent advancements in this [...] Read more.
Background: Malignant pleural effusion (MPE) represents a frequent and clinically challenging manifestation of advanced malignancy, particularly in metastatic non-small cell lung cancer (NSCLC). Its management requires integration of diagnostic imaging, symptom-directed therapeutic strategies, and, increasingly, molecular profiling technologies. Recent advancements in this field based on liquid medium (so-called liquid biopsy) have achieved a significant increase in sensitivity, enhancing our ability to investigate biofluids and suggesting their potential integration into standard diagnostic practices, far beyond the canonical plasma biopsies. Fluid obtained from MPE after cytological sample centrifugation is rich in cell-free DNA and less susceptible to nucleic acid degradation during processing, improving overall diagnostic accuracy. Methods: This narrative review summarizes current evidence on the clinical management of malignant pleural effusions in patients with metastatic NSCLC, integrating imaging, procedural management, and molecular profiling from a multidisciplinary tumor board perspective. The primary objective was to synthesize contemporary knowledge with particular attention to the feasibility, reliability, and reproducibility of pleural fluid-based molecular testing. Results: MPE poses diagnostic and therapeutic challenges for all members of the multidisciplinary tumor board, traditionally associated with an adverse prognosis. However, recent advances in cytopathology, histopathology, and liquid-based techniques demonstrate that MPE could be an important source of prognostic or predictive information. At the same time, optimal patient management requires careful integration of imaging findings and procedural strategies (such as pleurodesis or indwelling pleural catheters) with individualized systemic therapy selection. Cell-free DNA in pleural effusions is a promising field of exploration and study, potentially suitable for future guideline implementation, after validation in adequately powered studies, contributing to improving patient management, particularly useful in fragile subsets. Conclusions: The management of MPE in advanced NSCLC is evolving toward a multidisciplinary, precision-oriented model that integrates clinical evaluation, imaging, procedural interventions, and molecular testing. Liquid biopsy technology has gained enough analytical robustness and clinical feasibility to be a useful tool in routine analysis. Biofluid-based molecular testing may have outstanding potential, contributing to improving patient management, avoiding repetitive procedures, and optimizing the overall efficiency and cost-effectiveness of diagnostic practices. Moreover, collaborative projects among different specialties help in consolidating trust in the tumor board decision-making process. Full article
(This article belongs to the Special Issue Thoracic Malignancies: From Pathophysiology to Novel Therapeutic Approaches)
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