Leptin-mediated meta-inflammation may provide survival benefit in patients receiving maintenance immunotherapy for extensive-stage small cell lung cancer (ES-SCLC).

BACKGROUND: Only few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial. METHODS: Pre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR). RESULTS: In ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18-0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25-1.29] p = 0.07). CONCLUSIONS: Adipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.

Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study.

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.

Bronchoscopically-visible massive central airway cancer cavitation is associated with metastatic disease, lack of actionable mutations and poor prognosis: a case series.

Cavitating lung tumors occur in approximately 10-15% of the patients, are more commonly associated with squamous histology, and are typically located in the lung parenchyma. Herein we describe an exceedingly rare series of 5 patients, 4 of whom treatment-naïve, whose tumor caused the disruption of the normal airway anatomy at the level of lobar or segmental bronchi, leading to the formation of an endoscopically-visible cavity which ended up in the lung parenchyma or even into the pleural space. Sex (3 males, 2 females), smoking habit (2 never smokers, 2 former smokers, 1 current smoker), and histology (3 adenocarcinoma, 2 squamous cell carcinoma) were heterogeneous, but the 4 patients treatment-naïve presented with metastatic disease, poor ECOG performance status, similar clinical complaints of long duration, and lack of actionable mutations. The only patient who exhibited a meaningful response to treatment had the lowest symptoms' duration, the smallest size of the cavitated mass, and the best performance status at the time of diagnosis. This series provides the first comprehensive description of a rare presentation of lung cancer characterized by similar clinical complaints, delayed diagnosis and poor prognosis.

Application of the International System for Reporting Serous Fluid Cytopathology (TIS): A retrospective institutional study.

BACKGROUND: Cytology of serous effusions is an important diagnostic tool for the diagnosis of cancer, staging, and prognosis of the patient. Herein, we retrospectively applied the International System for Reporting Serous Fluid Cytopathology (TIS) and provided the corresponding risks of malignancy (ROMs). METHODS: Pleural, pericardial, and peritoneal effusion samples were retrieved from the archives of our department and reclassified according to the TIS. The ROM for each category was calculated based on available surgical follow-up. RESULTS: A total of 3790 effusions were studied. Pleural samples (1292) were reclassified as follows: 27 (2.1%) as non-diagnostic (ND), 1014 (78.5%) as negative for malignancy (NFM), 86 (6.6%) as atypia of undetermined significance (AUS), 29 (2.3%) as suspicious of malignancy (SFM), and 136 (10.5%) as malignant (M). Pericardial samples (241) were reclassified as follows: 4 (1.6%) as ND, 173 (71.8%) as NFM, 10 (4.1%) as AUS, 7 (3%) as SFM, and 47 (19.5%), as M. Peritoneal cases (2257) were re-categorised as follows: 31 (1.4%) as ND, 1897 (84%) as NFM, 39 (1.7%) as AUS, 53 (2.4%) as SFM, and 237 (10.5%) as M. The respective ROM values for each category were 18.5%, 15%, 45.3%, 93%, and 100% in pleural effusions; 25%, 13.2%, 35%, 100%, and 100% in pericardial effusions; and 19.3%, 10.4%, 43.5%, 100%, and 100% in peritoneal effusions. CONCLUSIONS: Pleural, pericardial, and peritoneal cytology show high specificity and moderate sensitivity in the evaluation of serous effusions. The ROMs reported in our study were mostly concordant with those published according to the TIS.

The value of cytology in distinguishing malignant mesothelioma: An institutional experience of 210 cases reclassified according to the International System for Reporting Serous Fluid Cytopathology (ISRSFC).

OBJECTIVE: Malignant mesothelioma (MM) is usually diagnosed by histological examination of tissue samples; however, effusion cytology offers an opportunity to identify a strong possibility for mesothelioma diagnosis at an early stage. We conducted a retrospective analysis of cytological specimens from a large series of histologically proven MM diagnosed over 19 years. The cases were reviewed and reclassified according to the International System for Reporting Serous Fluid Cytopathology (ISRSFC). METHODS: A total of 450 cases were identified. Cytological analysis was present in 210 patients (164 pleural and 46 peritoneal effusions). All cases were reviewed and reclassified according to the proposed ISRSFC scheme. A comparison among the cytomorphological features was made throughout the different diagnostic categories. RESULTS: The 210 cases were histologically diagnosed as follows: 192 (91.4%) cases had an epithelioid type and 18 (8.6%) had a sarcomatoid subtype of MM. The cytological cases were reclassified as follows: 2 (0.9%) as non-diagnostic (ND), 81 (38.6%) as negative for malignancy (NFM), 4 (1.9%) as atypia of undetermined significance (AUS), 11 (5.2%) as suspicious for malignancy (SFM), 112 (53.4%) as malignant (MAL). Sarcomatoid cells in the MAL category were characterised cytomorphologically by more pronounced discohesion. In comparison with the epithelioid subtype, the tumour cells appeared solitary with moderate or marked nuclear pleomorphism, and irregular chromatin. CONCLUSIONS: It is important to recognise the cytological characteristics of this aggressive entity to suggest an early and precise possible diagnosis. Morphological features, coupled with clinico-radiological data may help the clinicians in adequately managing the patients.

Diagnosis and Molecular Profiling of Lung Cancer by Percutaneous Ultrasound-Guided Biopsy of Superficial Metastatic Sites Is Safe and Highly Effective.

BACKGROUND: Diagnosis, staging, and molecular profiling of lung cancer are mostly carried out with bronchoscopy or CT-guided aspiration/biopsy. However, patients with locally advanced or advanced disease often harbor "superficial" metastases for which a percutaneous, ultrasound-assisted needle aspiration/biopsy (US-NAB) might represent an equally effective yet less invasive and costly alternative. PATIENTS AND METHODS: We reviewed a prospectively collected database of consecutive patients with known/suspected lung cancer who underwent a US-NAB of a suspected "superficial" metastasis. Cancer genotyping was carried out with next-generation sequencing using the Oncomine™ Focus DNA and RNA fusion panels. PD-L1 immunohistochemistry was performed with the SP263 antibody. Feasibility, diagnostic yield for tissue diagnosis, sensitivity for malignancy, diagnostic yield for the molecular profiling, and complications were the study endpoints. RESULTS: A total of 98 lesions were evaluated, and 93 were biopsied (95% feasibility). The spectrum of sampled sites included lymph nodes (63 patients), bone (11), subcutaneous tissue (8), muscle (7), and the pleura (4). The diagnostic yield for a tissue diagnosis was 93% (91/98). US-NAB correctly identified 85 of the 87 patients finally diagnosed with malignancy (98% sensitivity). Cancer genotyping and PDL1 testing were successfully completed in 41/42 patients (98%) and in 40/50 patients (80%) for whom these tests were requested, respectively. No complications were observed. CONCLUSION: US-NAB of "superficial" metastasis of lung cancer is safe and is associated with high success for diagnosis and molecular profiling. In this clinical setting, using US-NAB as a first-step technique would significantly limit the use of more invasive and costly diagnostic procedures.

Poor Concordance between Sequential Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy in the Diagnosis of Diffuse Interstitial Lung Diseases.

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)-versus surgical lung biopsy (SLB) as the current gold standard-in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5-8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01-0.44), percentage agreement = 38% (95% CI, 18-62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06-0.56), percentage agreement = 48% (95% CI, 26-70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27-0.75), percentage agreement = 62% (95% CI, 38-82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

Interobserver agreement between pathologist, pulmonologist and molecular pathologist to estimate the tumour burden in rapid on-site evaluation smears from endosonography and guided bronchoscopy.

OBJECTIVE: A growing number of studies have suggested that non-pathologists can reliably assess the adequacy and malignancy in rapid on-site evaluation (ROSE) smears prepared during endoscopic sampling procedures. However, no study has verified whether they can also consistently estimate the tumour burden, which is critical for the molecular profiling of lung cancer. We aimed to assess the interobserver agreement (IOA) between a pathologist, a pulmonologist (previously trained in lung and lymph node cytopathology) and a molecular pathologist for the tumour burden in ROSE smears. METHODS: The ROSE smears of consecutive patients with suspected lung cancer undergoing endosonography or guided bronchoscopy were assessed independently by a pathologist, a pulmonologist and a molecular pathologist (gold standard). The IOA for the tumour burden, assessed through k-statistics, was the primary outcome. RESULTS: A total of 322 ROSE smears obtained from 162 patients were evaluated. The IOA between the molecular pathologist and pulmonologist was very good (moderate to substantial), although slightly inferior to the IOA between the molecular pathologist and pathologist in the whole slide set (k: 0.707, 95% confidence interval [CI]: 0.677-0.739 vs 0.793, 95% CI: 0.762-0.815), as well as in smears prepared from lymphadenopathy (k: 0.783, 95% CI: 0.760-0.855 vs 0.827, 95% CI: 0.728-0.892) or from pulmonary nodules/masses (k: 0.558, 95% CI: 0.416-0.686 vs 0.715, 95% CI: 0.621-0.767). CONCLUSIONS: A professionally trained pulmonologist can reliably estimate the tumour burden in bronchoscopically derived ROSE smears, especially in the setting of lymphadenopathy. This can be particularly useful in institutions where a cytopathologist is not available regularly.

A Trained Pulmonologist Can Reliably Assess Endosonography-Derived Lymph Node Samples during Rapid On-Site Evaluation.

BACKGROUND: The widespread use of rapid on-site evaluation is hampered by constraints related to time and resources, inadequate reimbursement, and evidence from randomized trials that show a lack of increase in diagnostic yield and specimen adequacy associated with its usage. OBJECTIVE: We aimed to verify whether a pulmonologist can assess endosonography-derived lymph node samples after a comprehensive and reproducible training provided by a specialist pathologist. METHODS: Prospective, observational trial structured in three phases. In the first (training) phase, a pathologist critically evaluated the smears from 150 archival endosonography cases with a pulmonologist. In the second (test) phase, the pulmonologist was asked to assess 50 archival endosonography-derived samples. In the last (real-life) phase, the pulmonologist classified the samples from 200 patients during the endosonography. The overall agreement between pulmonologist and pathologist (gold standard), assessed through κ-statistics, was the primary outcome. The agreement for the identification of specific cytological categories was the secondary outcome. RESULTS: The overallagreement between pulmonologist and pathologist was 84% (κ0.765, 95% CI 0.732-0.826) in the test phase and 89.7% (κ 0.844, 95% CI 0.799-0.881) in the real-life phase. The agreement for specific cytological categories was 92.7% (95% CI 0.824-0.980) for inadequate samples, 90.3% (95% CI 84.5-94.5%) for reactive lymphadenopathies, 90.5% (95% CI 0.845-0.946) for malignancy, and 73% (95% CI 0.515-0.897) for granulomatous samples. CONCLUSIONS: A trained pulmonologist can reliably assess adequacy and malignancy for endosonography-derived samples, which could be useful in institutions where a cytopathologist/cytotechnician is not available regularly.

Increased frequency of bronchiolar histotypes in lung carcinomas associated with idiopathic pulmonary fibrosis.

AIMS: The association between lung cancer and idiopathic pulmonary fibrosis (IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry. METHODS AND RESULTS: Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 (TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5AC, markers of basal/squamous cell differentiation [cytokeratin (CK) 5/6 and ΔN-p63], and markers related to enteric differentiation (CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile (TTF1/napsin-A/SPA1-triple-positive) was observed in seven of 20 (35% versus 84% in non-IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non-IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component. CONCLUSIONS: The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non-IPF smokers. The prevalence of rare entities showing bronchiole-related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place.

DIPNECH: Association Between Histopathology and Clinical Presentation.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disorder which can be an incidental finding in imaging tests performed during the investigation of another condition, or is the final diagnosis in patients evaluated for chronic obstructive complaints. To explore the possible association between specific histopathology features and the mode of clinical presentation, we retrieved the clinical, functional, radiological, and pathological data of all 13 patients diagnosed with DIPNECH at our Institution over a 14-year period (2000-2014). As compared to patients with incidental disease (6/13, 46 %), patients with symptomatic disease were younger [mean (SD): 57.7 vs. 68.7 years, p = 0.046], were more likely to have mosaic attenuation (100 vs. 0 %, p = 0.001) and small multiple nodules (100 vs. 17 %, p = 0.005) at CT, and showed a significantly higher number of foci of linear neuroendocrine proliferation [median (IQR): 28 (13-37) vs. 6 (5-13), p = 0.018] and of tumorlets [median (IQR): 10 (8-20) vs. 1 (1-1), p = 0.002] at histology. Incidental disease was found in association with pulmonary adenocarcinoma in five out of six patients (83.3 %). The results of our study provide preliminary evidence that symptomatic patients with DIPNECH represent a specific subset characterized by younger age and a higher burden of foci of neuroendocrine proliferation.

Diffuse granulomatous lung disease: combined pathological-HRCT approach.

Granulomatous lung diseases include a large number of conditions among granulomas are the pathological hallmark. Some of these conditions are frequently encountered in clinical practice. Differentiating infectious from noninfectious forms is a priority for the different specialists approaching these diseases, given the different implications for management and treatment. However, differential diagnosis is not always straightforward and the diagnosis of granulomatous disease, considering separately the clinical, radiological and pathological aspects, is at times incomplete or uncertain and requires multidisciplinary assessment. In this paper, we propose a combined HRCT-pathological approach to assess both the topographical and morphological features of the lesions. Based on topography, we can distinguish between granulomatous lesions distributed along the lymphatic vessels, with random distribution or centred on the airways. The prototype of the disease with lymphatic granulomas is sarcoidosis. In contrast, diseases exhibiting a random distribution of granulomas are those with haematogenous spread, the most typical of which is miliary tuberculosis (TB). Many diseases have distribution along the airways including hypersensitivity pneumonia and granulomatous bronchiolitis (including infections with bronchial spread, especially mycobacteriosis). The anatomical approach is completed by the assessment of the morphological aspects of the lesions and associated signs, reflecting both the possible mechanisms of spread and the different types of pathological and/or reparative tissue related to the disease.

Case of a 33-Year-Old Woman With Hemoptysis and Migrant Nodular Cavitary Lesions.

We describe the case of a young 33-year-old woman that was referred to our clinic for evidence of migrant cavitary nodules at CT scan, dyspnea, and blood sputum. Her physical examination showed translucent and thin skin, evident venous vascular pattern, vermilion of the lip thin, micrognathia, thin nose, and occasional Raynaud phenomenon. We prescribed another CT scan that showed multiple pulmonary nodules in both lungs, some of which had evidence of cavitation. Because bronchoscopy was not diagnostic, we decided to perform surgical lung biopsy. At histologic examination, we found the presence of irregularly shaped, but mainly not dendritic, foci of ossification that often contained bone marrow and were embedded or surrounded by tendinous-like fibrous tissue. After incorporating data from the histologic examination, we decided to perform genetic counseling and genetic testing with the use of whole-exome sequencing. The genetic test revealed a heterozygous de novo missense mutation of COL3A1 gene, which encodes for type III collagen synthesis, and could cause vascular Ehlers-Danlos syndrome.

Intrathoracic Lymph Node Microcalcifications are Associated With a High Prevalence of Malignancy and Anaplastic Lymphoma Kinase Rearrangement: The "Calce" Study.

BACKGROUND: Microcalcifications are acknowledged as a malignancy risk factor in multiple cancers. However, the prevalence and association of intrathoracic lymph node (ILN) calcifications with malignancy remain unexplored. METHODS: In this cross-sectional study, we enrolled patients with known/suspected malignancy and an indication for endosonography for diagnosis or ILN staging. We assessed the prevalence and pattern of calcified ILNs and the prevalence of malignancy in ILNs with and without calcifications. In addition, we evaluated the genomic profile and PD-L1 expression in lung cancer patients, stratifying them based on the presence or absence of ILN calcifications. RESULTS: A total of 571 ILNs were sampled in 352 patients. Calcifications were detected in 85 (24.1%) patients and in 94 (16.5%) ILNs, with microcalcifications (78/94, 83%) being the predominant type. Compared with ILNs without calcifications (214/477, 44.9%), the prevalence of malignancy was higher in ILNs with microcalcifications (73/78, 93.6%; P<0.0001) but not in those with macrocalcifications (7/16, 43.7%; P=0.93). In patients with lung cancer, the high prevalence of metastatic involvement in ILNs displaying microcalcifications was independent of lymph node size (< or >1 cm) and the clinical stage (advanced disease; cN2/N3 disease; cN0/N1 disease). The anaplastic lymphoma kinase (ALK) rearrangement was significantly more prevalent in patients with than in those without calcified ILNs (17.4% vs. 1.7%, P<0.001), and all of them exhibited microcalcifications. CONCLUSION: ILN microcalcifications are common in patients undergoing endosonography for suspected malignancy, and they are associated with a high prevalence of metastatic involvement and ALK rearrangement.