The 2022 Banff Meeting Lung Report.

The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

Diaphragm Dysfunction Predicts Weaning Outcome after Bilateral Lung Transplant.

BACKGROUND: Diaphragm dysfunction and its effects on outcomes of ventilator weaning have been evaluated in mixed critical care populations using diaphragm thickening fraction (the ratio of the difference between ultrasound diaphragm thickness at end-inspiration and end-expiration to diaphragm thickness at end-expiration) or neuroventilatory efficiency (the ratio of tidal volume and peak electrical activity of the diaphragm). Such data are not available in bilateral-lung transplant recipients. The authors hypothesized that (1) diaphragm dysfunction, as defined by a diaphragm thickening fraction less than 29%, is more likely to occur in difficult weaning; (2) diaphragm thickening fraction and neuroventilatory efficiency predict weaning outcome; and (3) duration of mechanical ventilation before the first spontaneous breathing trial is associated with diaphragm dysfunction. METHODS: Adult bilateral-lung transplant patients admitted to the intensive care unit were screened at the time of the first spontaneous breathing trial (pressure-support of 5 cm H2O and 0 positive end-expiratory pressure). At the fifth minute, diaphragm thickening fraction and neuroventilatory efficiency were measured during three respiratory cycles. Weaning was classified as simple, difficult, or prolonged (successful extubation at the first spontaneous breathing trial, within three or after three spontaneous breathing trials, respectively). RESULTS: Forty-four subjects were enrolled. Diaphragm dysfunction occurred in 14 subjects (32%), all of whom had difficult weaning (78% of the subgroup of 18 patients experiencing difficult weaning). Both diaphragm thickening fraction (24 [20 to 29] vs. 39 [35 to 45]%) and neuroventilatory efficiency (34 [26 to 45] vs. 55 [43 to 62] ml/µV) were lower in difficult weaning (both P < 0.001). The areas under the receiver operator curve predicting difficult weaning were 0.88 (95% CI, 0.73 to 0.99) for diaphragm thickening fraction and 0.85 (95% CI, 0.71 to 0.95) for neuroventilatory efficiency. The duration of ventilation demonstrated a linear inverse correlation with both diaphragm thickening fraction and neuroventilatory efficiency. CONCLUSIONS: Diaphragm dysfunction is common after bilateral-lung transplantation and associated with difficult weaning. In such patients, average values for diaphragm thickening fraction and neuroventilatory efficiency were reduced compared to patients with simple weaning. Both parameters showed similar accuracy for predicting success of ventilator weaning, demonstrating an inverse relationship with duration of ventilation.

Safety and Efficacy of Salvage Surgery after Treatment With Immune-Checkpoint Adjuvant Inhibitors for Advanced Non-Small Cell Lung Cancer: A Multicentric Study.

OBJECTIVE: In advanced non-small cell lung cancer (NSCLC), immune-checkpoint inhibitors (ICIs) can achieve significant clinical responses. This raises the question of whether to consider salvage surgery as a curative treatment option. Few case series reported encouraging results in terms of pathological response. However, intraoperative risk and postoperative morbidity have been highlighted. This study aims to assess the safety and feasibility of surgery after ICIs administration and to evaluate its effectiveness on the final pathological examination. METHODS: We retrospectively identified stages III-IVA NSCLC consecutive patients who underwent surgery with radical intent after ICIs at three National Centers (2016-2022). Before treatment, all patients were considered unresectable by a multidisciplinary discussion. After surgery, pathological response was evaluated according to the International Association for the Study of Lung Cancer (IASLC) recommendation. RESULTS: Thirty-one patients were included; pretreatment clinical stage was: IIIA in 4 patients (10%), IIIB in 13 (42%), IIIC in 3 (13%), and IVA in 11 (35%). Median treatment duration was four cycles. Only anatomical resections were performed, with lobectomy that represent the main type of resection (22 patients, 74%). A minimally invasive approach was performed in 10 patients (32%), with a conversion rate of 0%. Postoperative complications were observed in eight patients (25%). Complete pathologic response (CPR) and major pathologic response (MPR) were 48% and 16%, respectively. Two and 3-years survival were 88%. CONCLUSIONS: Based on our experience, salvage surgery of advanced NSCLC treated with ICIs confirm his feasibility and safety in responder patients. Moreover, it is associated with low morbidity, high CPR rate, and satisfying medium-term survival.

Comparative Analysis of Comprehensive Genomic Profile in Thymomas and Recurrent Thymomas Reveals Potentially Actionable Mutations for Target Therapies.

Molecular profiles of thymomas and recurrent thymomas are far from being defined. Herein, we report an analysis of a comprehensive genetic profile (CGP) in a highly selected cohort of recurrent thymomas. Among a cohort of 426 thymomas, the tissue was available in 23 recurrent tumors for matching the biomolecular results obtained from primary and relapse samples. A control group composed of non-recurrent thymoma patients was selected through a propensity score match analysis. CGP was performed using the NGS Tru-SightOncology assay to evaluate TMB, MSI, and molecular alterations in 523 genes. CGP does not differ when comparing initial tumor with tumor relapse. A significantly higher frequency of cell cycle control genes alterations (100.0% vs. 57.1%, p = 0.022) is detected in patients with early recurrence (<32 months) compared to late recurrent cases. The CGPs were similar in recurrent thymomas and non-recurrent thymomas. Finally, based on NGS results, an off-label treatment or clinical trial could be potentially proposed in >50% of cases (oncogenic Tier-IIC variants). In conclusion, CGPs do not substantially differ between initial tumor vs. tumor recurrence and recurrent thymomas vs. non-recurrent thymomas. Cell cycle control gene alterations are associated with an early recurrence after thymectomy. Multiple target therapies are potentially available by performing a comprehensive CGP, suggesting that a precision medicine approach on these patients could be further explored.

Vascular/epithelial changes as late sequelae after recovery from SARS-COV-2 infection: an in-vivo comparative study.

AIMS: While there is partial evidence of lung lesions in patients suffering from long COVID there are substantial concerns about lung remodelling sequelae after COVID-19 pneumonia. The aim of the present retrospective comparative study was to ascertain morphological features in lung samples from patients undergoing tumour resection several months after SARS-CoV-2 infection. METHODS AND RESULTS: The severity of several lesions with a major focus on the vascular bed was analysed in 2 tumour-distant lung fragments of 41 cases: 21 SARS-CoV-2 (+) lung tumour (LT) patients and 20 SARS-CoV-2 (-) LT patients. A systematic evaluation of several lesions was carried out by combining their scores into a grade of I-III. Tissue SARS-CoV-2 genomic/subgenomic transcripts were also investigated. Morphological findings were compared with clinical, laboratory and radiological data. SARS-CoV-2 (+) LT patients with previous pneumonia showed more severe parenchymal and vascular lesions than those found in SARS-CoV-2 (+) LT patients without pneumonia and SARS-CoV-2 (-) LT patients, mainly when combined scores were used. SARS-CoV-2 viral transcripts were not detected in any sample. SARS-CoV-2 (+) LT patients with pneumonia showed a significantly higher radiological global injury score. No other associations were found between morphological lesions and clinical data. CONCLUSIONS: To our knowledge, this is the first study that, after a granular evaluation of tissue parameters, detected several changes in lungs from patients undergoing tumour resection after SARS-CoV-2 infection. These lesions, in particular vascular remodelling, could have an important impact overall on the future management of these frail patients.

Comprehensive bronchoalveolar lavage characterization in COVID-19 associated acute respiratory distress syndrome patients: a prospective cohort study.

COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1ß and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS.

Radiomics of spinal muscles: toward a radiological biomarker for allograft rejection in lung transplant.

PURPOSE: To assess the role of muscle composition and radiomics in predicting allograft rejection in lung transplant. MATERIAL AND METHODS: The last available HRCT before surgery of lung transplant candidates referring to our tertiary center from January 2010 to February 2020 was retrospectively examined. Only scans with B30 kernel reconstructions and 1 mm slice thickness were included. One radiologist segmented the spinal muscles of each patient at the level of the 11th dorsal vertebra by an open-source software. The same software was used to extract Hu values and 72 radiomic features of first and second order. Factor analysis was applied to select highly correlating features and then their prognostic value for allograft rejection was investigated by logistic regression analysis (level of significance p < 0.05). In case of significant results, the diagnostic value of the model was computed by ROC curves. RESULTS: Overall 200 patients had a HRCT prior to the transplant but only 97 matched the inclusion criteria (29 women; mean age 50.4 ± 13 years old). Twenty-one patients showed allograft rejection. The following features were selected by the factor analysis: cluster prominence, Imc2, gray level non-uniformity normalized, median, kurtosis, gray level non-uniformity, and inverse variance. The radiomic-based model including also Hu demonstrated that only the feature Imc2 acts as a predictor of allograft rejection (p = 0.021). The model showed 76.6% accuracy and the Imc2 value of 0.19 demonstrated 81% sensitivity and 64.5% specificity in predicting lung transplant rejection. CONCLUSION: The radiomic feature Imc2 demonstrated to be a predictor of allograft rejection in lung transplant.

Exploring the pathologist's role in understanding COVID-19: from pneumonia to long-COVID lung sequelae.

The crucial role of pathologists in enhancing our understanding of SARS-CoV-2-related disease, from initial pneumonia manifestations to persistent long COVID lung symptoms, is the focus of this review. Pathological explorations have offered unprecedented insights into the early stages of severe COVID-19, shedding light on the interplay between the virus and subsequent complications, thereby shaping clinical approaches. Growing interest is directed to residual lung abnormalities of COVID-19 survivors. Although various radiological studies reported long-lasting pulmonary changes (e.g., ground glass opacities, reticulations, and bronchiectasis), the true incidence of pulmonary fibrosis and corresponding pathological findings in these patients remains largely unknown. There are a few high-impact and knowledgeable works on late complications in COVID-19 survivors, several coming from explant or autopsy cases, and rare cases from in vivo sampling. The study of biopsy samples has further deepened our knowledge of the aftermath of COVID-19 on lung tissue, uncovering alterations at the cellular level and shifts in vascular and epithelial dynamics. Despite the substantial progress made, future research is needed to devise a uniform strategy for interpreting lung biopsies, with a focus on leveraging advanced tools such as molecular and digital pathology techniques, along with artificial intelligence.

Longitudinal liquid biopsy anticipates hyperprogression and early death in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionised treatment of advanced non-small cell lung cancer (aNSCLC), but a proportion of patients had no clinical benefit and even experienced detrimental effects. This study aims to characterise patients experiencing hyperprogression (HPD) and early death (ED) by longitudinal liquid biopsy. METHODS: aNSCLC receiving ICIs were prospectively enrolled. Plasma was collected at baseline (T1) and after 3/4 weeks of treatment, according to the treatment schedule (T2). Cell-free DNA (cfDNA) was quantified and analysed by NGS. cfDNA quantification and variant allele fraction (VAF) of tumour-associated genetic alterations were evaluated for their potential impact on outcome. The genetic alteration with the highest VAF (maxVAF) at baseline was considered as a reference. RESULTS: From March 2017 to August 2019, 171 patients were enrolled. Five cases matched criteria for HPD and 31 ED were recorded; one overlapped. Quantification of cfDNA at T2 and its absolute and relative variation (T2-T1) were significantly associated with the risk of ED (P = 0.012, P = 0.005, P = 0.009). MaxVAF relative change (T2-T1/T1) was significantly associated with the risk of HPD (P = 0.02). After identifying optimal cut-off values, a two-step risk assessment model was proposed. DISCUSSION: Liquid biopsy performed early during treatment has the potential to identify patients at high risk of ED and HPD.

Tumor Immune-Infiltrate Landscape After Chemo-Radiotherapy in a Case Series of Patients with Non-small Cell Lung Cancer: Pretreatment Predictors and Correlation With Outcome.

INTRODUCTION: Data on tumor immune-milieu after chemo-radiation (CT-RT) are scarce. Noninvasive tools are needed to improve the treatment of non-small cell lung cancer (NSCLC), especially in the locally advanced (LA) setting. METHODS: We collected a series of superior-sulcus (SS)- patients with NSCLC referred to our Institute (2015-2019), eligible for a preoperative CT-RT. We characterized tumor-infiltrating immune cells (TIICs), determined PD-L1-TPS and the residual viable tumor cells (RVTC). Radiological and metabolic responses were reviewed. We calculated pre-surgery neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Eight patients were included. Radiological responses were 6 disease stabilities (SD) and 2 partial responses (PR). Metabolic responses were 4 SD and 4 PR. CD68+-TIICs were correlated with metabolic response and lower RVTC. CD68+-TIICs were associated with higher PLR. Higher PLR values seemed linked with lower RVTC. CONCLUSIONS: These preliminary results could be useful for consolidation treatment selection for patients with LA-NSCLC without evaluable baseline PD-L1 and higher PLR values.