Faculty Bibliography

BACKGROUND AND OBJECTIVE/UNASSIGNED:Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung carcinoma cases and is often diagnosed at an advanced stage, leading to poor prognosis. Local tumor ablation is an emerging treatment option; however, thermal ablation techniques, such as radiofrequency ablation (RFA) or microwave ablation (MWA), can have many adverse events, such as a negative impact on the extracellular matrix (ECM) architecture, promoting tumor progression. Pulsed electric field (PEF) therapy is a non-thermal modality that induces electrostimulatory pulses, which can preserve the ECM architecture while stimulating anti-tumor immune responses. This narrative review evaluates the safety, efficacy, and immunomodulatory potential of PEF therapy in NSCLC. METHODS/UNASSIGNED:A comprehensive literature search was conducted in Google Scholar, MEDLINE, Embase, Scopus, PubMed, Web of Science, UpToDate, and the Cochrane Library through October 1, 2025. Eligible studies included adult patients (≥18 years) with histologically confirmed NSCLC treated with PEF. Two independent reviewers screened studies and extracted data on patient demographics, tumor characteristics, treatment modalities, adverse events, and outcomes. KEY CONTENT AND FINDINGS/UNASSIGNED:33%) compared with standard systemic therapy. CONCLUSIONS/UNASSIGNED:PEF may play a role in stimulating an anti-tumor response and represents a promising, safe, non-thermal ablation modality for NSCLC treatment. It preserves ECM integrity while inducing local and systemic immunomodulatory effects. Early clinical evidence suggests potential efficacy. Nevertheless, randomized controlled trials are required to confirm clinical benefit and identify the patient populations most likely to benefit from PEF therapy.

Lung cancer is the leading cause of cancer deaths, and despite therapeutic advances, recurrence and resistance persist. Local tumor ablation can function as an in situ vaccine, but thermal techniques may disrupt antigen and extracellular matrix integrity, potentially limiting immunogenicity, whereas cryoablation has been shown to preserve tumor antigens and matrix architecture while inducing immunogenic cell death. Bronchoscopic cryoimmunotherapy (BCI) aims to prime antitumor immunity rather than achieve complete tumor eradication. We review preclinical and clinical studies evaluating cryoablation and BCI in non-small cell lung cancer (NSCLC), focusing on immune mechanisms, delivery approaches, and combination with systemic therapies, particularly immune checkpoint inhibitors (ICIs). Preclinical models demonstrate that cryoablation releases danger signals and intact tumor antigens, drives dendritic cell maturation, expands effector CD8+ T cells, and activates STING-dependent type I interferon pathways. Early-phase human studies of BCI monotherapy show systemic immune stimulation, including reductions in the derived neutrophil-to-lymphocyte ratio and expansion of CD8+ effector memory populations. Combination cryoablation-ICI regimens have revealed improved response rates in some cohorts, although clinical outcomes have been limited by small, heterogeneous, and non-randomized studies. BCI is a mechanistically compelling, minimally invasive therapy, but its clinical benefit remains unproven and warrants rigorous randomized evaluation.

The abscopal effect, first described in 1953, refers to the regression of distant, non-irradiated tumors following localized therapy. Historically considered rare, interest in this phenomenon has increased with the introduction of immunotherapy and local treatments for non-small cell lung cancer (NSCLC). This review summarizes the current evidence on the pathophysiology, clinical observations, and assessment of the abscopal effect in NSCLC following radiotherapy, lung ablation, and combined multimodality therapies. Preclinical and early clinical studies suggest that radiotherapy and ablative techniques such as cryoablation, microwave ablation, and pulsed electric field therapy may induce immunogenic cell death, leading to the release of tumor antigens and danger-associated molecular patterns that can activate systemic antitumor immune responses. When combined with immune checkpoint inhibitors, these local therapies may enhance immune activation, potentially improving both local and distant tumor control. However, recognition of abscopal effects remains inconsistent, largely due to limitations of conventional response assessment criteria. While iRECIST partly captures atypical response patterns, unequivocal out-of-field tumor regression is not systematically recorded in most clinical trials. The available evidence, primarily from preclinical models and early-phase studies, suggests that the true incidence of abscopal effects in NSCLC may be underrecognized. Accordingly, we propose a working definition of the abscopal effect in NSCLC: the regression (complete or partial response by iRECIST) of one or more non-irradiated lesions distant from the primary treatment site, occurring after localized therapy with or without systemic treatment, and confirmed by follow-up imaging within 4-8 weeks. Establishing standardized terminology and assessment criteria will be essential for accurately identifying and integrating potential abscopal responses in future NSCLC research and clinical practice.

BACKGROUND:Pembrolizumab (anti-PD-1 antibody) plus lenvatinib (multityrosine kinase inhibitor) showed high clinical activity in PEMMELA cohort 1 in patients with pleural mesothelioma pre-treated with platinum-based chemotherapy. This study (cohort 2) aimed to investigate the clinical activity of this combination in patients with pleural mesothelioma who progressed after first-line nivolumab plus ipilimumab. METHODS:PEMMELA is a prospective, single-centre, single-arm, open-label, investigator-initiated phase 2 trial, done at the Netherlands Cancer Institute, Amsterdam, the Netherlands. Cohort 2 included patients aged 18 years and older with histologically confirmed pleural mesothelioma, an Eastern Cooperative Oncology Group performance status 0-1, and measurable disease according to the modified Response Evaluation Criteria in Solid Tumors for mesothelioma version 1.1, who progressed after treatment with nivolumab plus ipilimumab. Pembrolizumab (200 mg every 3 weeks intravenously) plus lenvatinib (20 mg orally daily) was administered for up to 2 years, or until disease progression, or unacceptable toxicity. The primary endpoint was objective response rate assessed by the local investigator. All patients who had received at least one cycle of pembrolizumab plus lenvatinib and had their disease evaluated were considered evaluable for the primary endpoint. All patients who received at least one cycle of the study treatment were included in the safety analysis set. Patients were not involved in study design. This study is registered with ClinicalTrials.gov (NCT04287829), and is complete. FINDINGS/RESULTS:Between Dec 14, 2022, and March 5, 2023, 24 patients were screened, of whom 20 were enrolled and received at least one cycle of pembrolizumab plus lenvatinib. Of these 20 patients, 17 patients (85%) were male and three (15%) were female. At data cutoff (Sept 1, 2024), with a median follow-up of 11·9 months (IQR 10·8-15·8), 12 (60%, 95% CI 36-81%) of 20 patients had an objective response. 14 (70%) of 20 patients developed grade 3 or 4 treatment-related adverse events, of which most common grade 3 events were hypertension (five patients [25%]) and fatigue including malaise (four patients [20%]). Ten treatment-related serious adverse events were observed in seven patients. Nine (45%) of 20 patients required at least one dose reduction and two (10%) discontinued treatment due to toxicity. There were no treatment related deaths. INTERPRETATION/CONCLUSIONS:This study met its primary endpoint, showing high clinical activity of pembrolizumab plus lenvatinib, but with substantial toxicity, in patients with pleural mesothelioma who had progressed after first-line nivolumab plus ipilimumab. This drug combination is promising for future studies in pleural mesothelioma. FUNDING/BACKGROUND:Merck Sharp and Dohme.

BACKGROUND/UNASSIGNED:Pleural mesothelioma is an aggressive malignancy with a poor prognosis. The role of surgery in its management remains controversial, with ongoing debate regarding the definition of resectable disease. Neoadjuvant therapy aims to reduce tumor burden. This systematic review evaluates prospective neoadjuvant trials in pleural mesothelioma to identify subgroups that may benefit from this approach. METHODS/UNASSIGNED:A systematic search was conducted from inception to July 01, 2024, for phase II/III prospective trials evaluating neoadjuvant systemic therapy followed by surgery in adult patients with histologically confirmed pleural mesothelioma. Data were extracted on patient characteristics, treatment regimens, surgical outcomes, survival, and adverse events. RESULTS/UNASSIGNED:. 24.8 months (IQR, 12.6-37.4 months), P=0.01}. CONCLUSIONS/UNASSIGNED:This review shows that the predominant neoadjuvant approach consists of platinum doublet chemotherapy, but the role of immunotherapy is being explored. Additional randomized trials are needed to determine the optimal neoadjuvant strategy and patient subgroups most likely to benefit.

BACKGROUND:High-grade pre-invasive endobronchial lesions have the potential to progress to squamous cell carcinoma (SCC), but their natural history varies. The optimal management of these lesions is controversial, with treatment strategies varying across institutions. This study aims to compare the progression free and overall survival outcomes between patients with high-grade pre-invasive endobronchial lesions who received primary treatment versus patients who were treated on progression. METHODS:We conducted a retrospective cohort study across two oncology centers: University College London Hospitals (UCLH, United Kingdom) and Amsterdam University Medical Center (AUMC, The Netherlands). Patients with high-grade pre-invasive lesions underwent surveillance with repeat bronchoscopy and CT scans. At AUMC, patients routinely received endobronchial primary treatment, whereas at UCLH, treatment was reserved for cases that progressed to SCC. Primary outcome was progression-free survival (PFS), and the secondary outcome was overall survival (OS). RESULTS:Between 1998 and 2017, 85 patients were included in the study: 34 (40 %) received primary treatment, while 51 (60 %) received treatment on progression. The latter group had a higher proportion of carcinoma in situ (CIS) compared to the primary treatment group (78.4 % vs. 38.2 %, p = 0.001) and was significantly younger (median age: 67.0 vs. 77.0 years, p = 0.001). Median overall follow-up time was 46.2 months. Primary treatment was associated with a significantly reduced risk of disease progression (HR = 0.39, 95 % CI: 0.21-0.73, p = 0.002). Median PFS was 71.0 months in the primary treatment group versus 38.0 months in the treatment on progression group (p = 0.002). Multivariate Cox regression analysis identified both primary treatment (HR = 0.47, 95 % CI: 0.26-0.87, p = 0.015) and age (HR = 1.04, 95 % CI: 1.01-1.07, p = 0.013) as independent predictors of OS. CONCLUSION/CONCLUSIONS:Our study showed that high-grade pre-invasive lesion patients who underwent primary treatment had a significantly improved PFS and OS.

METHODS:In this review, the historical development of tumor response criteria is examined and an interview was conducted with one of the original researchers behind the original study. This study, published nearly five decades ago, assessed tumor size through palpation and measurements of simulated tumor masses ("balls under mattresses"). The methodology used in that early study as well as in subsequent research that has influenced modifications of the current response evaluation criteria was critically evaluated. RESULTS:The current tumor response criteria trace back to a 1976 study by Moertel and Hanley, which relied on palpation to measure tumor size. The key outcome, a 50% reduction in the product of the longest perpendicular diameters of the most measurable tumor mass, formed the basis for later criteria. The World Health Organization criteria adopted these thresholds for response and introduced a 25% increase as a cutoff for progression. Later, unidimensional measurements replaced two-dimensional ones, with adjusted thresholds accordingly. These criteria further inspired the development of specialized response criteria such as Choi, mRECIST, and PERCIST. CONCLUSION/CONCLUSIONS:By analyzing the evolution of RECIST, it is highlighted that these criteria are not fixed standards but rather the product of a series of pragmatic choices and compromises rooted in their historical context. With advances in technology, including artificial intelligence and volumetric imaging, it is timely to reassess the reliability of current criteria and explore new approaches to tumor response evaluation.

BACKGROUND:Asbestosis, a rare pneumoconiosis marked by diffuse pulmonary fibrosis, arises from prolonged asbestos exposure. Its diagnosis, guided by the Helsinki criteria, relies on exposure history, clinical findings, radiology, and lung function. However, interobserver variability complicates diagnoses and financial compensation. This study prospectively validated the sensitivity of an AI-driven assessment for asbestosis compensation in the Netherlands. Secondary objectives included evaluating specificity, accuracy, predictive values, area under the curve of the receiver operating characteristic (ROC-AUC), area under the precision-recall curve (PR-AUC), and interobserver variability. MATERIALS AND METHODS/METHODS:Between September 2020 and July 2022, 92 adult compensation applicants were assessed using both AI models and pulmonologists' reviews based on Dutch Health Council criteria. The AI model assigned an asbestosis probability score: negative (< 35), uncertain (35-66), or positive (≥ 66). Uncertain cases underwent additional reviews for a final determination. RESULTS:The AI assessment demonstrated sensitivity of 0.86 (95% confidence interval: 0.77-0.95), specificity of 0.85 (0.76-0.97), accuracy of 0.87 (0.79-0.93), ROC-AUC of 0.92 (0.84-0.97), and PR-AUC of 0.95 (0.89-0.99). Despite strong metrics, the sensitivity target of 98% was unmet. Pulmonologist reviews showed moderate to substantial interobserver variability. CONCLUSION/CONCLUSIONS:The AI-driven approach demonstrated robust accuracy but insufficient sensitivity for validation. Addressing interobserver variability and incorporating objective fibrosis measurements could enhance future reliability in clinical and compensation settings. RELEVANCE STATEMENT/CONCLUSIONS:The AI-driven assessment for financial compensation of asbestosis showed adequate accuracy but did not meet the required sensitivity for validation. KEY POINTS/CONCLUSIONS:We prospectively assessed the sensitivity of an AI-driven assessment procedure for financial compensation of asbestosis. The AI-driven asbestosis probability score underperformed across all metrics compared to internal testing. The AI-driven assessment procedure achieved a sensitivity of 0.86 (95% confidence interval: 0.77-0.95). It did not meet the predefined sensitivity target.

Pleural mesothelioma (PM) is a lethal cancer often linked to asbestos exposure. The COVID-19 pandemic caused a global health crisis, raising concerns about its impact on cancer diagnoses and treatments. In response to the immense pressures on the healthcare system caused by the COVID-19 pandemic, many countries advised prioritizing essential healthcare services while postponing or suspending care considered non-emergent to prevent overburdening healthcare systems. This study assesses the impact of COVID-19 on the incidence, treatment, and overall survival of PM patients in the Netherlands between 2018 and 2022. Data were collected from the Netherlands Cancer Registry for 2,629 PM patients. Incidence, treatment patterns, and survival rates were analyzed using statistical methods, including Kruskal-Wallis and log-rank tests. PM incidence dropped 13.2% in 2020 during the pandemic, with a 58.8% increase in patients receiving best supportive care and a decline in chemotherapy use (from 39.4% to 32.0%). In 2021, diagnoses rebounded (+ 15.2%), and immunotherapy use rose following its approval. However, no significant difference in overall survival was found between 2018 and 2022. COVID-19 led to a temporary decline in PM diagnoses and systemic treatments in 2020, followed by recovery in 2021. Despite these changes, overall survival rates remained stable.