Faculty Bibliography

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.

The CheckMate 743 trial established nivolumab and ipilimumab as the standard first-line treatment for unresectable pleural mesothelioma. However, optimal management following disease progression after a durable response to dual immunotherapy remains unclear. We report two cases of patients with pleural mesothelioma (epithelioid subtype) initially treated with nivolumab-ipilimumab, achieving prolonged disease control. Both patients experienced disease progression several years after treatment discontinuation and were subsequently retreated with nivolumab-ipilimumab on regulatory approval. In both cases, retreatment resulted in stable disease for at least 12 months. However, immune-related toxicities occurred, with one patient developing recurrent colitis and the other experiencing nephrotic syndrome, ultimately leading to treatment discontinuation. These cases suggest that retreatment with dual immunotherapy may be a viable strategy for selected patients with previous durable responses, although the risk of immune-related toxicity remains significant. Given the lack of prospective data, further research is needed to determine whether rechallenge with nivolumab-ipilimumab offers superior outcomes compared with chemotherapy or best supportive care in this setting. Rechallenging patients with pleural mesothelioma with nivolumab-ipilimumab after a durable response is feasible but associated with immune-related toxicity.

Broncho-esophageal fistulas (BEFs) are a rare but serious complication that can occur after esophagectomy, often resulting in aspiration, respiratory issues, and infection. Management depends on fistula size and location, with options including conservative treatments, surgical closure and stenting. Conventional treatment involves esophageal stents, which may be insufficient for larger or more complex fistulas. This case report describes the first use of a 3D-printed airway stent in combination with an esophageal stent to treat a broncho-esophageal fistula. A 70-year-old patient with distal esophageal adenocarcinoma, treated with neoadjuvant chemoradiation, underwent robot-assisted minimally invasive esophagectomy. The procedure was complicated by a broncho-esophageal fistula, leading to multiple interventions. Despite dual stenting with a custom 3D airway stent, the fistula persisted, and the patient was transitioned to supportive care due to disease progression. This case, the first to use a 3D-printed airway stent for a broncho-esophageal fistula, demonstrates that the stent did not achieve closure, likely due to excessive pressure against the endobronchial wall. This underscores the need for improved 3D stent designs, offering important insights for interventional pulmonologists.

RET fusion-positive NSCLC accounts for 1% to 2% of lung carcinoma cases. Although two Food and Drug Administration-approved selective RET inhibitors, pralsetinib, and selpercatinib, have revealed efficacy in managing RET fusion-positive NSCLC, this case series is unique in its focus on the intracranial response to selpercatinib after disease progression during pralsetinib treatment. This report contributes to the literature by providing evidence of selpercatinib's potential as a treatment option in such refractory cases. The patients described in both cases were diagnosed with metastatic RET fusion-positive NSCLC and developed intracranial metastases during pralsetinib treatment. After switching to selpercatinib, both exhibited significant intracranial responses. The first patient reported a reduction in brain metastasis size and maintained a response for over 1.5 years. The second patient also responded intracranially to selpercatinib but unfortunately passed away 8 months later owing to pulmonary hemorrhage, possibly linked to prior radiation treatment. These cases highlight the potential efficacy of selpercatinib in treating intracranial metastases in RET fusion-positive patients with NSCLC after pralsetinib-refractory progression. The key takeaway is that selpercatinib may offer a viable treatment option in such scenarios, although more extensive studies are needed to determine its role as a monotherapy or in combination with other treatments.

INTRODUCTION:Persistent air leak (PAL) is associated with prolonged hospitalization, high morbidity and increased treatment costs. Conservative treatment consists of observation, chest tube drainage, and pleurodesis. Guidelines recommend surgical evaluation if air leak does not respond after 3-5 days. One-way endobronchial valves (EBV) have been proposed as a treatment option for patients with PAL in which surgical treatment is not feasible, high risk or has failed. We aimed to provide a comprehensive overview of reported EBV use for PAL and issue best practice recommendations based on multicenter experience. METHODS:We conducted a retrospective observational case-series study at four different European academic hospitals and provided best practice recommendations based on our experience. A systematic literature review was performed to summarize the current knowledge on EBV in PAL. RESULTS:We enrolled 66 patients, male (66.7%), median age 59.5 years. The most common underlying lung disease was chronic obstructive pulmonary disease (39.4%) and lung cancer (33.3%). The median time between pneumothorax and valve placement was 24.5 days (interquartile range: 14.0-54.3). Air leak resolved in 40/66 patients (60.6%) within 30 days after EBV treatment. Concerning safety outcome, no procedure-related mortality was reported and complication rate was low (6.1%). Five patients (7.6%) died in the first 30 days after intervention. CONCLUSION:EBV placement is a treatment option in patients with PAL. In this multicenter case-series of high-risk patients not eligible for lung surgery, we show that EBV placement resulted in air leak resolution in 6 out of 10 patients with a low complication rate. Considering the minimally invasive nature of EBV to treat PAL as opposed to surgery, further research should investigate if EBV treatment should be expanded in low to intermediate risk PAL patients.

INTRODUCTION/UNASSIGNED:Tracheobronchial amyloidosis is a rare idiopathic disorder characterised by extracellular deposition of misfolded protein fibrils in the tracheobronchial tree. It presents with nonspecific symptoms. Deciding on the best treatment approach can be challenging due to the lack of a treatment guideline. We undertook a review to assess the therapeutic options for tracheobronchial amyloidosis and to highlight gaps within the existing evidence. METHODS/UNASSIGNED:We performed a literature search from 1 January 1990 until 1 March 2022 to identify relevant literature regarding patient characteristics, symptoms, management and prognosis for patients with tracheobronchial amyloidosis. RESULTS/UNASSIGNED:77 studies consisting of 300 patients were included. We found a great heterogeneity in the management of tracheobronchial amyloidosis patients. Although a fifth of the reported patients were managed with a wait-and-see approach, many different treatments were used as a single intervention, or multiple treatments were combined. An interesting finding is the slightly higher percentage of patients with Sjögren syndrome (n=5, 1.7%) and tracheobronchial amyloidosis compared to the normal population (0.5-1.0%). CONCLUSIONS/UNASSIGNED:There is a great heterogeneity in the management of tracheobronchial amyloidosis patients. The treatment is still based on expert opinion due to the lack of a treatment guideline. Various treatment approaches include a wait-and-see approach, external beam radiotherapy, therapeutic bronchoscopy, immunosuppressive treatment and surgery.

PURPOSE/OBJECTIVE:Pleural plaques (PPs) are morphologic manifestations of long-term asbestos exposure. The relationship between PP and lung function is not well understood, whereas the time-consuming nature of PP delineation to obtain volume impedes research. To automate the laborious task of delineation, we aimed to develop automatic artificial intelligence (AI)-driven segmentation of PP. Moreover, we aimed to explore the relationship between pleural plaque volume (PPV) and pulmonary function tests. MATERIALS AND METHODS/METHODS:Radiologists manually delineated PPs retrospectively in computed tomography (CT) images of patients with occupational exposure to asbestos (May 2014 to November 2019). We trained an AI model with a no-new-UNet architecture. The Dice Similarity Coefficient quantified the overlap between AI and radiologists. The Spearman correlation coefficient ( r ) was used for the correlation between PPV and pulmonary function test metrics. When recorded, these were vital capacity (VC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO). RESULTS:We trained the AI system on 422 CT scans in 5 folds, each time with a different fold (n = 84 to 85) as a test set. On these independent test sets combined, the correlation between the predicted volumes and the ground truth was r = 0.90, and the median overlap was 0.71 Dice Similarity Coefficient. We found weak to moderate correlations with PPV for VC (n = 80, r = -0.40) and FVC (n = 82, r = -0.38), but no correlation for DLCO (n = 84, r = -0.09). When the cohort was split on the median PPV, we observed statistically significantly lower VC ( P = 0.001) and FVC ( P = 0.04) values for the higher PPV patients, but not for DLCO ( P = 0.19). CONCLUSION/CONCLUSIONS:We successfully developed an AI algorithm to automatically segment PP in CT images to enable fast volume extraction. Moreover, we have observed that PPV is associated with loss in VC and FVC.

BACKGROUND:The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy. METHODS:In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort. FINDINGS:Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required. INTERPRETATION:Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma. FUNDING:Merck Sharp & Dohme.