Lung Transplant Outcome From Selected Older Donors (≥70 Years) Equals Younger Donors (<70 Years): A Propensity-matched Analysis.

OBJECTIVE: To describe our experience with lung transplantation (LTx) from donors ≥70 years and compare short and long-term outcomes to a propensity-matched cohort of donors <70 years. BACKGROUND: Although extended-criteria donors have been widely used to enlarge the donor pool, the experience with LTx from older donors (≥70 years) remains limited. METHODS: All single-center bilateral LTx between 2010 and 2020 were retrospectively analyzed. Matching (1:1) was performed for the donor (type, sex, smoking history, x-ray abnormalities, partial pressure of oxygen/fraction of inspired oxygen ratio, and time on ventilator) and recipient characteristics (age, sex, LTx indication, perioperative extracorporeal life support, and cytomegalovirus mismatch). Primary graft dysfunction grade-3, 5-year patient, and chronic lung allograft dysfunction-free survival were analyzed. RESULTS: Out of 647 bilateral LTx, 69 were performed from donors ≥70 years. The mean age in the older donor cohort was 74 years (range: 70-84 years) versus 49 years (range: 12-69 years) in the matched younger group. No significant differences were observed in the length of ventilatory support, intensive care unit, or hospital stay. Primary graft dysfunction-3 was 26% in the older group versus 29% in younger donor recipients ( P = 0.85). Reintervention rate was comparable (29% vs 16%; P = 0.10). Follow-up bronchoscopy revealed no difference in bronchial anastomotic complications ( P = 1.00). Five-year patient and chronic lung allograft dysfunction-free survivals were 73.6% versus 73.1% ( P = 0.72) and 51.5% versus 59.2% ( P = 0.41), respectively. CONCLUSIONS: LTx from selected donors ≥70 years is feasible and safe, yielding comparable short and long-term outcomes in a propensity-matched analysis with younger donors (<70 years).

A randomized controlled phase II clinical trial on mRNA electroporated autologous monocyte-derived dendritic cells (TriMixDC-MEL) as adjuvant treatment for stage III/IV melanoma patients who are disease-free following the resection of macrometastases.

BACKGROUND: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. MATERIALS AND METHODS: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. RESULTS: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. CONCLUSION: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.

Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy.

BACKGROUND: Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. METHODS: Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAFV600 and NRASQ61/G12/G13 mutations. RESULTS: After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. CONCLUSIONS: Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.

Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial.

BACKGROUND: Patients with BRAFV600-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial. METHODS: In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAFV600-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigator-assessed overall response at any time (defined as complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed on two occasions, at least 28 days after the first response was recorded). Analyses were done in the intention-to-treat population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02296996. FINDINGS: Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment. INTERPRETATION: Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients. FUNDING: Vlaamse Liga Tegen Kanker, Novartis.

Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors.

BACKGROUND: BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors. METHODS: Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib. RESULTS: 245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27). CONCLUSIONS: Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.

BACKGROUND: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. METHODS: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). RESULTS: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. CONCLUSION: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.

Unraveling the spectrum of inflammatory myofibroblastic tumors in the lung: A comprehensive case series highlighting endobronchial, pleural, and lung parenchymal tumors.

Objectives: Diverse cases of inflammatory myofibroblastic tumors (IMTs) in the lung (pleural, endobronchial, and parenchymal) are presented while discussing the (preoperative) diagnostic challenges and treatment modalities. Other objectives include emphasizing the significance of gene rearrangements and highlighting the multidisciplinary approach in addressing IMTs. Methods: Four cases of IMT in the lung are presented, including a young adolescent girl with an ETV6-neurotrophic tyrosine receptor kinase 3 (NTRK3) gene rearrangement, a 5-year-old boy with challenging preoperative diagnosis, and 2 middle-aged women with respectively pleural and endobronchial tumors with one peribronchial relapse. Results: The cases demonstrate the diverse clinical presentations and diagnostic complexities associated with IMT in the lung. Surgical resection remains the primary treatment modality, with complete resection leading to a cure in most patients. Unfortunately, aggressive relapse can occur, as in our last case of an endobronchial tumor. Frozen section may confirm the presence of malignant cells perioperatively and impact further treatment. The presence of gene rearrangements, such as ETV6-NTRK3, suggests potential therapeutic implications. Conclusions: Early detection and complete surgical removal of IMT are crucial for effective treatment. Identifying gene rearrangements such as ETV6-NTRK3 holds promise for targeted therapies. Diagnostic challenges, including the controversy of biopsies and preoperative evaluations, underscore the importance of a multidisciplinary approach. Anatomopathological recognition of IMT stays demanding. Close surveillance is necessary due to potential relapse, whereas frozen section perioperatively can help further treatment. This case series emphasizes the diagnostic challenges and therapeutic considerations for IMT in the lung.

The use of intravenous indocyanine green in minimally invasive segmental lung resections: a systematic review.

Background: To identify intersegmental planes (ISPs) in video/robot-assisted thoracoscopic segmentectomies, indocyanine green (ICG) is commonly used. The aim of this systematic review is to evaluate the efficacy of intravenous ICG in the identification of ISP. Methods: A systematic search was performed. Studies evaluating patients who underwent a video/robot-assisted thoracoscopic segmentectomy using intravenous ICG were included. The primary outcome measure was the frequency and percentage of patients in whom the ISP was adequately visualized. Secondary outcomes encompassed the ICG dose, time to visualization, time to maximum ICG visualization, time to disappearance of ICG effect and adverse reactions to ICG. Results: Eighteen studies were included for systematic review, enrolling a total of 1,090 patients. Irrespective of the injected dose, intravenous ICG identified the ISP in 94% of the cases (range, 30-100%). Overall, there was a considerable amount of heterogeneity regarding the injected dose of ICG (range, 5-25 mg or 0.05-0.5 mg/kg). The mean time before first effect of ICG was visible ranged from 10 to 40 seconds. The mean total time of ICG visibility ranged from 90 to 140 seconds after a bolus injection and was 170 seconds after continuous infusion. No adverse reactions were reported. Conclusions: After administration of intravenous ICG, visualization of the ISP is successful in up to 94% of cases, even after administration of a low dose (0.05 mg/kg) of ICG. The use of intravenous ICG is safe with no reported adverse effects in the immediate peri-operative period.

Uniportal versus multiportal video-assisted thoracoscopic surgery for spontaneous pneumothorax.

BACKGROUND: Multiportal video-assisted thoracic surgery (mVATS) is the standard approach for the surgical treatment of spontaneous pneumothorax. However, uniportal VATS (uVATS) has emerged as an alternative aiming to minimize surgical morbidity. This study aims to strengthen the evidence on the safety and efficiency of uVATS compared to mVATS. METHODS: From January 2004 to December 2020, records of patients who had undergone surgical treatment for primary or secondary spontaneous pneumothorax were evaluated for eligibility. Patients who had undergone pleurectomy combined with bullectomy or apical wedge resection via uVATS or mVATS were included. Surgical characteristics and postoperative data were compared between patients who had undergone surgery via uVATS or mVATS. Univariable and multivariable analyses were performed to determine whether the surgical approach was associated with any complication (primary outcome), major complications (i.e., Clavien-Dindo ≥ 3), recurrence, prolonged hospitalization or prolonged chest drainage duration (secondary outcomes). RESULTS: A total of 212 patients were enrolled. Patients treated via uVATS (n = 71) and mVATS (n = 141) were significantly different in pneumothorax type (secondary spontaneous; uVATS: 54 [76%], mVATS: 79 [56%]; p = 0.004). No significant differences were observed in (major) complications and recurrence rates between both groups. Multivariable analyses revealed that the surgical approach was no significant predictor for the primary or secondary outcomes. CONCLUSIONS: This study indicates that uVATS is non-inferior to mVATS in the surgical treatment of spontaneous pneumothorax regarding safety and efficiency, and thus the uVATS approach has the potential for further improvements in the perioperative surgical care for spontaneous pneumothorax.

The features and management of acquired resistance to PD1-based therapy in metastatic melanoma.

BACKGROUND: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown. METHODS: Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated. RESULTS: 299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001). CONCLUSIONS: Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.

Lung transplantation following controlled hypothermic storage with a portable lung preservation device: first multicenter European experience.

Introduction: Compared with traditional static ice storage, controlled hypothermic storage (CHS) at 4-10°C may attenuate cold-induced lung injury between procurement and implantation. In this study, we describe the first European lung transplant (LTx) experience with a portable CHS device. Methods: A prospective observational study was conducted of all consecutively performed LTx following CHS (11 November 2022 and 31 January 2024) at two European high-volume centers. The LUNGguard device was used for CHS. The preservation details, total ischemic time, and early postoperative outcomes are described. The data are presented as median (range: minimum-maximum) values. Results: A total of 36 patients underwent LTx (i.e., 33 bilateral, 2 single LTx, and 1 lobar). The median age was 61 (15-68) years; 58% of the patients were male; 28% of the transplantations had high-urgency status; and 22% were indicated as donation after circulatory death. In 47% of the patients, extracorporeal membrane oxygenation (ECMO) was used for perioperative support. The indications for using the CHS device were overnight bridging (n = 26), remote procurement (n = 4), rescue allocation (n = 2), logistics (n = 2), feasibility (n = 1), and extended-criteria donor (n = 1). The CHS temperature was 6.5°C (3.7°C-9.3°C). The preservation times were 11 h 18 (2 h 42-17 h 9) and 13 h 40 (4 h 5-19 h 36) for the first and second implanted lungs, respectively, whereas the total ischemic times were 13 h 38 (4 h 51-19 h 44) and 15 h 41 (5 h 54-22 h 48), respectively. The primary graft dysfunction grade 3 (PGD3) incidence rates were 33.3% within 72 h and 2.8% at 72 h. Intensive care unit stay was 8 (4-62) days, and the hospital stay was 28 (13-87) days. At the last follow-up [139 (7-446) days], three patients were still hospitalized. One patient died on postoperative day 7 due to ECMO failure. In-hospital Clavien-Dindo complications of 3b were observed in six (17%) patients, and 4a in seven (19%). Conclusion: CHS seems safe and feasible despite the high-risk recipient and donor profiles, as well as extended preservation times. PGD3 at 72 h was observed in 2.8% of the patients. This technology could postpone LTx to daytime working hours. Larger cohorts and longer-term outcomes are required to confirm these observations.

Predicting Aesthetic Outcome of the Nuss Procedure in Patients with Pectus Excavatum.

Patients suffering from pectus excavatum often experience psychosocial distress due to perceived anomalies in their physical appearance. The ability to visually inform patients about their expected aesthetic outcome after surgical correction is still lacking. This study aims to develop an automatic, patient-specific model to predict aesthetic outcome after the Nuss procedure. Patients prospectively received preoperative and postoperative 3-dimensional optical surface scanning of their chest during the Nuss procedure. A prediction model was composed based on nonlinear least squares data-fitting, regression methods and a 2-dimensional Gaussian function with adjustable amplitude, variance, rotation, skewness, and kurtosis components. Morphological features of pectus excavatum were extracted from preoperative images using a previously developed surface analysis tool to generate a patient-specific model. Prediction accuracy was evaluated through cross-validation, utilizing the mean root squared deviation and maximum positive and negative deviations as performance measures. The prediction model was evaluated on 30 (90% male) prospectively imaged patients. The model achieved an average root mean squared deviation of 6.3 ± 2.0 mm, with average maximum positive and negative deviations of 12.7 ± 6.1 and -10.2 ± 5.7 mm, respectively, between the predicted and actual postoperative aesthetic result. Our developed 2-dimensional Gaussian model based on 3-dimensional optical surface images is a clinically promising tool to predict postsurgical aesthetic outcome in patients with pectus excavatum. Prediction of the aesthetic outcome after the Nuss procedure potentially improves information provision and expectation management among patients. Further research should assess whether increasing the sample size may reduce deviations and improve performance.

Modification of the Abramson procedure for minimally invasive repair of pectus carinatum: introduction of a pectus carinatum compression system.

Pectus carinatum is characterized by a protruding sternum. This deformity can be surgically corrected through the minimally invasive Abramson technique. In this procedure, a presternal metal correctional bar, secured to rib-attached stabilizers, is implanted to redress the sternum to a neutral position. To anticipate the intended position of the sternum, manual compression is applied over the sternal deformity. We describe a modified version of the Abramson procedure, encompassing a table-mounted PectusAssist™ System which generates a constant mechanical compression over the protruding sternum. The PectusAssist™ System, most importantly, eliminates the necessity of manually applying repetitive pressure on the deformity, and therefore maintains a more stable sternal position. This will ensure accuracy of the template used to bend the bar into its desired configuration. The modification we propose also simplifies presternal tunnel creation as the two bilateral retromuscular tunnels, that need to be connected presternally, are potentially better aligned due to a more stable and reduced position of the sternum. The PectusAssist™ System makes the procedure less labor intensive and reduces variability without interfering with the safety of the procedure. Therefore, we advise standard use of the PectusAssist™ System during minimally invasive repair of pectus carinatum by the Abramson procedure.

Pectus Excavatum: Consensus and Controversies in Clinical Practice.

BACKGROUND: Pectus excavatum is the most common congenital anterior chest wall deformity. Currently, a wide variety of diagnostic protocols and criteria for corrective surgery are being used. Their use is predominantly based on local preferences and experience. To date, no guideline is available, introducing heterogeneity of care as observed in current daily practice. The aim of this study was to evaluate consensus and controversies regarding the diagnostic protocol, indications for surgical correction, and postoperative evaluation of pectus excavatum. METHODS: The study consisted of 3 consecutive survey rounds evaluating agreement on different statements regarding pectus excavatum care. Consensus was achieved if at least 70% of participants provided a concurring opinion. RESULTS: All 3 rounds were completed by 57 participants (18% response rate). Consensus was achieved on 18 of 62 statements (29%). Regarding the diagnostic protocol, participants agreed to routinely include conventional photography. In the presence of cardiac impairment, electrocardiography and echocardiography were indicated. Upon suspicion of pulmonary impairment, spirometry was recommended. In addition, consensus was reached on the indications for corrective surgery, including symptomatic pectus excavatum and progression. Participants moreover agreed that a plain chest radiograph must be acquired directly after surgery, whereas conventional photography and physical examination should both be part of routine postoperative follow-up. CONCLUSIONS: Through a multiround survey, international consensus was formed on multiple topics to aid standardization of pectus excavatum care.

A Focused Review on Primary Graft Dysfunction after Clinical Lung Transplantation: A Multilevel Syndrome.

Primary graft dysfunction (PGD) is the clinical syndrome of acute lung injury after lung transplantation (LTx). However, PGD is an umbrella term that encompasses the ongoing pathophysiological and -biological mechanisms occurring in the lung grafts. Therefore, we aim to provide a focused review on the clinical, physiological, radiological, histological and cellular level of PGD. PGD is graded based on hypoxemia and chest X-ray (CXR) infiltrates. High-grade PGD is associated with inferior outcome after LTx. Lung edema is the main characteristic of PGD and alters pulmonary compliance, gas exchange and circulation. A conventional CXR provides a rough estimate of lung edema, while a chest computed tomography (CT) results in a more in-depth analysis. Macroscopically, interstitial and alveolar edema can be distinguished below the visceral lung surface. On the histological level, PGD correlates to a pattern of diffuse alveolar damage (DAD). At the cellular level, ischemia-reperfusion injury (IRI) is the main trigger for the disruption of the endothelial-epithelial alveolar barrier and inflammatory cascade. The multilevel approach integrating all PGD-related aspects results in a better understanding of acute lung failure after LTx, providing novel insights for future therapies.

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial.

BACKGROUND: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. METHODS: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. RESULTS: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39-72), and 85.7% (95% CI, 70-100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. CONCLUSIONS: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

A Comprehensive Review on the Surgical Aspect of Lung Transplant Models in Mice and Rats.

Lung transplantation improves the outcome and quality of life of patients with end-stage pulmonary disease. However, the procedure is still hampered by the lack of suitable donors, the complexity of the surgery, and the risk of developing chronic lung allograft dysfunction. Over the past decades, translational experiments in animal models have led to a better understanding of physiology and immunopathology following the lung transplant procedure. Small animal models (e.g., rats and mice) are mostly used in experiments regarding immunology and pathobiology and are preferred over large animal models due to the ethical aspects, the cost-benefit balance, and the high throughput possibility. In this comprehensive review, we summarize the reported surgical techniques for lung transplantation in rodent models and the management of perioperative complications. Furthermore, we propose a guide to help identify the appropriate species for a given experiment and discuss recent experimental findings in small animal lung transplant models.

Translation, cultural adaptation and linguistic validation of the pectus excavatum evaluation questionnaire.

Background: Pectus excavatum often imposes significant burden on the patients' quality of life. However, despite the known biopsychosocial effects, the deformity remains underappreciated. Patient reported outcome measures can be used to measure and appreciate results from a patient's perspective. The pectus excavatum evaluation questionnaire (PEEQ) is the most employed disease specific instrument to measure patient-reported outcome measures (PROMs). A translation and linguistic validation of this questionnaire is presented for its use in the Dutch pediatric pectus excavatum population. By providing an insight in our translation process, we want to encourage other researchers to perform translations to other languages to make the questionnaire available to clinicians and researchers worldwide. Methods: The 22-item PEEQ was translated and adapted according to the leading guidelines for the translation of patient reported outcome measures. Conceptual equivalence and cultural adaptation were emphasized. Results: One forward translation was produced through reconciliation of two forward translations. Back translation resulted in 15 identical items, as well as 6 literal, and 1 conceptual discrepancy. The latter was expected as during the forward translation a more culturally appropriate translation was chosen. Ten patients were involved during the cognitive debriefing process, following which one item was revised and the final Dutch version was established. Conclusions: We provide a culturally appropriate and linguistically validated Dutch version of the PEEQ.

Thoracic surgery in the Netherlands.

The purpose of this article, part of the Thoracic Surgery Worldwide series, is to provide a descriptive review of how thoracic surgery is organized in the Netherlands. General information is provided on the Dutch healthcare system, as well as on how Dutch thoracic surgeons are organized and trained. Additionally, this study provides information on our national quality surveillance system, an overview of the most common thoracic surgeries performed in our country, and details of academic research conducted by Dutch medical specialists. Furthermore, we discuss current challenges and future perspectives. In the Netherlands general thoracic surgical procedures are performed by approximately 110 general thoracic surgeons and 25 of the 135 cardiothoracic surgeons. Dutch thoracic surgeons provide minimally invasive lung surgery, chest wall surgery, thymic and mediastinal surgery, and surgical diagnosis and treatment of pleural disorders. Some recently published data on hospital mortality and postoperative adverse events of thoracic surgeries are reported. Furthermore, the structure of the thoracic surgical education and training program is discussed, highlighting the particular structure of two educational programs for thoracic surgery via a general thoracic and cardiothoracic surgery program. To assure high-quality surgical care, the Netherlands has a well-structured national quality surveillance system, involving frequent site visits and mandatory participation in the national lung cancer surgery registry for all hospitals. In terms of academic research, the Netherlands ranked 14th worldwide on number of clinical trials conducted across all medical disciplines in 2021. Furthermore, several thoracic-related (inter-)national multicenter randomized trials which are currently performed and initiated by Dutch hospital research groups are mentioned. Finally, future challenges and advances of Dutch thoracic surgery are addressed, including the implementation of lung cancer screening, imbalanced labor market, and centralization of care.