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Abstract: A 61-year-old woman, referred for recurrent pneumonia over a period of 3 months with insufficient response to antibiotic treatment, presented with coughing and intense right-sided chest pain. Previously, she underwent right upper lobectomy for locally advanced non-small cell lung cancer (squamous cell carcinoma) followed by adjuvant chemotherapy and subsequent partial chest wall resection with polytetrafluoroethylene net insert due to a pleurocutaneous fistula. 18 FDG plus a 68 Ga-labeled fibroblast activation protein inhibitor ( 68 Ga-FAPI) PET/CT scans were performed to rule out non-small cell lung cancer recurrence. Pathological workup with bronchoscopy and endobronchial ultrasound-guided transbronchial fine-needle aspiration of the lymph nodes showed no evidence of malignancy, but microbiology confirmed Aspergillus fumigatus infection of the middle lobe. Thus, the patient transitioned from antibiotic to antifungal therapy; no second-line oncologic treatment was initiated., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan ( 68 Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68 Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68 Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUV max and TLR peak ) in 68 Ga-SSO120 PET on a lesion level. Highest lesion SUV max /TLR peak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUV max /TLR peak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68 Ga-SSO120 SUV max and TLR peak of the hottest lesion per patient, whole-body TLR mean , MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLR peak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLR mean . Conclusion: In patients with SCLC, SSTR2 expression assessed by 68 Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68 Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications., Competing Interests: Competing Interests: Filiz Oezkan received personal fees from Sanofi Aventis, Janssen, DeciBio, ERBE and Genentech/Roche Ltd.; program funding to the institution was received from Olympus, Astrazeneca, ERBE and Janssen, all outside the submitted work. Lale Umutlu is a Speaker / Advisory Board Member for Bayer Healthcare and Siemens Healthcare and received research grants from Siemens Healthcare outside the submitted work. Rainer Hamacher was supported by the Clinician Scientist Program of the University Medicine Essen Clinician Scientist Academy (UMEA; Faculty of Medicine and Deutsche Forschungsgemeinschaft [DFG]); reports travel grants from Lilly, Novartis, and PharmaMar; and reports personal fees from Lilly and PharmaMar outside the submitted work. Jens Siveke is supported by German Cancer Aid (grant 70112505, PIPAC; grant 70113834, PREDICT-PACA), the Wilhelm-Sander Foundation (grant 2019.008.1), the DFG through grant SI1549/3-1 (Clinical Research Unit KFO337) and SI1549/4-1, and the Federal Ministry of Education and Research (BMBF; SATURN3 consortium); receives honoraria as a consultant or for continuing medical education presentations from AstraZeneca, Bayer, Immunocore, Roche, and Servier; receives research funding (to the institution) from Bristol Myers Squibb, Celgene, and Roche; and holds ownership and serves on the board of directors of Pharma15—all outside the submitted work. Wolfgang Fendler reports fees from SOFIE Biosciences (research funding), Janssen (consultant, speaker), Calyx (consultant, image review), Bayer (consultant, speaker, research funding), Novartis (speaker, consultant), Telix (speaker), GE Healthcare (speaker), Eczacıbaşı Monrol (speaker), Abx (speaker), Amgen (speaker), and Urotrials, all outside the submitted work. Marcel Wiesweg reports honoraria and advisory role from Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda, and research funding from Bristol-Myers Squibb, Takeda outside the submitted work. Ken Herrmann reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, personal fees from Aktis Oncology, personal fees from Theragnostics, personal fees from Pharma15, outside the submitted work. Martin Schuler reports personal fees as a consultant from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Takeda; honoraria for continuing medical education presentations from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, MSD, and Novartis; and research funding (to the institution) from AstraZeneca and Bristol Myers Squibb, all outside the submitted work. Hubertus Hautzel reports personal fees from Roche and Urenco, and other fees from Pari, Roche and Urenco, outside the submitted work. David Kersting reports speaker honoraria from Pfizer and Novartis outside the submitted work. A research grant from Pfizer outside the submitted work and funding by the German Research Foundation (DFG, KE2933/1-1), outside the submitted work., (© The author(s).)

Introduction: Bronchoscopic lung volume reduction (BLVR) with endobronchial valves has been shown to be a safe and effective treatment for patients with severe lung emphysema. Previous studies have reported a benefit in pulmonary function, exercise capacity, and quality of life after BLVR-treatment. The effect of BLVR with valves on the pulmonary gas exchange and its association with clinical outcomes has not been analyzed to date. The primary goal of this study was to investigate the impact of BLVR on the pulmonary gas exchange and the impact of the target lobe selection in patients with discordant target lobes in high-resolution computed tomography (HRCT) scan and perfusion scan on the pulmonary gas exchange and clinical outcomes. Methods: In this single-center study, we retrospectively analyzed pulmonary function tests, 6-min-walk-tests, HRCT scans, perfusion scans, and blood gas analyses in 77 patients over the course of 6 months following BLVR treatment. Results: We observed that complete lobar occlusion with bronchoscopic valves leads to a transient impairment of pulmonary gas exchange. Despite this, an overall positive clinical outcome could be shown in patients treated with endobronchial valves. If the target lobe selection based on HRCT and perfusion scans is discrepant, a selection based on the HRCT scan tends to be associated with a better outcome than a selection based on the perfusion scan. Conclusions: Complete lobar occlusion with bronchoscopic valves leads to a transient impairment of pulmonary gas exchange but nevertheless results in an overall positive clinical outcome.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive and irreversible airflow limitation, with individual body composition influencing disease severity. Severe emphysema worsens symptoms through hyperinflation, which can be relieved by bronchoscopic lung volume reduction (BLVR). To investigate how body composition, assessed through CT scans, impacts outcomes in emphysema patients undergoing BLVR. Fully automated CT-based body composition analysis (BCA) was performed in patients with end-stage emphysema receiving BLVR with valves. Post-interventional muscle and adipose tissues were quantified, body size-adjusted, and compared to baseline parameters. Between January 2015 and December 2022, 300 patients with severe emphysema underwent endobronchial valve treatment. Significant improvements were seen in outcome parameters, which were defined as changes in pulmonary function, physical performance, and quality of life (QoL) post-treatment. Muscle volume remained stable (1.632 vs. 1.635 for muscle bone adjusted ratio (BAR) at baseline and after 6 months respectively), while bone adjusted adipose tissue volumes, especially total and pericardial adipose tissue, showed significant increase (2.86 vs. 3.00 and 0.16 vs. 0.17, respectively). Moderate to strong correlations between bone adjusted muscle volume and weaker correlations between adipose tissue volumes and outcome parameters (pulmonary function, QoL and physical performance) were observed. Particularly after 6-month, bone adjusted muscle volume changes positively corresponded to improved outcomes (ΔForced expiratory volume in 1 s [FEV 1 ], r = 0.440; ΔInspiratory vital capacity [IVC], r = 0.397; Δ6Minute walking distance [6MWD], r = 0.509 and ΔCOPD assessment test [CAT], r = -0.324; all p < 0.001). Group stratification by bone adjusted muscle volume changes revealed that groups with substantial muscle gain experienced a greater clinical benefit in pulmonary function improvements, QoL and physical performance (ΔFEV 1 %, 5.5 vs. 39.5; ΔIVC%, 4.3 vs. 28.4; Δ6MWDm, 14 vs. 110; ΔCATpts, -2 vs. -3.5 for groups with ΔMuscle, BAR% < -10 vs. > 10, respectively). BCA results among patients divided by the minimal clinically important difference for forced expiratory volume of the first second (FEV 1 ) showed significant differences in bone-adjusted muscle and intramuscular adipose tissue (IMAT) volumes and their respective changes after 6 months (ΔMuscle, BAR% -5 vs. 3.4 and ΔIMAT, BAR% -0.62 vs. 0.60 for groups with ΔFEV1 ≤ 100 mL vs > 100 mL). Altered body composition, especially increased muscle volume, is associated with functional improvements in BLVR-treated patients., (© 2024. The Author(s).)

Bronchoscopic lung volume reduction is as a safe and effective therapy for patients with advanced emphysema, suffering from breathlessness despite optimal medical therapy. By reducing hyperinflation, it improves lung function, exercise capacity and quality of life. The technique includes one-way endobronchial valves, thermal vapor ablation and endobronchial coils. Patient selection is the key to a successful therapy; hence the indication should be evaluated in a multidisciplinary emphysema team meeting. The procedure can lead to a potentially life-threatening complication. Therefore, an adequate post-procedural patient management is crucial., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einem/den Sponsor(en) dieser Fortbildungseinheit; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einem/den Sponsor(en) dieser Fortbildungseinheit; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen K. Darwiche: Mitgliedschaft in DGP, WDGP, DKG, ERS, ECBIP, WABIP, BDI, (Thieme. All rights reserved.)

Background: Bronchoscopic lung volume reduction (BLVR) with endobronchial valves (EBV) can be a successful treatment for end-stage emphysema patients. The reduction of hyperinflation enhances ventilatory mechanics and diaphragm function. Understanding predictors for treatment success is crucial for further improvements., Purpose: The aim of this study was to assess the effect of the target lobe volume reduction (TLVR) in relation to the ipsilateral lung volume reduction (ILVR), affected by the compensatory expansion of the adjacent lobe, on the outcome after BLVR with valves., Patients and Methods: The volumetric relationship of ILVR% to TLVR%, addressed as R eduction R atio ( R ), was recorded in 82 patients and compared to changes in lung function, physical performance and quality of life. A small value for R implies a relatively low volume reduction of the ipsilateral lung (ILVR) compared to the volume reduction of the target lobe (TLVR). Additionally, the minimal clinically important difference (MCID) for R was calculated., Results: Patients with a smaller Reduction Ratio ( R <0.2) showed minor improvements at the 3 months follow-up compared to patients with R ≥0.2 (mean changes of 39 mL (5.8%), -395 mL (-4.9%) and 96 mL (7.1%) versus 231 mL (33%), -1235 mL (-20%) and 425 mL (29%) in the forced expiratory volume in 1s (FEV 1 ), residual volume (RV) and inspiratory vital capacity (IVC), respectively, and -3 m and 0 points versus 20.4 m and -3.4 points in the 6-minute-walking-distance (6MWD) and COPD assessment test (CAT) score respectively). With a combined value of 0.185, a MCID for R was calculated with established anchors (FEV 1 , RV, and 6MWD) for emphysema patients., Conclusion: Extensive compensatory hyperinflation of the adjacent non-treated lobe after BLVR results in decreased ILVR, which is responsible for a lack of meaningful improvements in ventilatory mechanics and clinical outcome, despite technically successful lobe volume reduction., Competing Interests: KD has received speaker fees from Olympus, Boston Scientific, Broncus Medical, Erbe, Böhringer I., Storz; consultant activities at bess, Boston Scientific, Broncus Medical, Fujifilm, FreeFlow, Storz, PulmonX, Böhringer I., Morair Medtech, Medtronic; research grants from Pulmonx, PneumRx, Nuveira, Epigenomics, Broncus, Novartis, Roche, Ambu, Gala Therapeutics. All other authors have no potential conflict of interest., (© 2022 Wienker et al.)

Background: Pneumothorax is a common side effect in interventional pulmonology. The ideal moment for detection with chest X-ray or ultrasound has not yet been defined. Earlier studies demonstrated the utility of performing these tests with a certain delay, which always results in a potentially dangerous gap., Methods: We prospectively enrolled patients with pulmonary interventions at increased risk of pneumothorax. Thoracic ultrasound was performed immediately after the intervention and at the moment of chest X-ray with a delay up to two hours., Results: Overall, we detected four pneumothoraxes in 115 procedures. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 75%, 100%, 100%, 99%, 99% for ultrasound and 75%, 90%, 21%, 99% und 89% for chest X-ray respectively. All pneumothoraces requiring chest tube were sufficiently detected by both methods., Conclusion: Thoracic ultrasound when performed immediately can more accurately exclude pneumothorax after interventional bronchoscopy when compared to chest X-ray. Further ultrasound examinations are unnecessary.

Background: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration increases the diagnostic yield of lung cancer staging. The left adrenal gland (LAG) is a common site for lung cancer metastasis. The modality of transesophageal examination with an EBUS bronchoscope (EUS-B) routinely for LAG has not been assessed., Objective: The aim of this study was to prospectively assess if evaluation and tissue sampling of the LAG could routinely be implemented in an EBUS procedure., Methods: Patients referred for EBUS between March and August 2017 had assessment of the LAG via EUS-B. Fine-needle aspiration (FNA) was performed in cases with a suspicious LAG. The detection rate, procedure time, and learning curve of four experienced EBUS-bronchoscopists was assessed, plus the diagnostic accuracy and complication rate of FNA., Results: In total, 313 consecutive patients were included. The overall LAG detection rate was 87.5%. After the initial learning curve, the detection rate for all four bronchoscopists was >93%. The detection rate did not correlate with any patient characteristics. EUS-B-FNA revealed nine LAG metastases, with a sensitivity, specificity, and accuracy of 75%, 100%, and 99%, respectively. The mean EUS-B operation time was 194.4 s, with 594.8 s for FNA. There were no FNA-associated complications., Conclusions: Evaluation of the LAG with EUS-B could routinely be included in an EBUS procedure if necessary. A high detection rate can be achieved after an initial learning period. FNA of the LAG was feasible and safe. EUS-B of the LAG could be integrated into the usual EBUS/EUS-B procedure in lung cancer staging workup., (© 2019 S. Karger AG, Basel.)

Background: Bronchoscopic lung volume reduction (BLVR) via valve implantation can be achieved by targeting severely hyperinflated and emphysematously destructed lung areas in patients with chronic obstructive lung disease. Lack of collateral ventilation (CV) is important for good outcomes with BLVR. CV can be measured using the catheter-based Chartis system. The aim of this study was to evaluate the correlation between total exhaled volume drained from the target lobe measured by Chartis and clinical outcomes after BLVR in CV-negative patients., Methods: From January 2016 to March 2019, 60 patients were included in this retrospective single-center analysis. Drained volume (TVol) measured by Chartis was recorded and compared with lung function and physical performance parameters. Outcome variables included the percentage change in lung function [forced expiratory volume in 1 s (FEV 1 ), residual volume (RV), and inspiratory vital capacity (IVC)]. Secondary outcomes were the degree of target lobe volume reduction (TLVR), change in 6-min walk distance (6MWD), and change in chronic obstructive pulmonary disease (COPD) assessment test (CAT) score., Results: Drained volume correlated significantly with post-BLVR change in FEV 1 ( r  = 0.663), IVC ( r  = 0.611), RV ( r  = -0.368), and TLVR ( r  = 0.635) (all p  < 0.05). In a priori -defined patient subgroups based on drained volume [<100 ml ( n  = 19), 100-400 ml ( n  = 33), and >400 ml ( n  = 8)]; mean changes in FEV 1 were 2.6%, 17.4%, and 51.3%; in RV were -3.9%, -10.6%, and -23.8%; in IVC were -4.0%, 10.6%, and 62.4%; and in TLVR were 525 ml (39%), 1375 ml (73%) and 1760 ml (100%), respectively. There were no significant correlations between absolute and percentage changes in 6MWD and the CAT score. Lung volume reduction was diagnosed in 32 (53%) cases., Conclusion: Drained volume measured by the Chartis system correlated with functional improvement in CV-negative patients undergoing BLVR. The reviews of this paper are available via the supplemental material section.

In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes.

In order to identify single-nucleotide polymorphisms (SNPs) and analyze their characteristics in a set of 111 genes, we resequenced exons and flanking regions in an average of 170 chromosomes from individuals of European origin. Genetic variability was decreased in noncoding regions highly conserved between human and rodents, indicating functional relevance of these regions. Furthermore, diversity of coding nonsynonymous SNPs was found lower in regions encoding a known protein sequence motif. SNPs predicted to be of functional significance were more common amongst rare variants. Despite the significant recent growth of SNP numbers in public SNP databases, only a small fraction of these rare variants is represented. This may be relevant in the investigation of the genetic causes of severe side effects, for which rare variants are plausible candidates. Estimation of htSNPs reduces the genotyping effort required in capturing common haplotypes, for certain genes, however, this accounts for only a small fraction of haplotype diversity.