Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms.

BACKGROUND: Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs. METHODS: The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored. RESULTS: Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively). CONCLUSIONS: LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.

Hyperbaric oxygen (HBO2) therapy in thermal burn injury revisited. Pressure does matter. Review.

For over five decades, many experimental and clinical studies have shown predominantly positive but controversial results on the efficacy of hyperbaric oxygen (HBO2) therapy in burns. The study aimed to define a common denominator or constellations, respectively, linked to the effects of HBO2 in burns with a special focus on dosage parameters. Based on original work since 1965, species, number of individuals, type of study, percentage of total body surface area (TBSA), region, depth of burn, causative agent, interval between burn and first HBO2 session, pressure, duration of individual session, number of HBO2 sessions per day, cumulative number of HBO2 sessions and type of chamber were assessed. Out of 47 publications included, 32 were animal trials, four were trials in human volunteers, and 11 were clinical studies. They contained 94 experiments whose features were processed for statistical evaluation. 64 (67.4%) showed a positive outcome, 16 (17.9%) an ambiguous one, and 14 (14.7%) a negative outcome. The only factor independently influencing the results was pressure with ATA (atmospheres absolute) lower than 3 ATA being significantly associated with better outcomes (p=0.0005). There is a dire need for well-designed clinical studies in burn centers equipped with hyperbaric facilities to establish dedicated treatment protocols.

Measuring the global mechanical properties of the human thorax: Costo-vertebral articulation.

Biomechanical simulation of the human thorax, e.g. for 3D-printed rib implant optimisation, requires an accurate knowledge of the associated articulation and tissue stiffness. The present study is focusing on determining the stiffness of the costo-vertebral articulations. Specimens of rib segments including the adjacent thoracic vertebrae and ligaments were obtained from two human post-mortem bodies at four different rib levels. The rib samples were loaded with a tensile force in the local longitudinal, sagittal and transverse direction and the resulting displacement was continuously measured. The moment-angle response of the rib articulations was also determined by applying a load at the rib end in the cranial - caudal direction and measuring the resulting displacement. The torsional load response of the costo-vertebral articulations at an applied moment between -0.1 Nm and 0.1 Nm corresponded to a median range of motion of 13.2° (6.4° to 20.9°). An almost uniform stiffness was measured in all tensile loading directions. The median displacement at the defined force of 28 N was 1.41 mm in the longitudinal, 1.55 mm in the sagittal, and 1.08 mm in the transverse direction. The measured moment-angle response of the costo-vertebral articulation is in line with the data from literature. On the contrary, larger displacements in longitudinal, sagittal and transverse directions were measured compared to the values found in literature.

Expanding Broad Molecular Reflex Testing in Non-Small Cell Lung Cancer to Squamous Histology.

Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.

Esophageal perforation with near fatal mediastinitis secondary to Th3 fracture.

A 74-year-old male patient was referred with signs of sepsis 5 days after having been diagnosed with a rib fracture following a fall out of bed. Novel hypodensities were visible on thoracic X­rays and laboratory tests revealed elevated inflammatory parameters. Subsequently performed thoracic computed tomography (CT) scan showed burst fracture of the 3rd thoracic vertebra, posttraumatic esophageal rupture at the same level and mediastinitis. Furthermore, marked degenerative changes of the spinal column (diffuse idiopathic skeletal hyperostosis) were present. The patient underwent emergency thoracotomy and esophagectomy. Gastric pull-up with esophagogastrostomy was postponed for 3 days. After 14 days on the intensive care unit (ICU) and 12 days of i.v. antibiotics, the patient was transferred to the general ward and 7 weeks after trauma the patient was infection-free without difficulties in swallowing. Up to the latest follow-up 41 months following injury, several endoscopic dilations with a bougie due to constrictions at the anastomosis have been performed. Similar to previous cases in the literature, esophageal injury was diagnosed delayed, with the patient already having developed severe complications. This extremely seldom injury should be suspected in young patients following high-energy trauma, but also in older patients after low-energy trauma but known degenerative changes of the vertebral column.

Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC.

BACKGROUND: The use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to predict response to treatment. One possible explanation could be a change in PD-L1 expression during the course of the disease and the neglect of reassessment. The purpose of this study was a longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC. METHODS: We retrospectively analyzed PD-L1 expression in patients with early-stage NSCLC and subsequent relapse in preoperative samples, matched surgical specimens and biopsy samples of disease recurrence. Ventana PD-L1 (SP263) immunohistochemistry assay was used for all samples. PD-L1 expression was scored based on clinically relevant groups (0%, 1%-49%, and ≥50%). The primary endpoint was the change in PD-L1 score group between preoperative samples, matched surgical specimens and relapsed tumor tissue. RESULTS: 395 consecutive patients with stages I-III NSCLC and 136 (34%) patients with a subsequent relapse were identified. For 87 patients at least two specimens for comparison of PD-L1 expression between early stage and relapsed disease were available. In 72 cases, a longitudinal analysis between preoperative biopsy, the surgically resected specimen and biopsy of disease recurrence was feasible. When comparing preoperative and matched surgical specimens, a treatment-relevant conversion of PD-L1 expression group was found in 25 patients (34.7%). Neoadjuvant treatment showed no significant effect on PD-L1 alteration (p=0.39). In 32 (36.8%) out of 87 cases, a change in PD-L1 group was observed when biopsies of disease relapse were compared with early-stage disease. Adjuvant treatment was not significantly associated with a change in PD-L1 expression (p=0.53). 39 patients (54.2%) showed at least 1 change into a different PD-L1 score group during the course of disease. 14 patients (19.4%) changed the PD-L1 score group twice, 5 (6.9%) of them being found in all different score groups. CONCLUSION: PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.

Real-World Treatment Patterns and Timeliness of Clinical Care Pathway for Non-Small Cell Lung Cancer Patients in Austria: The PRATER Retrospective Study.

This was a retrospective study of the profile and initial treatments of adults diagnosed with early-stage (ES) non-small cell lung cancer (NSCLC) during January 2018-December 2021 at 16 leading hospital institutions in Austria, excluding patients enrolled in clinical trials. In total, 319 patients were enrolled at a planned ~1:1:1 ratio across StI:II:III. Most tested biomarkers were programmed death ligand 1 (PD-L1; 58% expressing), Kirsten rat sarcoma virus (KRAS; 22% positive), and epidermal growth factor receptor (EGFR; 18% positive). Of 115/98/106 StI/II/III patients, 82%/85%/36% underwent surgery, followed by systemic therapy in 9%/45%/47% of those [mostly chemotherapy (ChT)]. Unresected treated StIII patients received ChT + radiotherapy [43%; followed by immune checkpoint inhibitors (ICIs) in 39% of those], ICI ± ChT (35%), and ChT-alone/radiotherapy-alone (22%). Treatment was initiated a median (interquartile range) of 24 (7-39) days after histological confirmation, and 55 (38-81) days after first medical visit. Based on exploratory analyses of all patients newly diagnosed with any stage NSCLC during 2018-2021 at 14 of the sites (N = 7846), 22%/10%/25%/43% had StI/II/III/IV. The total number was not significantly different between pre-COVID-19 (2018-2019) and study-specific COVID-19 (2020-2021) periods, while StI proportion increased (21% vs. 23%; p = 0.012). Small differences were noted in treatments. In conclusion, treatments were aligned with guideline recommendations at a time which preceded the era of ICIs and targeted therapies in the (neo)adjuvant setting.

Analysis of Pain Management after Anatomic VATS Resection in Austrian Thoracic Surgery Units.

BACKGROUND: Postoperative pain influences rehabilitation, postoperative complications and quality of life. Despite its impact, there are no uniform treatment guidelines. Different centers seem to use various strategies. This study aims to analyze pain management regimens used after anatomic VATS resections in Austrian thoracic surgery units, with a special interest in opioid usage and strategies to avoid opioids. METHODS: A questionnaire was designed to assess the use of regional anesthesia, postoperative pain medication and characteristics of individual pain management regimens. The questionnaire was sent to all thoracic surgery units in Austria, with nine out of twelve departments returning them. RESULTS: All departments use regional anesthesia during the procedure. Four out of nine centers use epidural analgesia or an intercostal catheter for postoperative regional anesthesia in at least 50% of patients. Two departments follow an opioid restrictive regimen, five depend on the visual analogue scale (VAS) and two administer opioids on a fixed schedule. Three out of nine departments use NSAIDs on a fixed schedule. The most used medication is metamizole (eight out of nine centers; six on a fixed schedule, two depending on VAS) followed by piritramide (six out of nine centers; none as a fixed prescription). CONCLUSIONS: This study reflects the heterogeneity in postoperative pain treatment after VATS anatomic lung resections. All departments use some form of regional anesthesia in the perioperative period; prolonged regional anesthesia is not utilized uniformly to reduce opioid consumption, as suggested in enhanced recovery after surgery programs. More evidence is needed to optimize and standardize postoperative pain treatment.