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Purpose The recommended treatment for small-cell lung cancer (SCLC) currently is surgery in stage I disease. We wondered about stage II SCLC and present a meta-analysis on mean-survival of patients that underwent surgery for stage I and II compared to controls. Methods A systematic literature search was performed on December 01st 2021 in Medline, Embase and Cochrane Library. We considered studies published on the effect of surgery in SCLC since 2004 and assessed them using ROBINS-I. We preformed I 2 -tests, Q-statistics, DerSimonian-Laird tests and Egger-regression. The meta-analysis was conducted according to PRISMA. Results Out of 6826 records, seven studies with a total of 11,241 patients (‘surgery group’: 3911 patients; ‘non-surgery group’: 7330; treatment period: 1984–2015) were included. Heterogeneity between the studies was revealed in absence of any publication bias. Patient characteristics did not differ between the groups (p-value > 0.05). The mean-survival in an analysis of patients in stage I was 36.7 ± 10.8 months for the ‘surgery group’ and 20.3 ± 5.7 months for the ‘non-surgery group’ (p-value = 0.0084). A combined analysis of patients in stage I and II revealed a mean-survival of 32.0 ± 16.7 months for the ‘surgery group’ and 19.1 ± 6.1 months for the ‘non-surgery group’ (p-value = 0.0391). In a separate analysis of stage II, we were able to demonstrate a significant survival benefit after surgery (21.4 ± 3.6 versus 16.2 ± 3.9 months; p-value = 0.0493). Conclusion Our meta-analysis shows a significant survival benefit after surgery not only in the recommended stage I but also in stage II SCLC. Our data suggests that both stages should be considered for surgery of early SCLC.

Small cell lung cancer (SCLC) is a difficult to treat subtype of lung cancer. One of the hallmarks of SCLC is its almost uniform chemotherapy sensitivity. However, chemotherapy response is typically transient and patients frequently succumb to SCLC within a year following diagnosis. We performed a transcriptome analysis of the major human lung cancer entities. We show a significant overexpression of genes involved in the DNA damage response, specifically in SCLC. Particularly CHEK1 , which encodes for the cell cycle checkpoint kinase CHK1, is significantly overexpressed in SCLC, compared to lung adenocarcinoma. In line with uncontrolled cell cycle progression in SCLC, we find that CDC25A, B and C mRNAs are expressed at significantly higher levels in SCLC, compared to lung adenocarcinoma. We next profiled the efficacy of compounds targeting CHK1 and ATR. Both, ATR- and CHK1 inhibitors induce genotoxic damage and apoptosis in human and murine SCLC cell lines, but not in lung adenocarcinoma cells. We further demonstrate that murine SCLC tumors were highly sensitive to ATR- and CHK1 inhibitors, while Kras G12D -driven murine lung adenocarcinomas were resistant against these compounds and displayed continued growth under therapy. Altogether, our data indicate that SCLC displays an actionable dependence on ATR/CHK1-mediated cell cycle checkpoints.

Objectives: Pleural mesothelioma (PM) is a rare cancer that often develops after a decades-long latency period and confers a grim prognosis. Novel, biomarker-based therapeutic modalities are expected to improve the outcome of patients with advanced PM. CUDC-907 (fimepinostat) is a dual inhibitor that affects both histone deacetylases and PI3K enzymes. Its antitumor activity was described in several cancer types, but it has not yet been explored in PM. Materials and Methods: The sensitivity of 22 PM cell lines—including 18 models established in our laboratory—to cisplatin and CUDC-907 was determined using a cell viability assay. BAP1, PTEN, and c-Myc expression, as well as MYC copy number variation, were measured. The effect of combination treatment with cisplatin was assessed with cell viability, cell cycle, and 3D spheroid formation assays. Results: Most PM cell lines were sensitive to CUDC-907 treatment, and the CUDC-907 response was significantly higher in cell lines with higher c-Myc expression due to MYC copy number gain or amplification. Importantly, all cisplatin-insensitive cell lines were sensitive to CUDC-907. Combination treatment with cisplatin synergistically decreased cell viability and induced G2/M arrest or cell death. We tested cisplatin-sensitive P31WT and cisplatin resistant P31cis isogeneic pair and found that in both 2D and 3D assays the cisplatin-resistant cells showed a higher sensitivity to CUDC-907 single treatment. Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. Conclusions: The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM.

Sarcomas are a heterogeneous group of rare and aggressive malignancies and have a propensity to metastasize to the thoracic cavity. While sarcoma lung metastasectomy is an established modality, only scarce information is available about potential prognostic factors for sarcoma patients with pleural dissemination. Accordingly, all consecutive sarcoma patients treated at our thoracic surgery department between 2010 and 2023 with pleural sarcomatosis and/or malignant pleural effusion were retrospectively analyzed. Preoperative circulating biomarker values were collected at the time of first pleural involvement. Overall survival was calculated from the first sarcoma diagnosis as well as from the first diagnosis of pleural dissemination. 98 patients (42 female) were included in the cohort with a median age of 54.6 years (range: 15.9–84.3 years) at the time of pleural involvement. 77 patients had soft tissue sarcoma, while 21 patients had primary sarcoma in the bone including 4 chondrosarcoma. Among the 19 different sarcoma types, synovial sarcoma (13%), liposarcoma (11%), undifferentiated pleomorphic sarcoma (11%), Ewing (like) sarcoma (10%) and leiomyosarcoma (9%) were the most frequent. Pleural dissemination was mostly metachronous, while only 7 cases were synchronous. The median pleural dissemination-free interval was 17.1 months after sarcoma diagnosis. The median overall survival after pleural dissemination was 12 months. WBC values outside the normal range had no significant impact on overall survival. High LDH (>250 U/L) and CRP (>1 mg/dL) conferred significantly lower overall survival (8.6 months vs. 19.1 months (p < 0.0001) and 4.9 months vs. 29 months (p < 0.0001), respectively). Albumin alone showed no prognostic impact, however, the modified Glasgow prognostic score (0, 1, and 2) was a strong prognosticator (20.4 vs. 8.6 vs. 1.7 months (p < 0.0001). In a multivariable analysis, CRP remained a significant prognostic factor. In conclusion, routine circulating biomarkers carry prognostic information for sarcoma patients with pleural dissemination and should be considered for risk stratification and personalized therapeutic decisions.

Background The prolonged air leak is probably the most common complication following lung resections. Around 10–20% of the patients who undergo a lung resection will eventually develop a prolonged air leak. The definition of a prolonged air leak varies between an air leak, which is evident after the fifth, seventh or even tenth postoperative day to every air leak that prolongs the hospital stay. However, the postoperative hospital stay following a thoracoscopic lobectomy can be as short as 2 days, making the above definitions sound outdated. The treatment of these air leaks is also very versatile. One of the broadly accepted treatment options is the autologous blood pleurodesis or “blood patch”. The purpose of this trial is to investigate the impact of a prophylactic autologous blood pleurodesis on reducing the duration of the postoperative air leak and therefore prevent the air leak from becoming prolonged. Methods Patients undergoing an elective thoracoscopic anatomic lung resection for primary lung cancer or metastatic disease will be eligible for recruitment. Patients with an air leak of > 100 ml/min within 6 h prior to the morning round on the second postoperative day will be eligible for inclusion in the study and randomization. Patients will be randomized to either blood pleurodesis or watchful waiting. The primary endpoint is the time to drain removal measured in full days. The trial ends on the seventh postoperative day. Discussion The early autologous blood pleurodesis could lead to a faster cessation of the air leak and therefore to a faster removal of the drain. A faster removal of the drain would relieve the patient from all the well-known drain-associated complications (longer hospital stay, stronger postoperative pain, risk of drain-associated infection, etc.). From the economical point of view, faster drain removal would reduce the hospital costs as well as the costs associated with the care of a patient with a chest drain in an outpatient setting. Trial registration German Clinical Trials Register (DRKS) DRKS00030810. 27 December 2022

BackgroundImmunotherapies targeting the programmed death receptor-1/programmed death ligand-1(PD-1/PD-L1) checkpoint have a major impact on the treatment of both resectable and advanced non-small cell lung cancer (NSCLC). Additional blockade of the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT)-receptor may synergistically foster the immune-related response. Several trials are currently investigating the combination of neoadjuvant platinum-based chemotherapy and dual checkpoint inhibition prior to curative surgery. The investigator-initiated NeoTRACK trial (EU CT number: 2022-501322-38-00; ClinicalTrials.gov identifier: NCT05825625; IKF056) aims to evaluate the feasibility and safety of perioperative anti-PD-L1 (by atezolizumab) and anti-TIGIT (by tiragolumab) treatment in combination with chemotherapy in patients with early stage NSCLC.Methods and analysisNeoTRACK is an open-label, single-arm, prospective, bicentric phase II trial. Patients with NSCLC in clinical stages II, IIIA and IIIB (only T3N2) will receive two cycles of standard platinum-based chemotherapy in combination with the anti-TIGIT antibody tiragolumab and the anti-PD-L1 antibody atezolizumab, followed by curative surgery. After surgery, patients without pathological complete response (pCR) will receive another two cycles of chemotherapy in combination with tiragolumab and atezolizumab, followed by tiragolumab/atezolizumab maintenance for up to 1 year (maximum 16 cycles). Patients with pCR will only receive dual immunotherapy. All patients will be followed-up for 30 months after the last study treatment. The clinical study will be aligned with a translational research programme to investigate treatment-naïve tumour tissues, surgical specimens and longitudinally collected blood samples. 35 patients are planned for enrolment. Patient recruitment started in August 2023, and treatment of the last patient is estimated to start 2.5 years thereafter.DiscussionThe NeoTRACK trial aims to assess the feasibility and efficacy of combining tiragolumab and atezolizumab as both neoadjuvant and adjuvant therapies in patients with resectable NSCLC. The concept of treatment personalisation based on postoperative pCR is of great clinical interest.Ethics and disseminationThe trial obtained ethical and regulatory approval in Germany through the Clinical Trials Information System (CTIS, ID: 2022-501322-38-00) and the Paul Ehrlich Institute (PEI, competent authority for approval of clinical trials using medicinal products for human use in Germany, process number: PB00148) on 30 March 2023. A data safety and monitoring board will meet regularly to review ongoing treatment in terms of safety.Study results will be published in peer-reviewed journals, presented at conferences and in the public registry of CTIS, following trial completion.Trial registration numberNCT05825625.

Background and Objectives: The incidence of distant metastases in patients with head and neck cancer (HNC) is approximately 10%. Pulmonary metastases are the most frequent distant location, with an incidence of 70–85%. The standard treatment options are chemo-, immuno- and radiotherapy. Despite a benefit for long-term survival for patients with isolated pulmonary metastases, pulmonary metastasectomy (PM) is not the treatment of choice. Furthermore, many otorhinolaryngologists are not sufficiently familiar with the concept of PM. This work reviews the recent studies of pulmonary metastatic HNC and the results after pulmonary metastasectomy. Materials and Methods: PubMed, Medline, Embase, and the Cochrane library were checked for the case series’ of patients undergoing metastasectomy with pulmonary metastases published since 1 January 2000. Results: We included the data of 15 studies of patients undergoing PM. The 5-year survival rates varied from 21% to 59%, with median survival from 10 to 77 months after PM. We could not identify one specific prognostic factor for long-term survival after surgery. However, at least most studies stated that PM should be planned if a complete (R0) resection is possible. Conclusions: PM showed reliable results and is supposedly the treatment of choice for patients with isolated pulmonary metastases. Patients not suitable for surgery may benefit from other non-surgical therapy. Every HNC patient with pulmonary metastases should be discussed in the multidisciplinary tumor board to optimize the therapy and the outcome.

Myasthenia gravis (MG) is a rare neuromuscular disorder. Symptoms can range from ptosis only to life threatening myasthenic crisis. Thymectomy is recommended for anti-acetylcholine receptor-antibody positive patients with early-onset MG. Here, we investigated prognostic factors shaping therapeutic outcomes of thymectomy to improve patient stratification. We retrospectively collected single-center data from a specialized center for MG from all consecutive adult patients that underwent thymectomy from 01/2012 to 12/2020. We selected patients with thymoma-associated and non-thymomatous MG for further investigations. We analyzed the patient collective regarding perioperative parameters in relation to the surgical approach. Furthermore, we investigated the dynamics of the anti-acetylcholine receptor-antibody titers and concurrent immunosuppressive therapies, as well as the therapeutic outcomes in dependence of clinical classifications. Of 137 patients 94 were included for further analysis. We used a minimally invasive approach in 73 patients, whereas 21 patients underwent sternotomy. A total of 45 patients were classified as early-onset MG (EOMG), 28 as late-onset MG (LOMG) and 21 as thymoma-associated MG (TAMG). The groups differed in terms of age at diagnosis (EOMG: 31.1 ± 12.2 years; LOMG: 59.8 ± 13.7 years; TAMG: 58.6 ± 16.7 years; p < 0.001). Patients with EOMG and TAMG were more often female than patients in the LOMG group (EOMG: 75.6%; LOMG: 42.9%; TAMG: 61.9%; p = 0.018). There were no significant differences in outcome scores (quantitative MG; MG activities of daily living; MG Quality of Live) with a median follow-up of 46 months. However, Complete Stable Remission was achieved significantly more frequently in the EOMG group than in the other two groups (p = 0.031). At the same time, symptoms seem to improve similarly in all three groups (p = 0.25). Our study confirms the benefit of thymectomy in the therapy of MG. Both, the concentration of acetylcholine receptor antibodies and the necessary dosage of cortisone therapy show a continuous regression after thymectomy in the overall cohort. Beyond EOMG, groups of LOMG and thymomatous MG responded to thymectomy as well, but therapy success was less pronounced and delayed compared to the EOMG subgroup. Thymectomy is a mainstay of MG therapy to be considered in all subgroups of MG patients investigated.

Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP.

Background/Objectives: Analysis of the density and spatial distribution of pulmonary infiltrates of patients with high-grade (≥3) pneumonitis after radiochemotherapy and durvalumab consolidation (RT/CTx + IO) was performed in order to define dosimetric hallmarks of the development of infiltrates following this multimodality treatment. Methods: Consecutive patients treated with RT/CTx + IO for stage III NSCLC were retrospectively reviewed with respect to the occurrence of grade ≥ 3 pneumonitis. Lung infiltrates were contoured on follow-up CT scans acquired around the time of maximum pneumonitis expression. The applied dose distribution was overlaid with the follow-up CT using elastic deformation, and infiltrates were binned according to their density in density strata of 50 HU. The dose and density dependence of partial infiltrate volumes per unit lung volume was analyzed using a mixed fixed and random effect model adjusting for patient, density and dose-dependent random effects. Results: Six patients with grade ≥ 3 pneumonitis were identified from 132 patients treated with RT/CT + IO at a comprehensive cancer center. Partial volumes of lung infiltrates captured by follow-up CT with maximum pneumonitis expression ranged from 15.5 to 60.0% (median 39.8%). A significant, systematic dose–response relationship was found for partial lung infiltrate volumes per dose and density bin. A unimodal density distribution of partial lung infiltrate volumes was also found over the infiltrate density range of −1000 to 100 HU. This was determined using a mixed model that adjusted for random effects (p < 0.0001 for both effects, F-test). There was no interaction effect between systematic dose and infiltrate density dependence of the partial infiltrate volumes. The proportion of infiltrate volumes that are attributable to the systematic dose–response relation amounts to a mean of 16.6% of the total infiltrate volume per patient according to this model. Compared to patients with pneumonitis of grade ≤ 2, patients with high-risk pneumonitis had higher partial infiltrate volumes, particularly in the low-dose regions in five grade dose bins up to 20 Gy (AUC = 1.0, p < 0.0001, likelihood-ratio test). Conclusions: Dose-dependent and -independent partial lung infiltrate volumes were found in patients with high-grade pneumonitis after RT/CTx + IO. These results indicate that pneumonitis involves contributions from both radiochemotherapy-induced and immunotherapy-related mechanisms.