Closing the RCT Gap-A Large Meta-Analysis on the Role of Surgery in Stage I-III Small Cell Lung Cancer Patients.

INTRODUCTION: Despite clear guideline recommendations, surgery is not consistently carried out as part of multimodal therapy in stage I small cell lung cancer (SCLC) patients. The role of surgery in stages II and III is even more controversial. In the absence of current randomized control trials (RCT), we performed a meta-analysis comparing surgery versus non-surgical treatment in stage I to III SCLC patients. METHODS: A systematic review of the literature was conducted on 1 July 2023, focusing on studies pertaining to the impact of surgery on small cell lung cancer (SCLC). These studies were evaluated using the ROBINS-I tool. Statistical analyses, including I² tests, Q-statistics, DerSimonian-Laird tests, and Egger regression, were performed to assess the data. In addition, 5-year survival rates were analyzed. The meta-analysis was conducted according to PRISMA standards. RESULTS: Among the 6826 records identified, 10 original studies encompassing a collective cohort of 95,323 patients were incorporated into this meta-analysis. Heterogeneity was observed across the included studies, with no discernible indication of publication bias. Analysis of patient characteristics revealed no significant differences between the two groups (p-value > 0.05). The 5-year survival rates in a combined analysis of patients in stages I-III were 39.6 ± 15.3% for the 'surgery group' and 16.7 ± 12.7% for the 'non-surgery group' (p-value < 0.0001). SCLC patients in stages II and III treated outside the guideline with surgery had a significantly better 5-year survival compared to non-surgery controls (36.3 ± 20.2% vs. 20.2 ± 17.0%; p-value = 0.043). CONCLUSIONS: In the absence of current RCTs, this meta-analysis provides robust suggestions that surgery might significantly improve survival in all SCLC stages. Non-surgical therapy could lead to a shortening of life. The feasibility of surgery in non-metastatic SCLC should always be evaluated as part of a multimodal treatment.

LIONS PREY: A New Logistic Scoring System for the Prediction of Malignant Pulmonary Nodules.

OBJECTIVES: Classifying radiologic pulmonary lesions as malignant is challenging. Scoring systems like the Mayo model lack precision in predicting the probability of malignancy. We developed the logistic scoring system 'LIONS PREY' (Lung lesION Score PREdicts malignancY), which is superior to existing models in its precision in determining the likelihood of malignancy. METHODS: We evaluated all patients that were presented to our multidisciplinary team between January 2013 and December 2020. Availability of pathological results after resection or CT-/EBUS-guided sampling was mandatory for study inclusion. Two groups were formed: Group A (malignant nodule; n = 238) and Group B (benign nodule; n = 148). Initially, 22 potential score parameters were derived from the patients' medical histories. RESULTS: After uni- and multivariate analysis, we identified the following eight parameters that were integrated into a scoring system: (1) age (Group A: 64.5 ± 10.2 years vs. Group B: 61.6 ± 13.8 years; multivariate p-value: 0.054); (2) nodule size (21.8 ± 7.5 mm vs. 18.3 ± 7.9 mm; p = 0.051); (3) spiculation (73.1% vs. 41.9%; p = 0.024); (4) solidity (84.9% vs. 62.8%; p = 0.004); (5) size dynamics (6.4 ± 7.7 mm/3 months vs. 0.2 ± 0.9 mm/3 months; p < 0.0001); (6) smoking history (92.0% vs. 43.9%; p < 0.0001); (7) pack years (35.1 ± 19.1 vs. 21.3 ± 18.8; p = 0.079); and (8) cancer history (34.9% vs. 24.3%; p = 0.052). Our model demonstrated superior precision to that of the Mayo score (p = 0.013) with an overall correct classification of 96.0%, a calibration (observed/expected-ratio) of 1.1, and a discrimination (ROC analysis) of AUC (95% CI) 0.94 (0.92-0.97). CONCLUSIONS: Focusing on essential parameters, LIONS PREY can be easily and reproducibly applied based on computed tomography (CT) scans. Multidisciplinary team members could use it to facilitate decision making. Patients may find it easier to consent to surgery knowing the likelihood of pulmonary malignancy. The LIONS PREY app is available for free on Android and iOS devices.

Postoperative Tobacco Cessation Improves Quality of Life, Lung Function and Long-Term Survival in Non-Small-Cell Lung Cancer Patients.

OBJECTIVES: About 90% of all non-small cell lung cancer (NSCLC) cases are associated with inhalative tabacco smoking. Half of patients continue smoking during lung cancer therapy. We examined the effects of postoperative smoking cessation on lung function, quality of life (QOL) and long-term survival. MATERIALS AND METHODS: In total, 641 patients, who underwent lobectomy between 2012 and 2019, were identified from our single institutional data base. Postoperatively, patients that actively smoked at the time of operation were offered a structured 'smoking cessation' program. For this retrospective analysis, two patient groups (total n = 90) were selected by pair matching. Group A (n = 60) had no postoperative tobacco smoking. Group B (n = 30) involved postoperative continued smoking. Lung function (FEV1, DLCO) and QOL ('SF-36' questionnaire) were measured 12 months postoperatively. We compared long-term outcomes using Kaplan-Meier curves. RESULTS: The mean age in group A was 62.6 ± 12.5 years and that in group B was 64.3 ± 9.7 years (p = 0.82); 64% and 62%, respectively, were male (p = 0.46). Preoperative smoking habits were similar ('pack years': group A, 47 ± 31; group B, 49 ± 27; p = 0.87). All relevant baseline characteristics we collected were similar (p > 0.05). One year after lobectomy, FEV1 was reduced by 15% in both groups (p = 0.98). Smoking cessation was significantly associated with improved DLCO (group A: 11 ± 16%; group B: -5 ± 14%; p <0.001) and QOL (vitality (VT): +10 vs. -10, p = 0.017; physical role function (RP): +8 vs. -17, p = 0.012; general health perceptions (GH): +12 vs. -5, p = 0.024). Patients who stopped smoking postoperatively had a significantly superior overall survival (median survival: 89.8 ± 6.8 [95% CI: 76.6-103.1] months vs. 73.9 ± 3.6 [95% CI: 66.9-80.9] months, p = 0.034; 3-year OS rate: 96.2% vs. 81.0%, p = 0.02; 5-year OS rate: 80.0% vs. 64.0%, p = 0.016). The hazard ratio (HR) was 2.31 [95% CI: 1.04-5.13] for postoperative smoking versus tobacco cessation. CONCLUSION: Postoperative smoking cessation is associated with improved quality of life and lung function testing. Notably, a significant increase in long-term survival rates among non-smoking NSCLC patients was observed. These findings could serve as motivation for patients to successfully complete a non-smoking program.

Guideline for the management of myasthenic syndromes.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline 'Diagnostics and therapy of myasthenic syndromes' has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Do skip-N2 metastases significantly impact overall survival and disease-free interval in N2 non-small-cell lung cancer patients? A multicentre analysis.

OBJECTIVES: Skip-N2 metastasis (N0N2), thus N2 metastasis in the absence of N1 metastasis, occurs in ∼20-30% of non-small-cell lung cancer patients. N0N2 patients have a better prognosis than continuous-N2 metastasis (N1N2) patients following surgery. However, this effect remains controversial. Therefore, we conducted a multicentre study to compare the long-term survival and disease-free interval (DFI) of N1N2- and N0N2 patients. METHODS: One- and 3-year survival rates were measured. Kaplan-Meier curves and a Cox proportional hazards model assessed survival and were used to identify prognostic factors for overall survival. In addition, we performed propensity score matching (PSM) to rule out confounding factors. All patients received adjuvant chemoradiation therapy according to European guidelines. RESULTS: Between January 2010 and December 2020, 218 stage IIIA/B N2 patients were included in our analysis. The Cox regression analysis revealed that N1N2 significantly influenced the overall survival rate. Before PSM, N1N2 patients showed significantly more metastatic lymph nodes (P < 0.001) and significantly larger tumours (P = 0.05). After PSM, baseline characteristics did not differ between groups. Before and after PSM, N0N2 patients showed significantly better 1- (P = 0.01; P = 0.009) and 3-year (P < 0.001) survival rates than N1N2 patients. Furthermore, N0N2 patients showed significantly longer DFI than N1N2 patients before and after PSM (P < 000.1). CONCLUSIONS: Prior and after PSM analysis, N0N2 patients were confirmed to have better survival and DFI than N1N2 patients. Our results demonstrate that stage IIIA/B N2 patients are heterogeneous and would benefit from a more precise subdivision and differential treatment.

The impact of thymectomy in subgroups of Myasthenia gravis patients: a single center longitudinal observation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

A comparative study of four thoracic mortality scores.

BACKGROUND: The percentage of patients in resectable stages at initial diagnosis of non-small cell lung cancer (NSCLC) raises due to better screening programs. Therefore, risk prediction models are becoming more critical. Here, we validated and compared four established scoring models, the Thoracoscore, Epithor, Eurloung 2, and the simplified Eurolung 2 (2b), in their ability to predict 30-day mortality. METHODS: All consecutive patients undergoing anatomical pulmonary resection were included. The performance of the four scoring systems was assessed with Hosmer-Lemeshow goodness-of-fit test (calibration) and receiver operating characteristic (ROC) curves (discrimination). We compared the area under the curve (AUC) of the ROC curves by DeLong's method. RESULTS: A total of 624 patients underwent surgery for NSCLC at our institution between 2012 and 2018 30-day mortality was 2.2% (14 patients). The AUC for Eurolung 2 and the simplified Eurolung 2 (0.82) were greater than those of the other scoring systems, Epithor (0.71) and Thoracoscore (0.65). In addition, the DeLong analysis showed a significant superiority of Eurolung 2 and Eurolung 2b over the Thoracoscore (p = 0.04); there were no significant differences compared to Epithor. CONCLUSION: Eurolung 2 and the simplified Eurolung 2 were the favorable scoring systems for predicting 30-day mortality compared to Thoracoscore and Epithor. Therefore, we recommend using Eurolung 2 or the simplified Eurolung 2 for preoperative risk stratification.

Prognostic impact of lymph node spreading pattern in N2 NSCLC patients.

BACKGROUND: One-third of non-small cell lung cancer (NSCLC) patients are diagnosed with locally advanced disease. Long-term survival in stage IIIA/B-N2 remains poor; this may also be due to lymph node spreading pattern. Therefore, we compared the overall survival of stage IIIA/B-N2 patients with superior mediastinal lymph nodes (SML) with infracarinal- or inferior mediastinal lymph nodes (IML) and with multilevel disease (MLD). RESEARCH DESIGN AND METHODS: One-, three-and five-year survival rates were measured. Kaplan-Meier curves and Cox proportional hazards model assessed survival and were used to identify prognostic factors. RESULTS: We reviewed data of stage IIIA/B-N2 patients (n = 129) who underwent surgery for NSCLC between 2012 and 2020. Patients with SML (n = 62) were compared to ILM (n = 37) and MLD (n = 30). SML patients showed significantly better one- (SML: 95.2% vs. IML: 78.6% vs. MLD: 69.4%, p = 0.03), three- (78.8% vs. 27.7 vs. 13.3%; p = <0.001) and five-year (61.1% vs. 17.1 vs. 3%; p < 0.001) survival rates, than IML and MLD patients. Kaplan-Meier curves showed prolonged overall survival for SML patients (log-rank SML, ILM, MLD p < 0.0001). CONCLUSIONS: This study showed significantly better long-term survival of SML patients than IML and MLD patients. The long-term survival of ILM and MLD patients was equally poor.

Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors.

BACKGROUND: Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of antigenic determinants on tumor cells. Creating an antigen-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an antigenic determinant is not known is a major challenge. METHODS: We use multiple cell line and poorly immunogenic syngeneic, autochthonous, and autologous mouse models to evaluate the efficacy of a novel combination immunotherapy named tripartite immunotherapy (TRI-IT). To elucidate TRI-ITs mechanism of action we use immune cell depletions and comprehensive tumor and immune infiltrate characterization by flow cytometry, RNA sequencing and diverse functional assays. RESULTS: We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells, cytokine-induced killer cells, Vγ9Vδ2-T-cells (γδ-T-cells) and T-cells enriched for tumor recognition (CTLs) display synergistic antitumor effects, which are further enhanced by cotreatment with anti-PD1 antibodies. Most strikingly, the full TRI-IT protocol, a combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, eradicates and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT coactivates adaptive cellular and humoral, as well as innate antitumor immune responses to mediate its antitumor effect without inducing off-target toxicity. CONCLUSIONS: Overall, TRI-IT is a novel, highly effective, antigen-agnostic, non-toxic combination immunotherapy. In this study, comprehensive insights into its preclinical efficacy, even in poorly immunogenic tumors, and mode of action are given, so that translation into clinical trials is the next step.

Sublobar resection without staging and lymphadenectomy for ≤2 cm Non-Small Cell Lung Cancer is no adequate therapy.

OBJECTIVE: Sublobar resection is frequently performed for Non-Small Cell Lung Cancer (NSCLC) patients with ≤2 cm nodules. Frequently, both proper staging and radical lymphadenectomy are omitted in these operations. Therefore, we decided to evaluate the number of lymph node metastases and the number of postoperative nodal upstaging in patients undergoing pulmonary resection due to NSCLC with tumors ≤2 cm at our institution. METHODS: Nodal upstaging, lymphangiosis- (L1), and hemangiosis carcinomatosa (V1) were analyzed. pN0 patients were compared to patients with postoperative nodal upstaging. One-, three, and five-year survival rates were measured. Survival was also assessed by the Kaplan-Meier method. RESULTS: 747 patients underwent surgery for NSCLC at our institution between 2012 and 2020. We retrospectively reviewed data of 236 NSCLC patients with ≤2 cm tumors. The mean tumor size was 1.4 cm ± 0.39 in our cohort. Of our patients, 14% showed a cT1a tumor, and 86% of patients cT1b. 24.0 ± 12.3 lymph nodes were dissected and analyzed per patient, and 0.7 ± 2.0 of those were affected. Of our patients, 16.1% showed L1 affection, and 7.6% a V1 affection. Lymph node involvement was diagnosed in 11(4.7%) patients preoperatively. 39(16.5%) patients were upstaged due to lymph node involvement postoperatively (p < 0.001). Upstaged patients showed significantly worse 3- (upstaged: 60.6% vs. pN0: 83.2%; p = 0.01) and 5-year (upstages: 38% vs. pN0 71.5%; p = 0.02) survival rates. CONCLUSION: 16.5% of patients with ≤2 cm NSCLC were nodal upstaged postoperatively. These results underline that lymphadenectomy and proper staging are crucial for NSCLC patients irrespective of the tumor size and the surgical approach.

Neoadjuvant chemoimmunotherapy as a potential therapeutic option in NSCLC UICC stage IIIA with multilevel N2 disease.

Lung Cancer is still one of the leading causes for cancer related death worldwide. The determination of an adequate therapeutic approach requests a precise staging, which contains computed tomography (CT) of the thorax, positron emission tomography computed tomography (PET-CT), cerebral magnetic resonance imaging (cMRI) and pulmonary function testing as well as the patient's opinion. In UICC stages I and II, if there is functional operability and technical resectability, the treatment of choice is primary surgery followed by adjuvant therapy depending on lymph node status, while patients in the metastatic stage IV, or with locally advanced, nonresectable disease are more likely to receive definitive chemoradiation therapy. The UICC Stage III (8th edition) combines a heterogeneous group of patients that remains the focus of discussion regarding the optimal therapeutic regimen, which ranges from primary surgical care to a neoadjuvant therapeutic approach, to definitive conservative treatment. Since March 2020, we have been treating a patient on an interdisciplinary basis who initially had a UICC stage IIIA multilevel N2 pulmonary adenocarcinoma and finally underwent successful surgery after a very good response to neoadjuvant chemoimmunotherapy. Our latest follow-up showed no evidence of recurrence. Similar to current ongoing studies our case shows, that neoadjuvant immunotherapy is a reasonable alternative to conventional neoadjuvant chemotherapy.

Redefining the role of surgery in early small-cell lung cancer.

PURPOSE: Resection is guideline recommended in stage I small-cell lung cancer (SCLC) but not in stage II. In this stage, patients are treated with a non-surgical approach. The aim of this meta-analysis was to assess the role of surgery in both SCLC stages. Surgically treated patients were compared to non-surgical controls. Five-year survival rates were analysed. METHODS: A systematic literature search was performed on December 01, 2021 in Medline, Embase and Cochrane Library. Studies published since 2004 on the effect of surgery in SCLC were considered and assessed using ROBINS-I. We preformed I2-tests, Q-statistics, DerSimonian-Laird tests and Egger-regression. The meta-analysis was conducted according to PRISMA. RESULTS: Out of 6826 records, we identified seven original studies with a total of 15,170 patients that met our inclusion criteria. We found heterogeneity between these studies and ruled out any publication bias. Patient characteristics did not significantly differ between the two groups (p-value > 0.05). The 5-year survival rates in stage I were 47.4 ± 11.6% for the 'surgery group' and 21.7 ± 11.3% for the 'non-surgery group' (p-value = 0.0006). Our analysis of stage II SCLC revealed a significant survival benefit after surgery (40.2 ± 21.6% versus 21.2 ± 17.3%; p-value = 0.0474). CONCLUSION: Based on our data, the role of surgery in stage I and II SCLC is robust, since it improves the long-term survival in both stages significantly. Hence, feasibility of surgery as a priority treatment should always be evaluated not only in stage I SCLC but also in stage II, for which guideline recommendations might have to be reassessed.