BACKGROUND:Locally advanced non-small cell lung cancer (LA-NSCLC) with spinal invasion presents a rare but challenging clinical scenario. Radical surgical approaches, though potentially curative, are often not feasible due to comorbidities, advanced age, poor performance status or technical inoperability. In this setting, the optimal multimodal treatment strategy including radiotherapy (RT) and systemic treatment remains to be fully defined. METHODS:We retrospectively analyzed seven patients with stage III/IV NSCLC and radiologically confirmed spinal invasion treated between 2023 and 2025. Treatment modalities included radiotherapy, systemic therapy, and surgical procedures. Patients were retrospectively stratified using the prognostic scoring system proposed by Lei et al. to assess clinical outcomes by risk group. RESULTS:Four patients were classified as low-risk (score 4-5), and three as intermediate-risk (score 6-7); no patients fell into the high-risk category. Two low-risk patients showed favorable outcomes, including long-term survival and disease stability, while two succumbed to local progression. All intermediate-risk patients died within 5-13 months due to disease progression. Radical surgery was not feasible in any case. Timely treatment initiation and multidisciplinary care were associated with improved outcomes in selected patients. CONCLUSION:RT-based multimodal treatment appears feasible in selected unfavorable patients with advanced NSCLC and spinal infiltration who are not candidates for radical surgery. The prognostic score can help in risk stratification, though timely therapeutic decision-making is equally critical. However, due to the small sample size, the impact on survival remains uncertain and requires validation in larger studies.

Abstract Background Prolonged Grief Disorder (PGD) affects approximately 10% of the bereaved adults, with prevalence rates in Germany ranging between 4.7–5.4%. Early identification through pre-death risk assessment is crucial for optimal bereavement care, yet no validated German-language instrument exists. The Bereavement Risk Assessment Tool (BRAT) represents a promising solution but requires cultural adaptation and validation. The aim of this study was to adapt the BRAT for German-speaking countries and evaluate its inter-rater reliability among healthcare professionals in palliative care and hospice settings. Methods A cross-sectional reliability study was conducted online. The BRAT was translated into German using forward and backward translation methodology, resulting in the Multiprofessioneller Fragebogen zur Trauerverarbeitung (MFT). Participants evaluated four case vignettes featuring 10 bereaved family members using the 40-item MFT. Inter-rater reliability was assessed using Gwet's AC and Krippendorff's α across multiple risk categorizations. Results A total of 55 healthcare professionals (78.2% female, M = 51.5 years) working in German palliative care and hospice settings were recruited. Participants included diverse professional groups: nursing staff, pastoral care workers, medical doctors, psychologists, and social workers. The MFT demonstrated good to excellent inter-rater reliability across most items. The majority of items showed good to almost perfect agreement between raters. Notable variations emerged between professional groups, with inter-rater reliability being influenced by the number of response categories used for risk assessment. Conclusions The German adaptation represents a reliable tool for pre-death bereavement risk assessment in German-speaking healthcare settings. Profession-specific training programs may enhance consistency across occupational groups. Further validation studies examining predictive validity for PGD outcomes are warranted.

Background:The lung tumor microenvironment (TME) plays a crucial role in the progression and metastasis of lung cancer. It consists of various cell types that interact in complex ways to influence tumor behavior. CD45+ cells, as a component of the TME, have complex and multifaceted roles in lung cancer. The balance between the anti-tumor and pro-tumor functions of CD45+ cells can significantly affect lung cancer outcomes. Understanding these roles is essential for developing targeted therapies that harness the beneficial effects of CD45+ cells while mitigating their harmful effects. Methods:We performed single-cell RNA sequencing of sorted CD45+ immune cells from healthy lungs, orthotopic LLC1 tumors, and KrasLA2 (Kras) genetically engineered tumors. Analyses included immune composition, transcriptional programs, differentiation trajectories, metabolic states, and ligand-receptor-based intercellular communication networks. Results:Four major immune compartments, B cells, T cells, NK cells, and macrophages, underwent model-specific remodeling. LLC1 tumors showed B cell expansion and T and NK cell reduction, with inflammatory, stress-response, and NF-κB/TNF-dominant programs. KrasLA2 tumors retained a balanced immune composition but exhibited metabolic rewiring, elevated antigen-presentation signatures, and selective intercellular signaling. Subclustering revealed specialized changes across B cell (resting, mature, pre-Bcr, late pro-B, plasma), T cell (Cd4+, Cd8+, memory, activated, Treg, Th17), NK cell (Fcgr3high, Fcgr3low, Xcl1+), and macrophage (Ace+, Bcr+, Ccr2+, Cd3+, metabolic, MHCII+) subsets. Ligand-receptor analyses highlighted dense inflammatory networks in LLC1 tumors versus metabolically tuned signaling in KrasLA2 tumors. Conclusion:Distinct CD45+ immune landscapes, characterized by inflammatory suppression in LLC1 and metabolic adaptation in KrasLA2 tumors, shape lung tumor biology. This atlas identifies genotype-specific immune vulnerabilities with potential relevance for precision immunotherapy in non-small cell lung cancer.

Abstract Evidence on prognosis and optimal treatment for patients with advanced NSCLC harboring non-EML4-ALK fusions (rare ALK) remains limited. In a retrospective real-world cohort from 29 centers across six countries, overall survival (OS) appeared shorter in patients with rare ALK fusions (n = 51) compared with those with EML4-ALK fusions (n = 277; median 27 vs. 57 months, p = 0.08). Among patients receiving first-line therapy, those with rare ALK fusions experienced significantly shorter progression-free survival (PFS) with platinum-based chemotherapy than with a TKI (5 vs. 23 months; HR 3.1, 95% CI 1.2–8, p = 0.02). In contrast, for patients treated first-line with an ALK-TKI, ORR (85% vs. 74%; p = 0.9) and PFS (median 25 vs. 23 months; HR 0.9, 95% CI 0.6–1.5) were similar between rare ALK and EML4-ALK groups. These findings support TKIs as preferred first-line therapy for advanced NSCLC with rare ALK fusions.

Rationale: Echocardiographic indicators of pulmonary hypertension have been reported to predict decreased survival in patients with lung cancer. Objectives: We tested the hypothesis that this may be associated with impaired right ventricular (RV)-systolic pulmonary arterial pressure (sPAP) coupling. Methods: This prospective observational study included 220 outpatients with non-small cell lung cancer examined using Doppler, strain, and three-dimensional echocardiography before starting therapy. Of the included patients, 41% were women, and the median age was 68 years (interquartile range, 61-74 yr). Prediction of one-year overall survival was assessed using univariable analysis followed by multivariate Cox regression, receiver operating characteristic curves and Kaplan-Meier analyses. Results: Median sPAP was within the limits of normal (31 mm Hg [interquartile range, 26-36 mm Hg]); 30% of the patients had sPAP ≥ 35 mm Hg. In univariable analysis, one-year overall survival was associated with RV systolic function and probability of pulmonary hypertension. In multivariate Cox regression, only RV global longitudinal strain (GLS):sPAP ratio (hazard ratio [HR], 8.76 [95% confidence interval (CI), 1.24-61.82]; P = 0.03), forced expiratory volume in 1 second (HR, 0.98 [95% CI, 0.96-1.00]; P = 0.03) and Eastern Cooperative Oncology Group performance status <2 (HR, 0.34 [95% CI, 0.17-0.68]; P = 0.003) independently predicted survival. The optimal receiver operating characteristic curve-derived RV GLS:sPAP cutoff to predict survival was -0.54%/mm Hg. Among patients in Union for International Cancer Control (UICC) stage 4, those with impaired RV-arterial coupling (RV GLS:sPAP > -0.54%/mm Hg) had worse survival than those with maintained RV-arterial coupling (HR, 2.89 [95% CI, 1.55-5.42]; P < 0.001); the latter subgroup had similar survival compared with patients in UICC stage 3 (HR, 0.65 [95% CI, 0.35-1.20]; P = 0.17). Conclusions: RV GLS:sPAP ratio as an echocardiographic measure of RV-arterial coupling adds to prognostication by UICC status in non-small cell lung cancer. Clinical trial registered with www.clinicaltrials.gov (NCT04467333).

Paradigms about anaplastic lymphoma kinase (ALK)-driven non-small cell lung cancer (NSCLC) have been shaped by EML4::ALK. There is little evidence on the remaining patients, presenting with a plethora of other fusion partners ( rare ALK ). We compared real-world data of patients with advanced NSCLC and rare ALK fusions to patients with EML4::ALK fusions. Patients with rare ALK fusions (n = 51) were older and more likely to have a history of smoking. Overall survival (OS) tended to be shorter. Tyrosine kinase inhibitors (TKI) were used less and chemotherapies more frequently as first-line palliative treatment. Patients with rare ALK fusions had a significantly shorter progression-free survival (PFS) when treated with first-line platinum-based chemotherapy as opposed to TKI. There was, however, no PFS difference between rare ALK and EML4::ALK positive patients receiving TKI as first-line treatment. Taken together, patients with advanced NSCLC harboring rare ALK fusions derive comparable benefit from TKI as patients with EML4::ALK.

The tumor microenvironment (TME) markedly affects cancer progression, yet traditional animal models do not fully recapitulate the situation in humans. To address this, we developed tumor-derived precision lung slices (TD-PCLS), an ex vivo platform for studying the lung TME and evaluating therapies. TD-PCLS, viable for 8-10 days, preserve the heterogeneity and metabolic activity of primary tumors, as confirmed by seahorse analysis. Using multispectral FACS and phenocycler multiplex imaging, we spatially profiled TME components and cancer cell functionality. Additionally, TD-PCLS revealed patient-specific responses to chemo-and immunotherapies. To complement TD-PCLS, we established tumor-cell-seeded PCLS (TCS-PCLS) by introducing tumor and immune cells into healthy lung slices. This model highlighted macrophage-tumor interactions as critical for tumor cell proliferation, migration, and immune modulation. Together, these platforms provide a robust tool for lung cancer research, enabling precision medicine and advancing therapeutic discovery.

8625 Background: More than 90% of ALK rearrangements in NSCLC lead to recurrent fusions with EML4. The remainder is a heterogeneous group involving more than twenty different fusion partners. Data on prognosis and management of these patients is limited to case reports. Methods: This is an international, multicenter, retrospective analysis of advanced NSCLC patients with a non-EML4::ALK-fusion ( rare ALK ) compared to a control cohort of patients harboring typical EML4::ALK-translocations. Results: Out of 26,152 NSCLC patients tested by NGS 0.2% showed rare ALK with 21 distinct fusion partners identified. The prevalence of typical EML4::ALK fusions in the cohort was within the expected range (1.9%). Sufficient clinical data was available for a total of 51 rare ALK and 277 EML4::ALK patients. Median age within the rare ALK cohort was 66 years. 59% were male. The majority (88%) presented with adenocarcinoma, 10% had squamous-cell carcinoma. The choice of first-line TKI in rare ALK patients was similar to the EML4::ALK control cohort and with alectinib used predominantly (around 50%). Compared to EML4::ALK, patients with rare ALK were significantly older, more likely to have ever smoked (59% vs 35%) and, among smokers, had more pack years (15 vs 7 pack years). Objective response rate (ORR) to firstline ALK inhibitor treatment across all treatment lines in patients with rare ALK was 68% (95% confidence interval [CI] 53%-80%), while EML4::ALK patients had an ORR of 85% (CI 80%-89%; p=0.01). ALK inhibitors in first-line palliative treatment led to similar PFS in the rare ALK (23 months [mo]; CI 7.1-38.9) and the EML4::ALK cohort (25 mo; CI 19.9-30.1; HR 0.92; CI 0.6-1.5; p=0.7). Median overall survival (OS) was 40 mo (CI censored) for rare ALK compared to 57 mo (CI 50.7-63.3) for EML4::ALK (HR 0.9; CI 0.5-1.6; p=0.6). Within the rare ALK cohort, first-line treatment with platinum-doublet chemotherapy was associated with shorter PFS as compared to ALK inhibitors (5 mo vs 23 mo; HR 3.1; CI 1.2-8.0; p = 0.021) and trended towards shorter OS (24 mo vs 40 mo; HR 2; CI 0.7-5.9; p=0.2). Conclusions: Acknowledging the limitations of a retrospective analysis, our data suggest that, compared to EML4::ALK, patients with rare ALK fusions derive similar benefit from treatment with ALK inhibitors, which should be preferred over platinum-based therapies as first-line palliative treatment.

Hintergrund: Das Bronchialkarzinom (BK) stellt global die führende Todesursache neoplastischer Erkrankungen dar. Patienten mit BK weisen ein vermehrtes Vorkommen von Komorbiditäten, insbesondere kardiopulmonal, auf, welche prognosebestimmend sein können. Zuletzt war die Pulmonale Hypertonie (PH) im Rahmen des BK als Komorbidität vermehrt in den Fokus gerückt. Obwohl die rechtsventrikuläre Funktion in Relation zur pulmonalarteriellen Nachlast, das sog. RV-PA Coupling, im Rahmen der PH ursächlich für klinische Symptome und prognosebestimmend ist, ist sie zum jetzigen Zeitpunkt noch nicht hinreichend bei Patienten mit BK untersucht worden.

Background Cancer is one of the leading causes of death worldwide, and cardiopulmonary comorbidities may further adversely affect cancer prognosis. We recently described lung cancer-associated pulmonary hypertension (PH) as a new form of PH and comorbidity of lung cancer. While patients with lung cancer with PH had significantly reduced overall survival compared with patients without PH, the prevalence and impact of PH in other cancers remain unclear.Methods In this retrospective, observational cohort study, we analysed the prevalence and impact of PH on clinical outcomes in 1184 patients with solid tumours other than lung cancer, that is, colorectal, head and neck, urological, breast or central nervous system tumours, using surrogate markers for PH determined by CT.Results PH prevalence in this cohort was 10.98%. A Cox proportional hazard model revealed a significant reduction in the median survival time of patients with cancer with PH (837 vs 2074 days; p<0.001). However, there was no correlation between pulmonary metastases and PH. A subgroup analysis showed that PH was linked to decreased lung and cardiac function. Additionally, PH was associated with systemic arterial hypertension (p<0.001) and coronary artery disease (p=0.014), but not emphysema.Conclusions In this study, fewer patients with cancer had surrogate parameters for PH compared with previously published results among patients with lung cancer. Consequently, the prevalence of PH in other cancers might be lower compared with lung cancer; however, PH still has a negative impact on prognosis. Furthermore, our data does not provide evidence that lung metastases cause PH. Thus, our results support the idea that lung cancer-associated PH represents a new category of PH. Our results also highlight the importance of further studies in the field of cardio-oncology.

We retrospectively investigate feasibility and safety of whole brain radiotherapy (WBRT) including a simultaneous-integrated boost technique (WBRT-SIB) in a cohort of patients with a very poor prognosis suffering from multiple and/or large brain metastases, unfavorable primary histology, poor performance status and/or symptomatic BMs. Thirty-five patients with high brain tumor burden, extracranial metastases and low life-expectancy were treated with WBRT-SIB mostly with 35-42 Gy/14 fractions. All metastases were boosted in patients with up to 12 BMs. In patients with > 12 BM, large and/or small metastases in critical brain regions were boosted up to a maximum of 12 SIB volumes. The median number of BM was 8 (range 2–45) and the median BM diameter was 12 mm (range 4–90 mm). Fifteen (43

The tumor microenvironment (TME) plays a central role in the development of cancer. Within this complex milieu, the endothelin (ET) system plays a key role by triggering epithelial-to-mesenchymal transition, causing degradation of the extracellular matrix and modulating hypoxia response, cell proliferation, composition, and activation. These multiple effects of the ET system on cancer progression have prompted numerous preclinical studies targeting the ET system with promising results, leading to considerable optimism for subsequent clinical trials. However, these clinical trials have not lived up to the high expectations; in fact, the clinical trials have failed to demonstrate any substantiated benefit of targeting the ET system in cancer patients. This review discusses the major and recent advances of the ET system with respect to TME and comments on past and ongoing clinical trials of the ET system.

A 69-year-old female patient and a 70-year-old male patient were admitted to hospital with recurrent, severe hypoglycemic episodes and a typical manifestation of Whipple's triad. In the female, elevated levels of insulin, C‑peptide and pro-insulin together with pathological findings during a fasting test proved the presence of an insulinoma, which could be detected by Ga-68-DOTATOC-PET-CT in the pancreas. There was a very rare co-existence of a neuroendocrine Merkel cell carcinoma. In the male, levels of insulin and C‑peptide were suppressed and a diagnosis of paraneoplastic hypoglycemia by IGF‑2 secretion was made with increased glucose disposal in skeletal muscle proven by 18F‑FDG-PET-CT.

Up to 20% of all non-small cell lung cancer patients harbor tumor specific driver mutations that are effectively treated with tyrosine kinase inhibitors. However, for the rare EGFR deletion-insertion mutation of exon 18, there is very little evidence regarding the effectiveness of tyrosine kinase inhibitors. A particular challenge for clinicians in applying tyrosine kinase inhibitors is not only diagnosing a mutation but also interpreting rare mutations with unclear therapeutic significance. Thus, we present the case of a 65-year-old Caucasian male lung adenocarcinoma patient with an EGFR Exon 18 p.Glu709_Thr710delinsAsp mutation of uncertain therapeutic relevance. This patient initially received two cycles of standard platinum-based chemotherapy without any therapeutic response. After administration of Osimertinib as second line therapy, the patient showed a lasting partial remission for 12 months. Therapy related toxicities were limited to mild thrombocytopenia, which ceased after dose reduction of Osimertinib. To our knowledge, this is the first report of effective treatment of this particular mutation with Osimertinib. Hence, we would like to discuss Osimertinib as a viable treatment option in EGFR Exon 18 p.Glu709_Thr710delinsAsp mutated lung adenocarcinoma.

BACKGROUND:Lung cancer is frequently diagnosed among elderly patients. However, this patient group is under-represented in or excluded from clinical trials and, therefore, evidence-based treatment is challenging. It is uncertain whether there are differences in the feasibility of adjuvant therapies between older and younger patients with NSCLC. The objective of this study was the analysis of treatment recommendations, adherence to adjuvant therapy, and overall survival in patients of at least 70 years of age with resected stage II, III or oligometastatic IV NSCLC in comparison to younger patients.METHODS:316 patients with NSCLC stage II to IV oligo resected with curative intent at the Giessen University Hospital between 2008 and 2019 were included, 115 of them 70 years or older. Patient and tumor characteristics, treatment type and survival data were extracted from the oncological database of the Mittelhessen lung cancer centre. Primary endpoints were indication and adherence to adjuvant treatment. Secondary endpoints were therapy-associated morbidity and overall survival.RESULTS:Elderly received significantly fewer recommendations for adjuvant therapy, both chemotherapy (OR=0.509) and radiochemotherapy (OR=0.455). Compared to younger patients, elderly patients commenced therapy significantly less often (OR=4.49) and were less likely to complete treatment (OR=0.423). The 5-year survival rates of treated elderly patients treated exceeded those of untreated elderly (Stage II, 51.9 vs 31.8%; stage III, 29.0 vs 25.8%), and were inferior to the survival rates of the younger patients (stage II, 69.8 vs. 69.8%; stage III 52.8 vs. 19.7%).CONCLUSION:In general, adjuvant therapy appears to be useful and feasible in selected patients over 70 years of age. However, its implementation and success are limited compared to younger patients. Adjuvant therapy is recommended and performed less frequently in older patients. The number of elderly patients treated remained unchanged over time, despite an increasing amount of therapy recommendations. Since the postoperative course, comorbidities, frailty and the toxicity of the therapy play a major role, the assessment of each individual case in an interdisciplinary oncological conference should serve as the basis for therapy decisions instead of age. Further studies are needed to collect representative data for the general elderly population. Newer, potentially better tolerated drugs such as tyrosine kinase inhibitors or immune checkpoint inhibitors appear to be promising.