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Introduction: Understanding prognosis, especially long-term outcome, in advanced nonsmall cell lung cancer (NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care., Methods: Prognostic factors influencing overall survival (OS) and progression-free survival (PFS) in 2082 patients with wild-type (WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP registry recruiting in >150 centres. Analysis for pre-therapeutic factors was based on results from Cox proportional hazard models., Results: Current M-descriptors of the Union for International Cancer Control-8 staging system were validated: M1a and M1b patients had significantly longer median time to events compared to M1c (OS/PFS 16.4/7.2 months, 17.8/6.7 months and 10.9/5.4 months, respectively). OS and PFS were influenced by number and location of metastatic organ systems. M1c and four or more metastatic organs involved had shorter OS and PFS than M1c with one to three organs (OS hazard ratio (HR) 1.69, p<0.001; PFS HR 1.81, p<0.001). M1b-liver metastases had shorter OS/PFS than M1b involving other organs (OS HR 2.70, p=0.006; PFS HR 2.48, p=0.007). Based on number of involved organs (orgsys) and liver metastases, two risk groups (low-risk: M1a, M1b-non-liver, M1c-1-3-orgsys-non-liver; high-risk: M1c-liver, M1b-liver, M1c-4+-orgsys) with significantly different prognoses could be amalgamated (median OS/PFS 14.3/6.5 months and 7.7/4.1 months, respectively). Other favourable factors were female gender and Eastern Cooperative Oncology Group stage 0, with age showing no impact. Those with T1- or N0-status were associated with longer OS than T2-4 or N2-3., Conclusion: In this large observational dataset, we further defined factors for outcome in WT-NSCLC, including increased number of involved metastatic organ systems and liver metastases, as those with overall poorer prognosis and reduced survival chance., Competing Interests: M. Metzenmacher has received honoraria for advisory boards from AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche, Sanofi Aventis and Takeda. F. Griesinger has received research funding (paid to institution) from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens, honoraria for educational lectures from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Sanofi Genzyme, Siemens, Tesaro/GSK and Amgen, honoraria for advisory boards from Abbvie, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme, Takeda and Aria, travel support from Roche, MSD, Merck, Takeda, Boehringer Ingelheim, Abbvie, Sanofi Genzyme, BMS and AstraZeneca, and has leadership roles at Ethikkommission, Forschungskommission, Fakultätsrat University of Internal Medicine of Oldenburg. H-D. Hummel has received travel, accommodation, or other expenses from Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb and Amgen. C. Elender declares that there is no conflict of interest. H. Schäfer has received honoraria for advisory boards from Boehringer Ingelheim, BMS, Pfizer and Roche. M. de Wit reports grants from AstraZeneca, Abbvie and Novartis (paid to institution), has received honoraria for lectures and writing from AstraZeneca, support for meetings and travel from AstraZeneca and Abbvie, and has a leadership position as member of the steering committee in the German Society for Hematology and Oncology (“Deutsche Gesellschaft für Hämatologie und Onkologie”; DGHO). U. Kaiser declares that there is no conflict of interest. J. Kern has received honoraria for scientific meetings from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, travel support from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Pfizer and Roche. M. Jänicke declares that there is no conflict of interest. L. Spring declares that there is no conflict of interest. S. Zacharias declares that there is no conflict of interest. A. Kaiser-Osterhues declares that there is no conflict of interest. A. Groth has received research funding (paid to the employer AIO-Studien-gGmbH) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Roche and Takeda. A. Hipper has received research funding (paid to the employer AIO-Studien-gGmbH) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Roche and Takeda. G. Zaun declares that there is no conflict of interest. S. Dörfel declares that there is no conflict of interest. B. Güldenzoph has received advisory board honoraria from MSD Oncology, Roche Pharma AG, Amgen and AstraZeneca, and support for travel from Amgen. L. Müller declares that there is no conflict of interest. J. Uhlig has received honoraria for advisory boards and workshops from: Roche, Amgen, Servier, MSD, Bristol-Myers Squibb, Sanofi, Merck, Celgene, Novartis, Janssen-Cilag, Boehringer Ingelheim, Bayer and Biogene. M. Thomas has received honoraria for scientific meetings from AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, advisory board honoraria from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, travel support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, research funding (paid to institution) from AstraZeneca, Bristol-Myers Squibb, Roche and Takeda. M. Sebastian has received research funding (paid to institution) from AstraZeneca, honoraria for advisory boards from AstraZeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Johnson & Johnson, Amgen, Tesaro and Eli Lilly, honoraria for educational lectures from AstraZeneca, BMS, Novartis, Pfizer, Boehringer Ingelheim, Roche, Lilly, Pfizer, Takeda, Sanofi, GSK, Amgen, MSD, Janssen-Cilag and Eli Lilly, travel support from BMS and Pfizer, patents from CureVax, BioTech, AstraZeneca, Boehringer Ingelheim, Novartis, BMS, Roche, Lilly, Pfizer, Takeda, Sanofi, GSK, Amgen, MSD and Janssen-Cilag. W.E.E. Eberhardt has received honoraria from AstraZeneca, Roche Pharma AG, Bristol Myers Squibb, MSD Oncology, Boehringer Ingelheim, Lilly, Takeda, Pfizer, Amgen, Novartis, Roche, Sanofi Aventis and Abbvie, consulting or advisory role for AstraZeneca, Roche, Bristol Myers Squibb, MSD Oncology, Bayer Health, Lilly, Boehringer Ingelheim, Takeda, Pfizer, MSD/Merck, Novartis, Takeda, Sanofi Aventis, Abbvie, Amgen, Bayer and Janssen-Cilag, research funding from AstraZeneca, Lilly and Bristol Myers Squibb, and is a member of the IASLC Staging Committee, M-track., (Copyright ©The authors 2023.)

Patients with advanced-stage bronchial cancer benefit from systemic cytostatic therapy, in particular from regimens integrating cisplatin and taxanes. However, eventual disease progression leads to a fatal outcome in most cases, originating from tumor cells resisting chemotherapy. We here show that the intracellular ATP-binding cassette transporter A3 (ABCA3), previously recognized as critical for the secretion of surfactant components from type 2 pneumocytes, is expressed in non-small-cell lung cancer (NSCLC) cells. With some heterogeneity in a given specimen, expression levels detected immunohistochemically in primary cancer tissue were highest in adenocarcinomas and lowest in small cell lung cancers. Genetic silencing of ABCA3 in the NSCLC cell line models A549, NCI-H1650 and NCI-H1975 significantly increased tumor cell susceptibility to the cytostatic effects of both cisplatin (in all cell lines) and paclitaxel (in two of three cell lines). Taken together, ABCA3 emerges as a modulator of NSCLC cell susceptibility to cytostatic therapy., (Copyright © 2013 S. Karger AG, Basel.)

Nelarabine, a purine analog with T-cell specific action, has been approved for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL). This is a report of a single-arm phase 2 study conducted in adults (18-81 years of age) with relapsed/refractory T-ALL/LBL. After 1 or 2 cycles, 45 of 126 evaluable patients (36%) achieved complete remission (CR), 12 partial remission (10%), and 66 (52%) were refractory. One treatment-related death was observed, and 2 patients were withdrawn before evaluation. A total of 80% of the CR patients were transferred to stem cell transplantation (SCT). Overall survival was 24% at 1 year (11% at 6 years). After subsequent SCT in CR, survival was 31% and relapse-free survival 37% at 3 years. Transplantation-related mortality was 11%. Neurologic toxicities of grade I-IV/grade III-IV were observed in 13%/4% of the cycles and 16%/7% of the patients. This largest study so far with nelarabine in adults showed impressive single-drug activity in relapsed T-ALL/T-LBL. The drug was well tolerated, even in heavily pretreated patients. A high proportion of CR patients were transferred to SCT with low mortality but a high relapse rate. Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted.

Objective: Localization of atherosclerotic plaques typically correlates with areas of biomechanical strain where shear stress is decreased while stretch, thought to promote atherogenesis through enhanced oxidative stress, is increased., Methods and Results: In human cultured endothelial cells, nitric oxide synthase expression was exclusively shear stress-dependent whereas expression of glutathione peroxidase-1 (GPx-1), but not that of Cu(2+)/Zn(2+)-superoxide dismutase or Mn(2+)-superoxide dismutase, was upregulated solely in response to cyclic stretch. GPx-1 expression was also enhanced in isolated mouse arteries perfused at high pressure. Combined pharmacological and decoy oligodeoxynucleotide blockade revealed that activation of p38 MAP kinase followed by nuclear translocation of CCAAT/enhancer binding protein plays a pivotal role in stretch-induced GPx-1 expression in human endothelial cells. Antisense oligodeoxynucleotide knockdown of GPx-1 reinforced both their capacity to generate hydrogen peroxide and the transient stretch-induced expression of CD40, monocyte chemoatractant protein-1, and vascular cell adhesion molecule-1. Consequently, THP-1 monocyte adhesion to the GPx-1-depleted cells was augmented., Conclusions: Stretch-induced proatherosclerotic gene expression in human endothelial cells seems to be hydrogen peroxide-mediated. The concomitant rise in GPx-1 expression, but not that of other antioxidant enzymes, may comprise an adaptive mechanism through which the cells maintain their antiatherosclerotic properties in spite of a decreased bioavailability of nitric oxide.

Objective: CD40 ligand (CD154) expressed on activated T helper cells is a key costimulatory molecule for antigen-presenting cells expressing the corresponding receptor CD40. Moreover, CD40 stimulation in nonimmune cells, such as endothelial cells, may play an important role in atherogenesis. One gene product that is induced in endothelial cells on exposure to CD154 is CD154 itself., Methods and Results: In human primary cultured endothelial cells, constitutive CD154 expression was virtually absent and insensitive to proinflammatory cytokines such as tumor necrosis factor alpha and/or interferon-gamma. However, CD154 expression was markedly induced, both on the mRNA and protein level, after CD40 stimulation. Moreover, CD40-positive human monocytes (THP-1 cell line) transmigrating through CD154-expressing endothelial cells responded with an increased expression of interleukin-1beta (IL-1beta) mRNA, indicative of their activation. This increase in IL-1beta expression was confirmed on the protein level and could be abrogated by prior treatment of the endothelial cells with a neutralizing anti-CD154 antibody., Conclusions: By way of CD154-induced CD154 expression, human endothelial cells thus seem capable of influencing the progression of proinflammatory reactions, including atherogenesis through activation of extravasating monocytes.

Objective: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert potent anti-inflammatory effects that are independent of their cholesterol-lowering action. We have investigated the effects of these drugs on cytokine-stimulated CD40 expression in human cultured endothelial cells and monocytes., Methods and Results: Reverse transcription-polymerase chain reaction and Western blot analysis revealed that treatment of either cell type with atorvastatin, cerivastatin, or pravastatin (1 to 10 micromol/L) inhibited interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by approximately 50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 micromol/L). In contrast, mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells. Transcription factor analysis revealed an inhibition by atorvastatin of nuclear factor-kappaB plus signal transducer and activator of transcription-1-dependent de novo synthesis of interferon regulatory factor-1, governing cytokine-stimulated CD40 expression in these cells. One consequence of this statin-dependent downregulation of CD40 expression was a decrease in CD40 ligand-induced endothelial interleukin-12 expression., Conclusions: By interfering with cytokine-stimulated CD40 expression in vascular cells, statins thus seem capable of attenuating CD40 ligand-induced proinflammatory responses, including atherosclerosis. In addition, they point to the coexistence of HMG-CoA reductase-dependent and -independent effects of statins in the same cell type.