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Glioblastoma cells rely on connexin 43 (Cx43)-based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood-brain-barrier-penetrating drug with GJ-inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks. Fluorescence-guided measurements of calcein cell-to-cell transfer were used to study functional intercellular connectivity. Specific DNA fragmentation rates of propidium iodide-stained nuclei were measured as a surrogate readout for cell death using flow cytometry. CRISPR/Cas9-mediated gene editing of Cx43 served as a validation tool of cellular effects related to Cx43 GJ inhibition. 3' mRNA sequencing was performed for molecular downstream analysis. We found that TO reduced intercellular GJ-mediated cytosolic traffic and yielded a significant reduction of tumor microtube (TM) length. TO-mediated inhibition of cellular tumor networks was accompanied by a synergistic effect for temozolomide-induced cell death. CRISPR/Cas9 Cx43-knockout revealed similar results, indicating that TO-mediated inhibitory effects rely on the inhibition of Cx43-based GJs. Gene set enrichment analyses found that GJ-mediated synergistic cytotoxic effects were linked to a significant upregulation of cell death signaling pathways. In conclusion, TO disrupts TM-based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ-targeted therapeutic approach from bench to bedside., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Both tobacco cessation and low-dose CT screening in at-risk individuals reduce lung cancer-specific and all-cause mortality. As part of a national screening program for the early detection of lung cancer, smoking cessation must be a mandatory part of the counseling given to participants. This increases the cost-benefit effectiveness of the screening program. As part of the initial consultation evidence-based measures for smoking cessation must be offered to smoking participants of the screening program in form of a minimal intervention. If participants do not want to participate in a quit smoking measure they must actively refuse (opt-out rule). The costs of quitting smoking, including the costs of withdrawal-inhibiting medication, have to be fully covered by statutory health insurance for participants in the lung cancer screening program., Competing Interests: Alexander Rupp ist Berater der Firma Sanero Medical GmbH Stuttgart, die eine Internetplattform und eine digitale Gesundheitsanwendung (DiGA) zur Tabakentwöhnung betreibt.Christa Rustler ist Leiterin des Büros des Deutschen Netz rauchfreier Krankenhäuser und Gesundheitseinrichtungen (DNRfK), welches zur Implementierung des „rauchfrei tickets“ Zuwendungen der Bundeszentrale für gesundheitliche Aufklärung (BZgA) erhält.Die anderen Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Tobacco control, psychosocial and medical assistance regarding tobacco cessation is still a hidden potential within the German health care system. So far doctors rarely talk to their patients about their smoking status and physical and psychological benefits of quitting.This paper focusses on recommended current diagnostic and treatment standards, as well as evidence-based methods to address the topic on how to stop smoking and its association with certain diseases such as COPD, lung cancer and COVID-19 infection. The role of e-cigarettes as a cessation tool and its health related risks are critically examined. Consequences and advice how to implement smoking cessation procedures into daily practice are presented., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Data on the training and continuing education situation of residents in the field of internal medicine and rheumatology are not available for Germany. For this reason, the Commission for Education and Training of the German Society of Rheumatology (DGRh) initiated the BEWUSST survey on the working, training and research conditions of residents in rheumatology., Methods: A total of 102 questions on the topics of working conditions in everyday professional life, continuing medical education and training, compatibility of career and family, compatibility of work and research, perspectives as a rheumatologist and practical activities were included in an online questionnaire., Results: A total of 102 participants took part in the survey. Of the respondents 48.1% were satisfied with their professional situation, 40.2% of the participants were supervised by a specialist mentor and 54.9% were working as scientists during their work as a physician. A compatibility of family and career was possible for 34.7%. After completion of the residency 52.9% of the respondents aspired to a combined clinical and outpatient activity., Conclusion: Half of the trainee rheumatologists are satisfied with their professional activities, although mentoring of the assistants in training should be further improved. With respect to the desired combined clinical and outpatient activity, the existing options should be expanded or new professional fields of activity should be established, so that the specialty remains attractive for the upcoming generations., (© 2023. The Author(s).)

Tobacco smoking is widespread in Germany. An increase in the number of teenagers and young adults that smoke has recently been a cause for concern. The high prevalence in Germany is contrasted by inadequate preventive measures compared to international standards. Smoking behavior should always be inquired about and documented in the same way as vital signs. All smokers, regardless of the reason for contact and motivation, should receive short, low-threshold advice, e.g. using the ABC approach (ask, brief advice, cessation). In addition to repeated advice and referral to further services, the use of nicotine replacement or drug therapy is essential for the success of quitting. The combination of long- and short-acting nicotine replacement products doubles the success rate. Electronic nicotine delivery systems are not recommended for smoking cessation., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Tobacco smoking is the greatest preventable health risk. The effects are serious, both individually and societal. Nevertheless, the current prevalence of tobacco smokers in Germany is still high at around 35 %. A recent strong increase in actively smoking adolescents (14- to 17-year-olds, current prevalence approx. 16 %) and young adults (18- to 24-year-olds, current prevalence approx. 41 %) is also a cause for concern. About a third of all inpatients continue smoking while being treated. The hospitalization of active smokers in acute and rehabilitation hospitals serves as a "teachable moment" for initiation of cessation offers. An intervention that begins in hospital and continues for at least a month after discharge results in about 40 % additional smokefree patients. It is scientifically well-researched, effective and cost-efficient. After initiation in hospital these measures can be continued via ambulatory cessation programs, rehabilitation facilities, an Internet or telephone service. In Germany, there are structured and quality-assured cessation offers, both for the inpatient and for the outpatient area. The biggest obstacle to broad establishment of such offers is the lack of reimbursement. Two feasible ways to change this would be the remuneration of the existing OPS 9-501 "Multimodal inpatient treatment for smoking cessation" and the establishment of quality contracts according to § 110a SGB V. An expansion of tobacco cessation measures in healthcare facilities would reduce smoking prevalence, associated burden of disease and consecutive costs., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Introduction: Checkpoint-inhibitor pneumonitis (CIP) represents a major immune-related adverse event (irAE) in patients with lung cancer. We aimed for the clinical characterization, diagnostics, risk factors, treatment and outcome in a large cohort of patients from everyday clinical practice., Patients and Methods: For this retrospective analysis, 1,376 patients having received checkpoint inhibitors (CPI) in any line of therapy from June 2015 until February 2020 from three large-volume lung cancer centers in Berlin, Germany were included and analyzed., Results: With a median follow-up of 35 months, all-grade, high-grade (CTCAE ≥ 3) and fatal CIP were observed in 83 (6.0%), 37 (2.7%) and 12 (0.9%) patients, respectively, with a median onset 4 months after initiation of CPI therapy. The most common radiologic patterns were organizing pneumonia (OP) and non-specific interstitial pneumonia (NSIP) (37% and 31%). All except 7 patients with G1-2 CIP interrupted treatment. Corticosteroids were administered to 74 patients with a median starting dose of 0.75 mg/kg. After complete restitution (n = 67), re-exposure to CPI (n = 14) led to additional irAE in 43% of the cases. Thoracic radiotherapy targeting the lung was the only independent risk factor for CIP (odds ratio 2.8, p < 0.001) and pretherapeutic diffusing capacity for carbon monoxide inversely correlated with CIP severity. Compared with patients without CIP and non-CIP irAE, CIP was associated with impaired overall survival (hazard ratios 1.23, p = 0.24 and 2.01, p = 0.005)., Conclusions: High-grade CIP accounts for almost half of all CIP cases in an allcomer lung cancer population. A continuous vigilance, rapid diagnostics and adequate treatment are key to prevent disease progression associated with impaired survival., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Frost reports consulting fees for being an advisory board member from AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol Myers&Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi and Takeda; Support for attending meetings and/or travel from Amgen, AstraZeneca, BMS, Janssen, Lilly and Takeda; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for the “Deutsche Gesellschaft für Pneumologie (DGP)” and the “Deutsche Krebsgesellschaft (DKG): Arbeitsgemeinschaft Internistische Onkologie, Sektion Thoraxonkologie”. Mrs. Unger has nothing to disclose. Dr. Blum has nothing to disclose. Dr. Misch has nothing to disclose. Dr. Kurz has nothing to disclose. Dr. Lüders has nothing to disclose. Dr. Olive has nothing to disclose. Dr. Raspe has nothing to disclose. Dr. Hilbrandt has nothing to disclose. Dr. Koch reports consulting fees for AstraZeneca and Roche, travel support from Boehringer Ingelheim and participation on a data safety monitoring board or advisory board for Roche and Janssen-Cilag. Dr. Böhmer reports consulting fees from Varian Medical Systems. Dr. Senger has nothing to disclose. Dr. Witzenrath reports having received research grants from the „Deutsche Forschungsgemeinschaft“, „Bundesministerium für Bildung und Forschung“, „Deutsche Gesellschaft für Pneumologie“, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Foundation, Capnetz Foundation, International Max Planck Research School, personal fees for lectures or consulting from: Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Gilead, Glaxo Smith Kline, Hexal, Insmed, Novartis, Noxxon, Pantherna, Roche, Teva, Vaxxilon; Patents planned, issued or pending: EPO 12181535.1: IL-27 for modulation of immune response in acute lung injury (Issued 2012), WO/2010/094491: Means for inhibiting the expression of Ang-2 (Issued 2010); PCT/EP2021/066543: A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor (Issued 2021); PCT/EP2021/075627: New medical use of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (Issued 2021). Dr. Grohé reports having received research grants from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens; Participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens; Dr. Bauer has nothing to disclose. Dr. Modest reports consulting fees from Amgen, Merck Serono, Servier, Pierre Fabre, BMS, MSD, Lilly, AstraZeneca, Onkowissen, Sanofi, Taiho, G1 and Transgene; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Merck Serono, Servier, Pierre Fabre, BMS, MSD, Lilly, AstraZeneca, Onkowissen, Sanofi, Taiho, G1 and Transgene; Support for attending meetings and/or travel from Amgen. Dr. Kollmeier has nothing to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Since 2020, digital health applications (DiGA) can be prescribed at the expense of the German statutory health insurance (SHI) system after undergoing an approval procedure by the Federal Institute for Drugs and Medical Devices (BfArM). DiGA can be approved provisionally for 1 year (with the option of extension) or permanently. The latter is dependent on scientific evidence of a positive effect on care, which can be a medical benefit or a patient-relevant structural and procedural improvement in care. However, it is apparent that the investigation of DiGA in scientific studies is challenging, as they are often complex interventions whose success also includes user and prescriber factors. In addition, health services research data underpinning the benefits of DiGA are lacking to date. In the current article, methodological considerations for DiGA research are presented, and a selection of internal medicine DiGAs is used to critically discuss current research practice., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: The experience of a second victim phenomenon after an event plays a significant role in health care providers' well-being. Untreated; it may lead to severe harm to victims and their families; other patients; hospitals; and society due to impairment or even loss of highly specialised employees. In order to manage the phenomenon, lifelong learning is inevitable but depends on learning motivation to attend training. This motivation may be impaired by overconfidence effects (e.g., over-placement and overestimation) that may suggest no demand for education. The aim of this study was to examine the interdependency of learning motivation and overconfidence concerning second victim effects., Methods: We assessed 176 physicians about overconfidence and learning motivation combined with a knowledge test. The nationwide online study took place in early 2022 and addressed about 3000 German physicians of internal medicine. Statistics included analytical and qualitative methods., Results: Of 176 participants, 83 completed the assessment. Analysis showed the presence of two overconfidence effects and in-group biases (clinical tribalism). None of the effects correlated directly with learning motivation, but cluster analysis revealed three different learning types: highly motivated, competent, and confident "experts", motivated and overconfident "recruitables", and unmotivated and overconfident "unawares". Qualitative analysis revealed four main themes: "environmental factors", "emotionality", "violence and death", and "missing qualifications" contributing to the phenomenon., Discussion: We confirmed the presence of overconfidence in second victim management competencies in about 3% of all persons addressed. Further, we could detect the same three learning motivation patterns compared to preceding studies on learning motivation in other medical competencies like life support and infection control. These findings considering overconfidence effects may be helpful for safety managers, medical teachers, curriculum developers and supervisors to create preventive educational curricula on second victim recognition and management.

The current data on climate change and environmental degradation are dramatic. The consequences of these changes are already having a significant impact on people's health. Physicians - as advocates of the patients, but also as citizens - have an ethical obligation to be involved in efforts to stop these changes. The European Federation of Internal Medicine (EFIM) strongly encourages the Internal Medicine societies and internists across Europe to play an active role in matters related to climate change and environmental degradation. At a national level, this includes advocating the adoption of measures that reduce greenhouse gas (GHG) emissions and environmental degradation and contributing to policy decisions related to these issues. At a hospital level and in clinical practice, supporting actions by the health sector to reduce its ecological footprint is vital. At the level of EFIM and its associated internal societies, promoting educational activities and developing a toolkit to prepare internists to better care for citizens who suffer from the consequences of climate change. In addition to advocating and implementing effective actions to reduce the ecological footprint of the health industry, recommending the introduction of these themes in scientific programs of Internal Medicine meetings and congresses and the pre- and postgraduate medical training. At a personal level, internists must be active agents in advocating sustainable practices for the environment, increasing the awareness of the community about the health risks of climate change and environmental degradation, and being role models in the adoption of environmentally friendly behaviour., Competing Interests: Declaration of Competing Interest The authors declare they have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Local ablative therapy (LAT) improves survival in oligometastatic lung cancer (OMD), but there is limited information on recurrence patterns, re-treatments and in particular the role of brain metastases during the course of disease. We therefore conducted a retrospective multicenter analysis to evaluate course of disease, sequence of therapies and predictors for long-term disease-control in the brain and survival endpoints., Patients and Methods: Clinical data of patients with synchronous, single organ OMD with ≤4 metastases were collected from 5 certified German lung cancer centers. All patients underwent thorough initial staging including a 18 FDG-PET/CT scan, brain imaging and mediastinal staging, if necessary, and received LAT to all sites of disease., Results: In total, 164 patients were included (median age 62 years [range 41-84], non-squamous histology 80%, N0-1 64%, single metastasis 84%), 103 had brain (cohort A), 61 extracranial metastases (cohort B). With a median follow-up of 66 months, 115 patients (70%) experienced recurrent disease with a different distribution of sites: In cohort A vs. B, brain relapses occurred in 56% vs. 18% and new distant metastases in 5% vs. 40%. In total, LAT for every relapse was possible for 25% (29/115) of the patients. Patients with initial and secondary onset brain metastases experienced long-term disease-control in the brain and subsequently favorable survival with the application of repeated LAT (disease in the brain controlled vs. not-controlled, HR 0.21, p < 0.001). Comparable long-term overall survival was observed in patients with no or isolated brain relapses (5-years OS 74% and 92%) in contrast to patients with extracranial relapses (5-years OS 19.6%, p < 0.001)., Conclusions: Repeated LAT for recurrent synchronous single organ OMD results in a long-term favorable outcome. Disease control in the brain appears crucial and likely determines survival., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Importance: Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce., Objective: To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection., Design, Setting and Participants: This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated., Exposures: Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection., Main Outcomes and Measures: Median overall survival., Results: From the whole cohort of patients with NSCLC (N = 384), 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001)., Conclusions and Relevance: Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients.

Since 2020 physicians can prescribe digital health applications (DiGA), also colloquially known as apps on prescription, which are reimbursed by the statutory health insurance when they are approved by the Federal Institute for Drugs and Medical Devices (BfArM) and are included in the DiGA Ordinance. Currently, there is one approved DiGA (indication obesity) for internal medicine. There are many questions on the practical use of the DiGA, ranging from the prescription, the effectiveness, the complexities and reimbursement as well as the liability risks. The DiGA are innovative new means, which maybe support internal medicine physicians in the diagnostics and treatment in the future. The benefits in this field of indications are limited by unclarified issues, especially on the prescription practice and the currently low number of DiGA available in internal medicine., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Tobacco control, psychosocial and medical assistance regarding tobacco cessation is still a hidden potential within the German health care system. So far doctors rarely talk to their patients about their smoking status and physical and psychological benefits of quitting.This paper focusses on recommended current diagnostic and treatment standards, as well as evidence-based methods to address the topic on how to stop smoking and its association with certain diseases such as COPD, lung cancer and COVID-19 infection. The role of e-cigarettes as a cessation tool and its health related risks are critically examined. Consequences and advice how to implement smoking cessation procedures into daily practice are presented., Competing Interests: Erklärung zu finanziellen InteressenForschungsförderung erhalten: ja, von einer anderen Institution; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht-Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein.Erklärung zu nicht-finanziellen InteressenA. Batra: Wissenschaftlicher Aktionskreis Tabakentwöhnung (WAT) e. V. (Vorsitzender), Deutsche Gesellschaft für Suchtforschung und Suchttherapie (DG-Sucht, Vorstandsmitglied), Deutsche Gesellschaft für Suchtmedizin (DGS), Deutsche Gesellschaft für Psychiatrie, Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN) e. V. (stell. Referatsleiter Abhängigkeitserkrankungen).A. Rupp: Berater für Nichtraucherhelden.de., (Thieme. All rights reserved.)