[Local Therapy in Stage IV Lung Cancer with Oligopersistent or Oligoprogessive Disease]. / Lokaltherapie im Stadium IV bei Oligopersistenz oder Progression.

Oligopersistent and oligoprogressive disease are defined as distinct situations of metastastatic lung cancer. Oligopersistence describes a situation in which a limited number of metastases remain following effective systemic therapy. Oligoprogression represents a largely controlled tumour disease with a few metastases showing significant progression. In the oligopersistence, treatment aims to establish complete tumour control with subsequent improvement of the prognosis by means of additional local ablative treatment of all remaining lesions. In the oligoprogressive situation, local ablative treatment aims to reestablish complete tumour control while continuing systemic therapy. The concepts are based on ideas that were introduced in oncology more than 30 years ago by Hellman and Weichselbaum by using the term oligometastases. Multimodal therapy concepts have gained importance in the situation of oligopersistence and oligoprogression, particularly due to molecular targeted therapies for oncogene-driven lung cancer and chemo-immunotherapy regimes with high response rates and long response duration. The available evidence will be presented and explained by case studies.

Ribbon-Ordered Superlattice Enables Reversible Anion Redox and Stable High-Voltage Na-Ion Battery Cathodes.

High-voltage layered oxide cathodes attract great attention for sodium-ion batteries (SIBs) due to the potential high energy density, but high voltage usually leads to rapid capacity decay. Herein, a stable high-voltage NaLi0.1Ni0.35Mn0.3Ti0.25O2 cathode with a ribbon-ordered superlattice is reported, and the intrinsic coupling mechanism between structure evolution and the anion redox reaction (ARR) is revealed. Li introduction constructs a special Li-O-Na configuration activating reversible nonbonded O 2p (|O2p)-type ARR and regulates the structure evolution way, enabling the reversible Li ions out-of-layer migration instead of the irreversible transition metal ions out-of-layer migration. The reversible structure evolution enhances the reversibility of the bonded O 2p (O2p)-type ARR and inhibits the generation of oxygen dimers, thus suppressing the irreversible molecular oxygen (O2)-type ARR. After the structure regulation, the structure evolution becomes reversible, |O2p-type ARR is activated, O2p-type ARR becomes stable, and O2-type ARR is inhibited, which largely suppresses the capacity degradation and voltage decay. The discharge capacity is increased from 154 to 168 mA h g-1, the capacity retention after 200 cycles significantly increases from 35 to 84%, and the voltage retention increases from 78 to 93%. This study presents some guidance for the design of high-voltage, O3-type oxide cathodes for high-performance SIBs.

DNA-sensing inflammasomes cause recurrent atherosclerotic stroke.

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

Severity and outcome of a first episode of idiopathic acute pancreatitis is not more severe than pancreatitis of other etiologies.

BACKGROUND: With respect to severity and outcome of an index episode of idiopathic acute pancreatitis the current literature reports conflicting retrospective results. One reason might be the retrospective study design precluding in depth analysis resulting in mixed etiologies and combination of index episode versus recurrent idiopathic acute pancreatitis. METHODS: In this retrospective monocentric cohort study, we retrieved all patients with a first acute pancreatitis episode treated between 2005 and 2021 at the LMU University Hospital from our clinical information system based on the respective ICD-10 codes. In an initial sample of 1390 presumed idiopathic pancreatitis patients we identified 68 confirmed idiopathic acute pancreatitis patients and compared those to 75 first-time alcohol-induced acute pancreatitis patients and 390 first-time biliary-induced acute pancreatitis patients. Clinical outcome (severity, SIRS, mortality, and re-admission rate) was set as outcome measures. Multinomial logistic regression analysis was performed. RESULTS: In alcohol-induced acute pancreatitis moderate and severe courses occur significantly more often when compared to idiopathic acute pancreatitis (17.33 % vs. 10.29 %; multinomial logistic regression p = 0.0021). There were no significant differences in mortality between first-time alcoholic, idiopathic and biliary pancreatitis (p = 0.6328). Patients with idiopathic acute pancreatitis had significantly more hospital readmissions (within 30 days) compared to alcohol-induced pancreatitis patients (p = 0.0284). CONCLUSION: In the context of a first episode of acute pancreatitis, idiopathic acute pancreatitis remains a challenging diagnosis posing an increased risk of recurrence, but not an increased risk for a more severe disease course.

Electronic data capture in resource-limited settings using the lightweight clinical data acquisition and recording system.

Our prototype system designed for clinical data acquisition and recording of studies is a novel electronic data capture (EDC) software for simple and lightweight data capture in clinical research. Existing software tools are either costly or suffer from very limited features. To overcome these shortcomings, we designed an EDC software together with a mobile client. We aimed at making it easy to set-up, modifiable, scalable and thereby facilitating research. We wrote the software in R using a modular approach and implemented existing data standards along with a meta data driven interface and database structure. The prototype is an adaptable open-source software, which can be installed locally or in the cloud without advanced IT-knowledge. A mobile web interface and progressive web app for mobile use and desktop computers is added. We show the software's capability, by demonstrating four clinical studies with over 1600 participants and 679 variables per participant. We delineate a simple deployment approach for a server-installation and indicate further use-cases. The software is available under the MIT open-source license. Conclusively the software is versatile, easily deployable, highly modifiable, and extremely scalable for clinical studies. As an open-source R-software it is accessible, open to community-driven development and improvement in the future.

Innate immune memory after brain injury drives inflammatory cardiac dysfunction.

The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1ß was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1ß or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1ß-mediated comorbidities, offering a framework for secondary prevention immunotherapy.

K-Doping Suppresses Oxygen Redox in P2-Na0.67Ni0.11Cu0.22Mn0.67O2 Cathode Materials for Sodium-Ion Batteries.

In P2-type layered oxide cathodes, Na site-regulation strategies are proposed to modulate the Na+ distribution and structural stability. However, their impact on the oxygen redox reactions remains poorly understood. Herein, the incorporation of K+ in the Na layer of Na0.67Ni0.11Cu0.22Mn0.67O2 is successfully applied. The effects of partial substitution of Na+ with K+ on electrochemical properties, structural stability, and oxygen redox reactions have been extensively studied. Improved Na+ diffusion kinetics of the cathode is observed from galvanostatic intermittent titration technique (GITT) and rate performance. The valence states and local structural environment of the transition metals (TMs) are elucidated via operando synchrotron X-ray absorption spectroscopy (XAS). It is revealed that the TMO2 slabs tend to be strengthened by K-doping, which efficiently facilitates reversible local structural change. Operando X-ray diffraction (XRD) further confirms more reversible phase changes during the charge/discharge for the cathode after K-doping. Density functional theory (DFT) calculations suggest that oxygen redox reaction in Na0.62K0.03Ni0.11Cu0.22Mn0.67O2 cathode has been remarkably suppressed as the nonbonding O 2p states shift down in the energy. This is further corroborated experimentally by resonant inelastic X-ray scattering (RIXS) spectroscopy, ultimately proving the role of K+ incorporated in the Na layer.

Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis.

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.

Comparison of transbronchial biopsy techniques using needle and forceps biopsies in lung cancer for molecular diagnostics: a prospective, randomized crossover trial.

Background: In lung cancer, molecular testing and next-generation sequencing (NGS) are needed to identify therapeutic targets and are increasingly being used in earlier stages of the disease. Despite its longstanding use, it remains unclear whether transbronchial needle aspiration (TBNA) of peripheral lung lesions provides as adequate material for genetic testing as transbronchial forceps biopsies (TBFBs). In this study, we aim to analyze the use of TBNA using median viable cell area (MVCA) as a surrogate parameter to analyze sample quality. Methods: This prospective single-center study analyzed biopsy specimens or aspirates of patients who underwent bronchoscopy with transbronchial biopsy. Patients underwent bronchoscopy with TBFB and TBNA for suspected lung cancer in peripheral lung lesions. Patients were randomized 1:1 to receive either TBFB or TBNA as the first biopsy technique and then switched to the other. After routine workup, sample slides were digitally scanned, and MVCA was calculated by a pathologist blinded to the biopsy technique used. The primary endpoint was MVCA of TBNA versus TBFB. Secondary endpoints were complications categorized as bleeding, pneumothorax, and other. Results: Between August 2021 and April 2022, 15 patients were included in the per-protocol analysis. Six patients were included in cohort 1 and nine patients in cohort 2. A malignant diagnosis was confirmed in 11/15 (73.3%) cases, of which nine were primary lung malignancies. Overall, MVCA in samples obtained by TBFB was significantly larger than TBNA samples {TBFB-MVCA 9.80 mm2 [interquartile range (IQR), 2.70-10.39 mm2] vs. TBNA-MVCA 2.70 mm2 (IQR, 0.14-8.21 mm2), P=0.008}. Despite this difference, molecular testing was feasible in both TBNA and TBFB samples. No major complications were observed. Conclusions: Despite a significantly smaller MVCA provided by TBNA, samples were still considered feasible for NGS, indicating that TBNA represents an alternative method to obtain sufficient tumor tissue in peripheral nodules as part of the diagnosis of suspected lung cancer.

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia.

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

Severity of Gallstone-, Sludge-, or Microlithiasis-Induced Pancreatitis-All of the Same?

BACKGROUND/AIM: Severity of microlithiasis- and sludge-induced pancreatitis in comparison to gallstone-induced pancreatitis has never been studied for a lack of definition. MATERIALS AND METHODS: In this retrospective cohort study, 263 patients with acute biliary pancreatitis treated at a tertiary care center from 2005 to 2021 were stratified according to the recent consensus definition for microlithiasis and sludge. The gallstone-pancreatitis cohort was compared to microlithiasis, sludge, and suspected stone passage pancreatitis cohorts in terms of pancreatitis outcome, liver function, and endosonography/endoscopic retrograde cholangiopancreatography results using one-way analysis of variance and χ 2 test. Multinomial logistic regression analysis was performed to correct for bias. RESULTS: Microlithiasis- and sludge-induced pancreatitis, classified according to the revised Atlanta classification, did not present with a milder course than gallstone-induced pancreatitis ( P = 0.62). Microlithiasis and sludge showed an increase in bilirubin on the day of admission to hospital, which was not significantly different from gallstone-induced pancreatitis ( P = 0.36). The likelihood of detecting biliary disease on endosonography resulting in bile duct clearance was highest on the day of admission and day 1, respectively. CONCLUSIONS: Microlithiasis and sludge induce gallstone-equivalent impaired liver function tests and induce pancreatitis with similar severity compared with gallstone-induced acute biliary pancreatitis.

Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Mutual regulation of CD4+ T cells and intravascular fibrin in infections.

Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell-dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T-helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin-CD4+ T-cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T-cell activation, which is initially triggered by IL-12p40- and MHC-II-dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the thrombin-activatable fibrinolysis inhibitor (TAFI) with fibrin whereby fibrin deposition is increased by TAFI in the absence but not in the presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1-dependent T-helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.

As-needed low-dose inhaled corticosteroid/formoterol therapy in patients with severe asthma included in the German Asthma Net cohort.

After the GINA update in 2019, the proportion of SMART therapy increased with evidence for better disease control in SMART patients compared to SABA alone https://bit.ly/3SSPX1C.

Helicobacter pylori Diagnosis and Treatment in Africa: The First Lagos Consensus Statement of the African Helicobacter and Microbiota Study Group.

BACKGROUND: Helicobacter pylori (H. pylori) infection is the most prevalent type of bacterial infection. Current guidelines from different regions of the world neglect specific African conditions and requirements. The African Helicobacter and Microbiota Study Group (AHMSG), founded in 2022, aimed to create an Africa-specific consensus report reflecting Africa-specific issues. SUMMARY: Eighteen experts from nine African countries and two European delegates supported by nine African collaborators from eight other countries prepared statements on the most important African issues in four working groups: (1) epidemiology, (2) diagnosis, (3) indications and prevention, and (4) treatment. Limited resources, restricted access to medical systems, and underdeveloped diagnostic facilities differ from those of other regions. The results of the individual working groups were presented for the final consensus voting, which included all board members. KEY MESSAGES: There is a need for further studies on H. pylori prevalence in Africa, with diagnosis hinged on specific African situation. Treatment of H. pylori in the African setting should be based on accessibility and reimbursement, while indication and prevention should be defined in specific African countries.

Helicobacter pylori Infection: A 40-Year Journey through Shifting the Paradigm to Transforming the Management.

BACKGROUND: Helicobacter pylori (H. pylori) was discovered 40 years ago and has set a milestone in human medicine. The discovery led to rejection of the dogma of the acidic stomach as a sterile organ and requested to rewrite the chapters on gastric pathophysiology and gastroduodenal diseases. SUMMARY: Over a period of 40 years following the discovery, more than 50,000 articles can be retrieved in PubMed as of today and illustrate the amount and the intensity of research around the role of this bacterium. H. pylori emerged as cause of chronic gastritis and principal cause of peptic ulcer disease (PUD). Eradication of H. pylori became standard of care in management in PUD. The importance of this was highlighted in 2005 with the Nobel Prize in Medicine awarded to Barry Marshall and Robin Warren. H. pylori became eventually recognized for its oncogenic potential in the stomach and as the main risk factor for gastric cancer development. KEY MESSAGES: H. pylori gastritis is defined as infectious disease and requires therapy in all infected individuals. Strategies of gastric cancer prevention and development of therapies to overcome the increasing antibiotic resistance are main targets in clinical research of today.

Prolonged Intake of Luvos Healing Earth does not alter the Composition of the Gut Microbiota in Patients with Diarrhea-predominant Irritable Bowel Syndrome and Healthy Controls.

BACKGROUND AND AIMS: The mineral compound Luvos Healing Earth (LHE) is a commercially available remedy empirically used for a variety of gastrointestinal disorders. The aim of this study was to investigate the possible effect of prolonged LHE therapy on gut microbiota in healthy individuals and in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: In this prospective exploratory study, a total of 20 participants, including 12 healthy controls and 8 patients with IBS-D, received treatment with LHE (Magenfein Granulat, 1 sachet bid) for 6 weeks. Fecal samples were collected for microbiota analysis in the morning fasting state at regular intervals at 6 different timepoints: 2 weeks before starting therapy (Screen), and every 2 weeks during LHE therapy (V0-V3). Additionally, a follow-up visit was scheduled 4 weeks after the end of treatment (V4). Microbiota analysis was performed using the GA-map® Dysbiosis Test Lx v2. Dysbiosis Index, bacterial diversity, as well as the balance or imbalance of functionally important bacteria were assessed. RESULTS: The microbiota analysis revealed an overlap in gut microbiota profiles between healthy controls and patients with IBS-D. Bacterial communities were consistently stable during the entire treatment period, and no significant variations in composition were observed 4 weeks after the end of the therapeutic intervention. There was a remarkable stability of microbiota profiles over time within each individual and a high inter-individual variation. The majority of fecal samples exhibited profiles, reflecting an eubiotic state, with no significant changes in dysbiosis index, functional bacteria profiles, or bacterial diversity. CONCLUSION: Our findings indicate intraindividual resilience of microbiota consortia during the entire study period. Prolonged intake of LHE does not cause significant alterations in fecal microbiota profiles in healthy controls and patients with IBS-D. Luvos Healing Earth does not affect the stability of gut microbial diversity and bacterial functions.

RE.GA.IN.: the Real-world Gastritis Initiative-updating the updates.

At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis.