Therapeutic Concepts Research Articles

Management of venous aneurysms and the vascular surgical treatment options : Selection of representative case constellations illustrating experiences at acenter for vascular surgery

Venous aneurysms are arare entity in vascular surgery, which are mostly described in individual case series and meta-analyses generated from them. The treatment concepts are diverse and surgical treatment is highlighted due to the risk of thrombosis and pulmonary embolism. There is still an ongoing debate regarding the postoperative necessity and duration of anticoagulation. Case series of aconsecutive patient cohort with venous aneurysms from the last 18years in acenter of (highly specialized care) vascular surgery including i)own experiences obtained in daily vascular surgical practice and ii)aselected and current literature search of relevant references on possible and, in particular, established diagnosis-specific therapeutic concepts. Between 2005 and 2023, atotal of 11cases of venous aneurysms were reported in patients aged 30-84years (mean: 52.5, median: 50), with 1 patient requiring surgery for a recurrence after 2years. The gender ratio was 7:3 (m:f) and the popliteal vein was the most frequently affected anatomical region with 36.4%, followed by the internal jugular vein and axillary/subclavian vein each with 18.2%. Aneurysms of the inferior vena cava, the common iliac vein and the cubital vein occurred only once. Surgical treatment of the aneurysms was performed in 9cases. The surgical methods used were i)tangential resection of the aneurysm wall and continuous purse-string suture, ii)resection of the aneurysm and interposition of an 8‑mm GORE-TEX® vascular graft prosthesis (Gore, Putzbrunn, Germany), iii)ligation of the aneurysm and iv)ligation with subsequent resection of the aneurysm. The rarity of venous aneurysms should be a reason to register these cases centrally (possibly, nationwide diagnosis-related register). Surgical treatment is usually unproblematic and associated with few complications. The risk of pulmonary embolism appears to be significantly increased in venous aneurysms of the extremities, pelvic veins and inferior vena cava, while venous aneurysms of the head and neck are significantly less prone to this. Perioperative and postoperative anticoagulation has been adapted to the development of specific anticoagulants and novel drugs, in favor of treatment with direct oral anticoagulants (DOAC). In personal experience, immediate postoperative heparin perfusion (low dose) and subsequent therapeutic bridging with low-molecular-weight heparin before switching to an anticoagulant for outpatient clinic-based care appears to safeguard the perioperative phase with respect to keeping the surgery-related complication rate (e.g., thrombosis, bleeding) low.

Application and mechanism of Chinese herb medicine in the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver condition closely associated with metabolic syndrome, with its incidence rate continuously rising globally. Recent studies have shown that the development of NAFLD is associated with insulin resistance, lipid metabolism disorder, oxidative stress and endoplasmic reticulum stress. Therapeutic strategies for NAFLD include lifestyle modifications, pharmacological treatments, and emerging biological therapies; however, there is currently no specific drug to treat NAFLD. However Chinese herb medicine (CHM) has shown potential in the treatment of NAFLD due to its unique therapeutic concepts and methods for centuries in China. This review aims to summarize the pathogenesis of NAFLD and some CHMs that have been shown to have therapeutic effects on NAFLD, thus enriching the scientific connotation of TCM theories and facilitating the exploration of TCM in the treatment of NAFLD.

Special entities of the head and neck region: cancers of the nasopharynx, (para)nasal cavities, salivary glands, and the thyroid gland : Post ASCO 2024

Malignancies of the nasopharynx (NPC), the (para)nasal cavities, the salivary glands, and the thyroid gland are distinct to head and neck squamous cell carcinomas (HNSCC) in the oro-/hypopharynx and larynx in terms of etiology, tumor biology, and the therapeutic concept. The contributions to the 2024 American Society of Oncology (ASCO) Annual Meeting provide insight into the latest developments in these "special entities of the head and neck region." Abstracts were examined for their clinical relevance and placed into context with current therapeutic concepts. In the treatment of locally advanced NPC, arandomized phaseIII study showed equivalence of induction (ICT) and adjuvant therapy (AT; NCT03306121). PD-1inhibitors have become established in the palliative therapy of NPC in recent years and could now also play an increasing role in curation: the phaseIII study "Dipper" showed asignificantly better 3‑year event-free survival in patients adjuvantly treated with camrelizumab versus placebo after IT and definitive platinum-containing chemoradiotherapy (dRCT; 89% vs.80%; NCT03427827). The phaseIII study "Beacon" showed complete remission in 30.5% of patients after IT with gemcitabine/cisplatin and the PD‑1 inhibitor tislelizumab (three cycles), arate almost twice as high as with gemcitabine/cisplatin alone (NCT05211232). Intensification of dRCT in NPC using EGFR and VEGF inhibitors appears promising (NCT04447326). Abstracts on salivary gland and nasal and sinus cancers emphasize the importance of targeted therapies. In anaplastic thyroid carcinoma, the combination of aPD‑1 inhibitor and aCTLA4 inhibitor showed a50% response.

Thermophysical Insights into the Anti-Inflammatory Potential of Magnetic Fields

Background: Inflammation is caused by an excess of Sodium ions inside the cell. This generates a variation in the cell’s membrane electric potential, becoming a steady state from a thermodynamic viewpoint. Methods: This paper introduces a thermodynamic approach to inflammation based on the fundamental role of the electric potential of the cell membrane, introducing an analysis of the effect of heat transfer related to the inflammation condition. Results: The direct proportionality between the reduction in temperature and the increase of Na+ outflow may ameliorate the inflammation cascade. Conclusions: Based on these ion fluxes, we suggest the consideration of a ‘companion’ electromagnetic therapeutic wave concept in support of the present anti-inflammatory treatment.

Therapeutic approaches and conceptions of practice of osteopaths in Australia - a national cross-sectional study and exploratory factor analysis of the Osteo-TAQ

BackgroundHealth professionals develop their own approach to patient care based on education, experience and philosophical stance. Literature suggests that this practice approach informs patient care, and clinical outcomes. The Osteopaths’ Therapeutic Approaches Questionnaire (Osteo-TAQ) is a novel 36-item instrument developed from qualitative grounded theory research with osteopaths in the United Kingdom. The aim of the study was to develop evidence for the structural and construct validity of the Osteo-TAQ in the Australian osteopathic profession and provide initial descriptive data about the therapeutic approaches of osteopaths in Australia.MethodsA cross-sectional study design was used to collect data from registered osteopaths in Australia using the Osteo-TAQ and analysed with Exploratory Factor Analysis (EFA). The EFA utilised parallel analysis to determine the number of factors to extract and McDonald’s omega calculated as the reliability estimation statistic.Results691 Australian osteopaths provided data for the study, representing 25% of the Australian osteopathic profession. Empirically the number of factors to extract based on the parallel analysis was seven. Two- and three-factor solutions were evaluated given the underpinning theory identifying two conceptions of practice and three interrelated therapeutic approaches. Both the two- and three-factor solutions were consistent with the underpinning theory with acceptable reliability estimations for each factor. Descriptive data suggested the most common element of the therapeutic approach of Australian osteopaths was establishing rapport, while the least common was ‘only talking’ with their patients.ConclusionsThis study provides evidence for the structural, content and construct validity of the Osteo-TAQ in an Australian osteopathic practitioner population. The results support both a two- and three-factor structure for the Osteo-TAQ in an Australian osteopathic population, with each factor demonstrating acceptable reliability estimations supporting the items comprising each factor as measuring a single construct. From a theoretical and empirical perspective, it can be inferred that the Osteo-TAQ tool encapsulates an osteopaths’ conception of practice (professional artistry and technical rational) and three main therapeutic approaches to patient care: Educator, Communicator and Treater. Further research is required to explore each of these therapeutic approaches to better understand how they relate to an individual osteopath’s conception of practice, and their associations with other measures of practice including clinical outcomes.

Antimicrobial resistance: Biofilms, small colony variants, and intracellular bacteria

Soft tissue and bone infections continue to be a serious complication in orthopedic and trauma surgery. Both can lead to a high burden for the patients and the healthcare system. Musculoskeletal infections can be induced by intraoperative contamination, bacterial contamination of open wounds or hematogenous bacterial spread. During the recent decades, advances were achieved in the understanding of pathogenesis and antibiotic resistance. Despite some progress in the diagnosis and advancing of therapeutic concepts, groundbreaking successful improvement of treatment concepts is still missing. Current therapy concepts are based on the two pillars consisting of surgical debridement with joint or bone reconstruction as well as prolonged antibiotic therapy. An improved understanding of both host and pathogen-related factors leading to treatment failure is essential in musculoskeletal infections. Therefore, this review aims to give an overview of pathogen-related pathophysiology in musculoskeletal infections. It describes defense strategies of pathogens such as (1) biofilm, its development, characteristics, and treatment options. In addition, (2) characteristics of small colony variants and (3) intracellular bacteria are highlighted. Lastly (4) an outlook for potential and promising future therapeutic strategies is provided.

A multidimensional approach to the management of patients in prolonged weaning from mechanical ventilation - the concept of treatable traits - a narrative review.

Background Established structured weaning approaches, which are effective for patients in simple and difficult weaning, are often not appropriate for patients undergoing prolonged weaning. Addressing the complexity of weaning failure requires personalized precision medicine. The therapeutic concept of Treatable Traits (TTs) has been proposed as a new paradigm for the management of chronic respiratory diseases. It is based on a multidimensional assessment of specific characteristics, which can be addressed by specific interventions that go beyond traditional diagnostic criteria. The concept is increasingly adopted for other complex diseases. Summary This is a narrative review and an expert opinion on the development of a concept of TTs for patients undergoing prolonged weaning. The proposed TTs are based on a systematic review of risk factors for prolonged weaning, an analysis of claims data to assess risk factors within 96 hours of IMV onset and data from the WEAN-SAFE study. A multidisciplinary team identified clinically important TTs and determined appropriate interventions. The following TTs have been identified: Airway disorders and complications associated with tracheostomy or intubation, such as airway obstruction, strictures or tracheomalacia, infectious aspects, anxiety, depression, delirium, post-traumatic stress disorder, anemia, pulmonary and cardio-renal disease. The multidimensional holistic approach also includes tailored sedation and pain management, nutritional therapy, early mobilization and physiotherapy. Key message We propose a framework of relevant considerations for a multidimensional approach to the management of patients undergoing prolonged weaning that supports the regain of respiratory capacity, reduces the respiratory load and thus could resolve the respiratory workload imbalance.

Acute hemodynamic effect of oral ketones in patients with acutely decompensated heart failure and low cardiac output syndrome: a prospective randomized study.

Abstract Background Preliminary studies showed positive inotropic effect of mild ketosis in patients with heart failure with reduced ejection fraction (HFrEF). Purpose To evaluate the acute hemodynamic effect of oral administration of beta-hydroxybutyrate (OHB) in patients with HFrEF and low cardiac output syndrome. Methods Patients with acutely decompensated HFrEF treated with inotropic therapy were randomized (1:1) to enteral bolus of OHB (25g of OHB monoester in 65 ml of solution; H.V.M.N Ketone Ester, H.V.M.N, USA) administered three times with 3-hour intervals or to euvolemic placebo. The serum concentration of OHB, biochemical markers, and invasive hemodynamics (Swan-Ganz catheter with continuous thermodilution) were repeatedly measured before and during 24 hours after administration of OHB. The primary endpoint was the maximum change in cardiac index (CI). Results The study included 20 patients with decompensated HFrEF (age: 57 ± 8 years; left ventricular ejection fraction: 21 ± 4%; non-ischemic cardiomyopathy: 16 [80%], median INTERMACS class: 3 [IQR 2 - 4]), who were treated with milrinone (0.5 ± 0.1 ug/kg/min, n=18) or levosimendan (0.1 ug/kg/min up to 25 mg, n=2). Patients in the OHB group (n = 10) did not differ from the placebo group (n = 10) in baseline clinical, biochemical, hemodynamic or echocardiographic characteristics. Baseline OHB concentration was normal (<0.6 mmol/L) in all patients. Administration of OHB increased serum concentration from 0.3 ± 0.2 mmol/L to a maximum of 2.4 ± 0.7 mmol/L (<0.001). Concentrations of OHB peaked at 1.5 ± 0.5 hours after administration of each OHB drink, and the maximum concentration was achieved at 4.1 ± 2.5 hours (Figure 1). No changes in OHB concentration were observed in the placebo group. In both study groups, there was a significant increase of CI at 3 hours compared to baseline, but the increase was significantly greater in the OHB group (OHB: 3.2 ± 0.6 vs. 2.1 ± 0.4 L/min/m2; placebo: 2.3 ± 0.4 vs. 2.0 ± 0.3 L/min/m2; both p<0.001 compared to baseline; p < 0.001 for OHB vs. placebo at 3 hours). The maximum relative increase of CI was 60 ± 24% in the OHB group (p <0.001) and 18 ± 8% in the placebo group (p< 0.01). The change of CI correlated with the change of OHB concentration in the OHB group (r = 0.58, p<0.001) but not in the placebo group (r = 0.1, p = 0.3). The changes in CI were not related to heart rate or concentration of norepinephrine, which did not change significantly throughout the study in both groups. Conclusion Oral administration of OHB leads to a significant temporary increase in myocardial contractility. This novel therapeutic concept might be a promising adjunction to inotropic support in patients with decompensated HFrEF.

Update on HPV-associated head and neck cancers-highlights of the 2024 ASCO Annual Meeting

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is becoming increasingly important in head and neck oncology. At this year's conference of the American Society of Clinical Oncology (ASCO), alarge number of papers were presented on the topic of HPV-associated HNSCC, particularly with regard to neoadjuvant treatment approaches, radiation de-escalation strategies, therapeutic vaccines, and treatment monitoring. In this context, study results on the treatment of HPV-related recurrent respiratory papillomatosis (RRP) were also presented. Based on contributions to the 2024 ASCO Annual Meeting, an insight into the latest developments in HPV-associated diseases of the head and neck is provided. The papers were reviewed for clinical relevance and contextualized based on current therapeutic concepts. Alarge number of studies on liquid biopsies (LB) were presented. It was shown that although the methods for analyzing LBs for HPV-positive patients are well developed and can be used for diagnostics, risk classification, treatment management, or tumor follow-up, the methods vary considerably, and their clinical application has not yet been sufficiently validated. With regard to therapeutic HPV vaccination, three large studies were presented for the treatment of recurrent/metastatic HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The only randomized study was on the vaccine ISA101b (peltopepimut-S) and did not reach its primary endpoint; however, the vaccine seemed to be highly effective in patients with a combined positive score (CPS) ≥ 20. Furthermore, data from aphaseIstudy on PRGN2012, an adenovirus-based immunotherapy used therapeutically for the treatment of recurrent respiratory papillomatosis (RRP), were presented. PRGN2012 led to areduction in surgical interventions for RRP, and the US Food and Drug Administration (FDA) designated PRGN2012 as abreakthrough therapy and orphan drug. However, the vaccine is not yet approved for the treatment of RRP.

Analysis of methotrexate use practice in patients with rheumatoid arthritis and psoriatic arthritis

Background. Pharmacoepidemiological studies play a key role in optimizing pharmacotherapy for various diseases. In particular, significant progress in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) necessitates a detailed analysis of the consumption of disease-modifying antirheumatic drugs. The modern therapeutic concept for these conditions focuses on achieving and maintaining long-term remission, which positions methotrexate (MTX) as a first-line agent, characterized by high effectiveness, safety and advantageous pharmacoeconomic profiles.Objective: to investigate the characteristics of MTX use in real clinical practice among patients with RA and PsA during outpatient medical care.Material and methods. The study comprised two parts: a retrospective cross-sectional analysis of MTX consumption dynamics in 2018, 2020, and 2023 via ATC/DDD (Anatomical Therapeutic Chemical classification, ATC; defined daily dose, DDD) methodology, and a longitudinal non-interventional pharmacoepidemiological study conducted in 2023 using the medical information system “BARS. Healthcare”.Results. The ATC/DDD analysis demonstrated a significant increase in MTX consumption among patients with RA and PsA: from 302,428.6 to 319,114.3 DDDs per 1,000 patients per year for RA, and from 28,157.1 to 310,771.6 DDDs per 1,000 patients per year for PsA in 2018 and 2023, respectively. The most frequently prescribed dose of MT was 15 mg/week. The primary therapeutic combination for 55.8% of patients was “MT + nonsteroidal anti-inflammatory drugs”, with 32.7% of patients also receiving glucocorticoids (GCs) as part of this combination. The study identified a high frequency of prescriptions for proton pump inhibitors, GCs, and cholecalciferol, highlighting the activity of diseases under consideration, potential complications, and the necessity for the prevention of clinically significant drug interactions.Conclusions. The conducted study confirmed that MTX remains the main drug for the treatment of RA and PsA. The ATC/DDD analysis demonstrated a significant increase in MTX consumption in recent years, correlating with its therapeutic effectiveness and accessibility. The high frequency of concomitant prescriptions underscores the complexity of treating RA and PsA and the need for an interdisciplinary approach to ensure safety and efficacy of the therapy.

Research progress of antiviral treatment for patients with chronic hepatitis B combined with metabolic fatty liver disease

Chronic hepatitis B (CHB) mainly causes cirrhosis and hepatocellular carcinoma (HCC). Metabolic fatty liver disease (MAFLD) has become the most common chronic liver disease worldwide with the continuous changes in lifestyle and dietary patterns and the increase in the number of obese individuals. Consequently, the incidence rate of CHB combined with MAFLD is rapidly increasing. However, the pathogenesis, treatment, and clinical prognosis remain unclear due to the interaction between CHB and MAFLD. Notably, in the academic community, there are still controversies as to whether patients with CHB and MAFLD should immediately start antiviral treatment, whether MAFLD affects the antiviral efficacy in CHB patients, and whether nucleos(t)ide analogues (NAs) affect the body's metabolism. This article reviews the epidemiology, clinical prognosis, treatment management strategies (especially the antiviral efficacy of NAs drugs), and NAs drug effects on the body's metabolism in patients with CHB combined with MAFLD so as to provide diagnostic and therapeutic concept for clinicians.

Dual responsive drug-loaded nanomotor based on zwitterionic materials for the treatment of peritoneal metastatic cancer

Innovative treatments for peritoneal metastatic cancer have attracted widespread attention from researchers. Here, we propose a drug-loaded nanomotor (PSBMA/l-Arg/DOX, PLD) based on zwitterionic materials for the treatment of peritoneal metastatic cancer through intraperitoneal injection. Zwitterionic polymer nanocarriers (PSBMA NPs) are obtained by radical polymerization with zwitterionic SBMA as the polymerization monomer and N,N’-Bis(acryloyl)cystamine (BAC) as the cross-linking agent. The zwitterionic substrate of this nanomotor has the ability to resist non-specific protein adsorption in ascites. The loaded l-arginine enables the nanomotor to have the ability to chemotaxis towards high concentrations of ROS/iNOS in tumors and be catalyzed to produce NO, achieving deep penetration into tumor tissue. Furthermore, the disulfide bond (SS) carried by the crosslinking agent used in the preparation of the nanomotor can respond to the high expression of reducing glutathione in the tumor microenvironment and undergo degradation, releasing a large amount of loaded drug DOX. Cell and animal disease model experiments confirme the good therapeutic effect of this drug-loaded nanomotor, providing new therapeutic concepts and strategies for the treatment of peritoneal metastatic cancer.

Emotion regulation as affective neoliberal governmentality.

Emotion regulation is central in many therapy models, including couple and family therapy models. This article draws on poststructuralist governmentality studies and processual affect theory to offer insight into how the therapeutic concept of emotion regulation may reflect and support neoliberal affective forms of self-governance. We suggest that couple and family therapy-through using professional discourses and affect-oriented techniques or interventions-may be another site wherein neoliberal governmentality is implemented and extended in contemporary westernized neoliberalized societies. In facilitating emotion regulation, we argue that there is a risk that therapists may implicitly promote a neoliberal worldview that encourages clients to mobilize neoliberal techniques to become self-improving, entrepreneurial subjects, responsible for their happiness and well-being. Conditions of precarity associated with individualist, neoliberal capitalist ideologies and policies (e.g., unemployment, job insecurity, forced migration, wealth inequalities, mass incarceration, social isolation) generate emotional burdens for people to manage that professional techniques or interventions may normalize as clients' self-management tasks. We theorize emotion regulation as an affective governmentality tactic of power and suggest that couple and family therapy can offer points of resistance to individualization and responsibilization and opportunities for creating or affirming alternative subjectivities and affectivities.

An Overview of the Anticancer Potential of Silver Nanostructures against Cervical Cancer.

Women are impacted by the extremely common cancer known as cervical cancer worldwide. Although preventive vaccines for cervical cancer are successful, treatment of cervical cancer is far less satisfactory because of multidrug resistance and side effects. There is an increasing need for alternative treatment modalities due to the rather aggressive and non-specific nature of conventional chemotherapeutics. With the advent of new technologies, scientists are working harder to create novel drug delivery strategies for chemotherapy of cervical cancer. Metal nanoparticles, and particularly silver nanoparticles, are a relatively new class with a lot of promise in the field of cancer biology. Nanoparticle therapeutics are attractive platforms for clinically relevant drug development because of their powerful anti-cancer properties, correspondingly attenuated side effects, and cancer-specific targeting. In this review, we provide an overview of the most recent uses of nanotechnology, particularly silver nanostructures, in the diagnosis and treatment of cervical cancer. The salient features of silver nanoparticle-based therapeutic concepts that are novel, viable, and attainable are emphasized in this review, along with those that pose a significant obstacle to their progress toward clinical application.

Treatment of Gastroesophageal Reflux Disease Based on the Intestinal Flora Theory from Sweetness Reaches Spleen

Context: Cases of gastroesophageal reflux disease (GERD) have shown an increasing trend over time, severely impacting patients' quality of life. Gut flora issues are a hot research topic, and their metabolites are strongly associated with host disease. Studies have shown that intestinal flora dysbiosis is not only related to diseases of the digestive system, but also has a certain connection with the endocrine system, nervous system and rheumatoid immune system. Recent national and international studies have shown a strong association between intestinal flora dysbiosis and GERD. Spleen-boosting herbs have also been found to help regulate the intestinal flora. The digestive system is synergized by the spleen and stomach of Chinese medicine and the intestinal flora; Purpose: Explore the connections between intestinal flora, TCM spleen and stomach, and GERD; Methods: Based on the pathomechanism of GERD, we will explore the mechanism of intestinal flora and its metabolites, the spleen and stomach of TCM, and the influence of TCM on related diseases to build a "hub" connecting TCM, intestinal flora, and GERD; Results: Through the anatomical structure and physiological properties of the digestive system, the scientific arguments related to the influence of intestinal flora on GERD through immunity and the central nervous system were constructed, which also revealed the importance of traditional Chinese medicine in regulating intestinal flora and influencing GERD; Conclusion: Herbal medicine can be used to treat GERD by regulating the intestinal flora. Dysbiosis of the intestinal flora influences the development of GERD through several pathways, The interconnection between spleen and stomach and flora in Chinese medicine and the effects of both on GERD were explored with the clue that sweetness reaches the spleen. It also provides a new therapeutic concept for the clinical treatment of GERD.

Towards an Anthropological Perspective on Human Flourishing in Education

ABSTRACT While many recognise the impact formal education has on human flourishing, often overlooked are the forces in society that shape our conception of the good life. Our understanding of flourishing is formed as much by the culture we live in as by the classrooms we learn in. This oversight impacts our ability to think clearly about flourishing because it keeps us from seeing the foundations upon which our idea of the good life is built. Contending that the language used by psychologists often reduces our understanding of human flourishing and existence we argue that the notion of the good life many of us adopt simply by existing in our modern therapeutic culture has been deeply distorted. On this basis, we advance a corrective for constricted therapeutic conceptions of flourishing, arguing that human flourishing needs ‘anthropology’ in two senses – one employed by social scientists and one by theologians and philosophers – and we make the case for the educational importance of turning to ‘anthropologies of the good’ as a positive, constructive examination of flourishing that is philosophically and theologically sophisticated enough to parse the several empirical investigations of human nature and bring clarity and insight to their findings.

In vivo CAR T cell therapy against angioimmunoblastic T cell lymphoma

BackgroundFor angioimmunoblastic T cell lymphoma (AITL), a rare cancer, no specific treatments are available and survival outcome is poor. We previously developed a murine model for AITL that mimics closely human disease and allows to evaluate new treatments. As in human AITL, the murine CD4+ follicular helper T (Tfh) cells are drivers of the malignancy. Therefore, chimeric antigen receptor (CAR) T cell therapy might represent a new therapeutic option.MethodsTo prevent fratricide among CAR T cells when delivering an CD4-specific CAR, we used a lentiviral vector (LV) encoding an anti-CD4 CAR, allowing exclusive entry into CD8 T cells.ResultsThese anti-CD4CAR CD8-targeted LVs achieved in murine AITL biopsies high CAR-expression levels in CD8 T cells. Malignant CD4 Tfh cells were eliminated from the mAITL lymphoma, while the CAR + CD8 T cells expanded upon encounter with the CD4 receptor and were shaped into functional cytotoxic cells. Finally, in vivo injection of the CAR + CD8-LVs into our preclinical AITL mouse model carrying lymphomas, significantly prolonged mice survival. Moreover, the in vivo generated functional CAR + CD8 T cells efficiently reduced neoplastic T cell numbers in the mAITL tumors.ConclusionThis is the first description of in vivo generated CAR T cells for therapy of a T cell lymphoma. The strategy described offers a new therapeutic concept for patients suffering from CD4-driven T cell lymphomas.

Pulmonary Administration of TLR2/6 Agonist after Allergic Sensitization Inhibits Airway Hyper-Responsiveness and Recruits Natural Killer Cells in Lung Parenchyma.

Asthma is a chronic lung disease with persistent airway inflammation, bronchial hyper-reactivity, mucus overproduction, and airway remodeling. Antagonizing T2 responses by triggering the immune system with microbial components such as Toll-like receptors (TLRs) has been suggested as a therapeutic concept for allergic asthma. The aim of this study was to evaluate the effect of a TLR2/6 agonist, FSL-1 (Pam2CGDPKHPKSF), administered by intranasal instillation after an allergic airway reaction was established in the ovalbumin (OVA) mouse model and to analyze the role of natural killer (NK) cells in this effect. We showed that FSL-1 decreased established OVA-induced airway hyper-responsiveness and eosinophilic inflammation but did not reduce the T2 or T17 response. FSL-1 increased the recruitment and activation of NK cells in the lung parenchyma and modified the repartition of NK cell subsets in lung compartments. Finally, the transfer or depletion of NK cells did not modify airway hyper-responsiveness and eosinophilia after OVA and/or FSL-1 treatment. Thus, the administration of FSL-1 reduces airway hyper-responsiveness and bronchoalveolar lavage eosinophilia. However, despite modifications of their functions following OVA sensitization, NK cells play no role in OVA-induced asthma and its inhibition by FSL-1. Therefore, the significance of NK cell functions and localization in the airways remains to be unraveled in asthma.

Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study.

Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients' nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties. The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, and creep (myotonometry). Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity. Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.

German expert consensus on programmed cell death ligand1 (PD-L1) testing in perioperative systemic therapy of muscle invasive bladder cancer

The risk of recurrence in patients with muscle invasive bladder cancer (MIBC) after radical cystectomy depends on the pathological tumor stage. In particular, patients with lymph node metastasis (pN+), locally advanced (≥pT3), or residual muscle invasive tumor despite neoadjuvant chemotherapy are at high risk. Currently, the importance of adjuvant therapy with immune checkpoint inhibitors is increasing in the context of perioperative systemic therapeutic concepts. The indication for the PD‑1 inhibitor nivolumab currently approved in the European Union requires testing of PD-L1 (programmed cell death ligand1) protein expression by immunochemistry in tumor tissue. Focusing on MIBC patients at high risk of recurrence, new questions arise regarding the implementation and interpretation of PD-L1 testing. An interdisciplinary group of experts from Germany has discussed relevant issues from aclinicopathological point of view and developed practical recommendations to facilitate the implementation of validated and quality-assured PD-L1 testing for the approved indications in daily clinical practice.