Therapeutic Concepts Research Articles

Pneumologie meets Onkologie

Lung cancer is common and associated with a high mortality. After major therapeutic advances in the palliative situation of non-small cell lung cancer (NSCLC), new therapeutic concepts including immunotherapy and targeted tumor therapy have now also reached the curative stages. Osimertinib and atezolizumab have recently been approved under certain conditions in adjuvant therapy after complete tumor resection. In addition, the first approval of a neoadjuvant immunochemotherapy in Germany is expected soon. In the palliative therapy setting, comprehensive molecular pathological diagnostics on oncogenic mutations are required. Many drugs addressing these targets are now available predominantly for first line therapy but also although less for second line therapy. If there are no possibilities to address driver mutations, immunotherapy and immunochemotherapy are available depending on the programmed death ligand 1 (PD-L1) status. Overall, these new therapeutic options have already significantly improved therapy tolerability and the prognosis of lung cancer. Specific side effects must be considered. For small cell lung cancer (SCLC), palliative immunochemotherapy provides a moderate improvement in the prognosis. The introduction of lung cancer screening by low-dose computed tomography (CT) in Germany is to be expected in the coming years. The advantages are a relative reduction in lung cancer mortality of approximately 20% with a number needed to screen of 250. The disadvantage is particularly the expected number of false positive findings. A screening program must be established as a structured and quality assured procedure.

Fascial Distortion Model (FDM) by Stephen Typaldos from the modern research and therapeutic concepts point of view

This article presents information regarding the original concept proposed by the American osteopath S. Typaldos — Fascial Distortion Model. This paper describes the diagnostic approach and the therapeutic techniques principles of the model. The article focuses on the theoretical substantiation of the model from the currently available modern data in the field of anatomy and physiology of the connective tissue (fascia) point of view. Also parallels are drawn between therapeutic FDM manipulations and therapeutic techniques of other manual methods known in Russia.

Prediction of Cervical Cancer Outcome by Identifying and Validating a NAD+ Metabolism-Derived Gene Signature.

Cervical cancer (CC) is the second most common female cancer. Excellent clinical outcomes have been achieved with current screening tests and medical treatments in the early stages, while the advanced stage has a poor prognosis. Nicotinamide adenine dinucleotide (NAD+) metabolism is implicated in cancer development and has been enhanced as a new therapeutic concept for cancer treatment. This study set out to identify an NAD+ metabolic-related gene signature for the prospect of cervical cancer survival and prognosis. Tissue profiles and clinical characteristics of 293 cervical cancer patients and normal tissues were downloaded from The Cancer Genome Atlas database to obtain NAD+ metabolic-related genes. Based on the differentially expressed NAD+ metabolic-related genes, cervical cancer patients were divided into two subgroups (Clusters 1 and 2) using consensus clustering. In total, 1404 differential genes were acquired from the clinical data of these two subgroups. From the NAD+ metabolic-related genes, 21 candidate NAD+ metabolic-related genes (ADAMTS10, ANGPTL5, APCDD1L, CCDC85A, CGREF1, CHRDL2, CRP, DENND5B, EFS, FGF8, P4HA3, PCDH20, PCDHAC2, RASGRF2, S100P, SLC19A3, SLC6A14, TESC, TFPI, TNMD, ZNF229) were considered independent indicators of cervical cancer prognosis through univariate and multivariate Cox regression analyses. The 21-gene signature was significantly different between the low- and high-risk groups in the training and validation datasets. Our work revealed the promising clinical prediction value of NAD+ metabolic-related genes in cervical cancer.

Clinician Scientists in der kardiovaskulären Medizin

Policy makers in academic medicine, the educational and research sectors, and industry all agree: clinician scientists, physicians engaged in research, are the key to translating and implementing innovative therapeutic concepts into clinical practice. To this end, research on cardiovascular diseases, which cause most cases of death in the world, must be prioritized. Following internal group discussions and surveying physicians working in university hospitals and affiliated research institutes, the German Cardiac Society thoroughly analyzed the current and future situation and role of clinician scientists in cardiovascular medicine. Modern cardiology at university hospitals is characterized by higher workloads with more patients, shorter hospital stays, and increasingly more complex interventions, making it difficult for physicians and department heads to combine their research interests and activities with their clinical duties and training. This position paper discusses possibilities to improve working conditions and career perspectives for clinician scientists in cardiovascular medicine.

Therapieoptionen bei Weight-Regain nach Bariatrischer Operation

The purpose of this article is to create an overview of diagnostic and therapeutic options for weight regain (WR) and insufficient weight loss (IWL) after bariatric surgery (BS). With increasing popularity of BS, WR is becoming more relevant. We combined recent literature on WR and IWL with personal experience to suggest possible proceedings if WR or IWL is diagnosed. If an anatomical-pathological cause can be detected, surgical therapy is the most effective. If WR or IWL is idiopathic, a multimodal therapeutic concept is necessary for sufficient therapeutic success. Depending on the initial BS, a combination of lifestyle intervention, medication and surgical therapy seems most effective. Extensive diagnostic testing is necessary prior to any surgical intervention. In idiopathic WR after Roux-en-Y Gastric Bypass (RYGB), we suggest lengthening the biliopancreatic limb and shortening the common channel. After Sleeve-Gastrectomy (SG), we currently see RYGB as most effective in patients with gastroesophageal reflux disease (GERD) and SADI-S as a feasible option if no GERD is present.

Amniotic membrane as a substrate and delivery vehicle for stem cells

AbstractNew therapeutic concepts and clinical strategies are emerging for the different kinds of human amniotic membranes (hAM). There are new commercial forms of hAM that are under investigation for old and new applications, from ocular surface epithelial persistent defects to the hAM extract eyedrops or the new use of hAM as a delivery platform and substrate for stem cells for ocular surface repair.Although there are more substrates used as support for growth, maintenance, and delivery of cultivated stem cells onto the ocular surface, hAM is still the most used universally, followed by fibrin‐based substrates. This is due to the notable biological properties of this live tissue. The only disadvantage may be that it must come from tissue banks and as such, there can be some shortages and the cost is not irrelevant.Several other types of synthetic substrates such as lotrafilcon A, siloxane hydrogels or poly lactide‐co‐glycolic acid (PLGA) polymers, have been used over the last years to facilitate cell culture and the subsequent transplantation onto the ocular surface. In addition, several polymeric biomaterials like polycaprolactone, polylactic glycolic acid, chitosan and gelatin membranes, collagen or elastin‐like polymers are being also used to support ocular epithelial cells in preclinical studies. However, none of those attempts to substitute hAM have been translated inti clinical use.We have successfully used hAM as substrate and delivery platform in preclinical research, both in vitro and in vivo models of stem cell deficiency, and in the two clinical trials that have been completed and published, with both cultivated epithelial cells from the limbal niche and bone marrow‐derived mesenchymal stem cells.

The Recording Cure: A Media Genealogy of Recorded Voice in Psychotherapy

This article explores the relationship between psychotherapy and sound reproduction technologies from the early 20th century to the present. Subscribing to a media genealogy approach, it traces the changing status of the recorded voice in therapy as set against broader transformations in the field of mental health. Delving into the recorded voice’s diverse applications across psychotherapeutic approaches, it demonstrates how technology worked to unravel the temporal and spatial formations of the therapeutic setting, thereby unsettling established hierarchies, terminologies, and techniques while at the same time supporting the integrity of the therapeutic situation. The article points to sound media’s capacity to bifurcate the voice into somatic and expressive elements and reassemble them in various configurations, thereby producing the ‘psyche’ through alternative access points. The story of the recorded voice in therapy provides a glimpse into the way technological affordances inform therapeutic concepts and practices, which in turn implement technology in study, training, and treatment.

“If you are in the search of eternity—live in the present, live in love”: intersubjectivity and its relation to religion and spirituality in self-help literature

ABSTRACT Our era is marked by ‘therapeutic culture’, referring to the increasing prevalence of therapeutic concepts and psychological knowledge in the way people understand and make sense of their lives. A marked part of therapeutic culture is self-help literature. It comprises a wide array of items that centre around managing everyday life issues, self-development, and psychological growth. Existing research portrays self-help books as deeply individualistic. However, there is little knowledge about the spiritual and religious dimensions of the genre. The aim of this article is to explore human intersubjectivity, and its religious dimensions, in self-help literature. Drawing on a content analysis of eleven self-help books, we address the issues of whether, how, and to what extent self-help books represent humans as relational beings and how the notions of religion and spirituality underlying the books relate to these issues. The findings illustrate the centrality of intersubjectivity in the genre. The conclusions on religion are multifaceted: spirituality in the books has positive connotations, while institutional religion is seen as negative, or even as a threat, to well-being and intersubjectivity.

TGF-β Inhibitors for Therapeutic Management of Kidney Fibrosis.

Kidney fibrosis is a common pathophysiological mechanism of chronic kidney disease (CKD) progression caused by several underlying kidney diseases. Among various contributors to kidney fibrosis, transforming growth factor-β1 (TGF-β1) is the major factor driving fibrosis. TGF-β1 exerts its profibrotic attributes via the activation of canonical and non-canonical signaling pathways, which induce proliferation and activation of myofibroblasts and subsequent accumulation of extracellular matrix. Over the past few decades, studies have determined the TGF-β1 signaling pathway inhibitors and evaluated whether they could ameliorate the progression of CKD by hindering kidney fibrosis. However, therapeutic strategies that block TGF-β1 signaling have usually demonstrated unsatisfactory results. Herein, we discuss the therapeutic concepts of the TGF-β1 signaling pathway and its inhibitors and review the current state of the art regarding regarding TGF-β1 inhibitors in CKD management.

Herbal remedies as a way to treat benign pathology of the mammary gland

Violations of neuroendocrine homeostasis under stressful conditions against the background of increased estrogen presence in tissues can become a stimulus for the development of benign breast pathology, both in the form of pain syndrome – cyclic mastalgia, less often non-cyclic mastalgia, and in the form of benign breast dysplasia (DMDM), one of symptoms of which can also be mastalgia. The diagnosis and treatment of benign breast pathology has been the responsibility of a gynecologist since 2009. This is correct, the pathogenetic commonality of pain syndromes and diseases associated with abnormal proliferation is obvious in gynecological practice. The goal of treating mastalgia is to improve the quality of life of the patient, but if mastalgia has a morphological substrate in the form of DMDM, then in addition to pain relief. It is necessary to provide for curbing the progression of the disease to reduce the risk of developing breast cancer. Hormonal treatment has limited possibilities here and the search for therapeutic concepts is usually carried out in the direction of therapy with plant-derived molecules that can influence the metabolism of estrogens in tissues. In addition to this lever of influence on the abnormal proliferation processes abnormal proliferation in the mammary gland, there are other targets involved in the pathophysiology of abnormal proliferation and pain in the mammary gland, in particular, oxidative stress, the immune system, etc. In this regard, molecules with pleiotropic biological effects are of interest, such as resveratrol, simultaneously exhibiting the properties of phytoestrogen, antioxidant, insulin sensitizer, etc. The combination of resveratrol and indole-3-carbinol for the treatment of cyclic mastalgia and DMDM seems to be an attractive option for improving the quality of life and preventing malignant neoplasms.

ECMO Support in Refractory Cardiogenic Shock: Risk Factors for Mortality.

Veno-arterial extracorporeal membrane oxygenation (va-ECMO) is a specialized temporary support for patients with refractory cardiogenic shock. The true value of this potentially lifesaving modality is still a subject of debate. Therefore, we aimed to investigate the overall in-hospital mortality and identify potential risk factors for mortality. We retrospectively analyzed the data of 453 patients supported with va-ECMO over a period of 14 years who were admitted to intensive care units of a tertiary university center in Austria. We observed in-hospital mortality of 40% for patients with refractory cardiogenic shock. Hemorrhage, ECMO initiation on weekends, higher SAPS III score, and sepsis were identified as significant risk factors for mortality. Hemorrhage was the most common adverse event (46%), with major bleeding events dominating in deceased patients. Thromboembolic events occurred in 25% of patients, followed by sepsis (18%). Although the rates of complications are substantial, a well-selected proportion of patients with refractory cardiogenic shock can be rescued from probable death. The reported risk factors could be used to increase the awareness of clinicians towards the development of new therapeutic concepts that may reduce their incidence.

Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy.

Despite intense research into the multifaceted etiology of neurodegenerative diseases (ND), they remain incurable. Here we provide a brief overview of several major ND and explore novel therapeutic approaches. Although the cause (s) of ND are not fully understood, the accumulation of misfolded/aggregated proteins in the brain is a common pathological feature. This aggregation may initiate disruption of Ca++ signaling, which is an early pathological event leading to altered dendritic structure, neuronal dysfunction, and cell death. Presently, ND gene therapies remain unidimensional, elusive, and limited to modifying one pathological feature while ignoring others. Considering the complexity of signaling cascades in ND, we discuss emerging therapeutic concepts and suggest that deciphering the molecular mechanisms involved in dendritic pathology may broaden the phenotypic spectrum of ND treatment. An innovative multiplexed gene transfer strategy that employs silencing and/or over-expressing multiple effectors could preserve vulnerable neurons before they are lost. Such therapeutic approaches may extend brain health span and ameliorate burdensome chronic disease states.

Elevated platelet–leukocyte complexes are associated with, but dispensable for myocardial ischemia–reperfusion injury

AimsP-selectin is an activatable adhesion molecule on platelets promoting platelet aggregation, and platelet–leukocyte complex (PLC) formation. Increased numbers of PLC are circulating in the blood of patients shortly after acute myocardial infarction and predict adverse outcomes. These correlations led to speculations about whether PLC may represent novel therapeutic targets. We therefore set out to elucidate the pathomechanistic relevance of PLC in myocardial ischemia and reperfusion injury.Methods and resultsBy generating P-selectin deficient bone marrow chimeric mice, the post-myocardial infarction surge in PLC numbers in blood was prevented. Yet, intravital microscopy, flow cytometry and immunohistochemical staining, echocardiography, and gene expression profiling showed unequivocally that leukocyte adhesion to the vessel wall, leukocyte infiltration, and myocardial damage post-infarction were not altered in response to the lack in PLC.ConclusionWe conclude that myocardial infarction associated sterile inflammation triggers PLC formation, reminiscent of conserved immunothrombotic responses, but without PLC influencing myocardial ischemia and reperfusion injury in return. Our experimental data do not support a therapeutic concept of selectively targeting PLC formation in myocardial infarction.

The sound stimulation method and EEG change analysis for development of digital therapeutics that can stimulate the nervous system: Cortical activation and drug substitution potential.

The purpose of this study is to propose a treatment method and the effect on the nervous system of digital therapeutics, which is a new treatment method to replace surgery and drug prescription for the treatment and prevention of diseases. The 20 subjects who participated in the experiment, including men and women, had an average age of 26 ± 2.40 years. The proposed treatment method used three types of sound stimulation and air or bone conduction sound transmission methods to induce total of 6-time EEG electroencephalogram(EEG) changes. EEG was measured with 200 sampling rate each in the P4, Cz, F8 and T7 channel located in the parietal, central, frontal and temporal lobes, respectively, according to the 10/10 system. A total of 2min of data were created by extracting EEG signals with less noise from the measured data and the extracted data were applied with a 1-40 Hz Butterworth filter and a 50 Hz notch filter with a quality factor of 30. After that, EEG are subdivided into delta (0.5-4Hz), theta (4-8Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-45 Hz) bands. Finally, EEG changes in response to sound stimuli were analyzed using power spectral density and T-test validation in the frequency band. When a sound stimulus of less than 1 KHz was stimulated by air conduction, brainstem activation was induced and the reticular activation system was activated. In addition, a great potential for replacing drugs was confirmed by inducing changes in the nervous system similar to drugs used for sedation. These results will be able to expand the concept of digital therapeutics, and it is expected that it will be developed as a safer treatment method that can replace surgery and drugs.

Odevixibat: an investigational inhibitor of the ileal bile acid transporter (IBAT) for the treatment of biliary atresia

ABSTRACT Introduction Biliary atresia (BA) is a rare, non-curable cholestasis-causing disease in infancy, due to progressive ascending bile duct sclerosis. Even after restoration of bile flow following Kasai portoenterostomy, about half of these children need a liver transplant by their 2nd birthday, due to progressive fibrosis. Toxicity of bile acids may play a central role in disease progression, but drug therapies are not yet available. With ileal bile acid transporter (IBAT) inhibitors, there is a potential novel drug option that inhibits the absorption of bile acids in the small intestine. As a result of reduced bile acid accumulation in the cholestatic liver, it may be possible to delay hepatic remodeling. Areas covered This review summarizes the dataset on bile acids and the potential effects of odevixibat, an IBAT inhibitor, in children with BA. Expert opinion Systemic reduction of bile acids with the aim of preventing inflammation, and thus liver remodeling, is a novel, promising, therapeutic concept. In principle, however, the time until diagnosis and surgical treatment of BA should still be kept as short as possible in order to minimize liver remodeling before medical intervention can be initiated. IBAT inhibitors may add to the medical options in limiting disease progression in BA.

Optogenetics for visual restoration: From proof of principle to translational challenges.

Degenerative retinal disorders are a diverse family of diseases commonly leading to irreversible photoreceptor death, while leaving the inner retina relatively intact. Over recent years, innovative gene replacement therapies aiming to halt the progression of certain inherited retinal disorders have made their way into clinics. By rendering surviving retinal neurons light sensitive optogenetic gene therapy now offers a feasible treatment option that can restore lost vision, even in late disease stages and widely independent of the underlying cause of degeneration. Since proof-of-concept almost fifteen years ago, this field has rapidly evolved and a detailed first report on a treated patient has recently been published. In this article, we provide a review of optogenetic approaches for vision restoration. We discuss the currently available optogenetic tools and their relative advantages and disadvantages. Possible cellular targets will be discussed and we will address the question how retinal remodelling may affect the choice of the target and to what extent it may limit the outcomes of optogenetic vision restoration. Finally, we will analyse the evidence for and against optogenetic tool mediated toxicity and will discuss the challenges associated with clinical translation of this promising therapeutic concept.

Long-Term Results of a Multimodal Treatment Regimen in Patients With Auricular Keloids.

Objectives: The treatment of auricular keloids is challenging, as they tend to recur; further, the treatment may impact quality of life and implies cosmetic and functional impairment for each patient. There is no standardized therapeutic concept established, and the literature is lacking long-term results of available treatment modalities. Methods: Patients suffering from auricular keloids were included in the study. All patients had undergone surgical resection, intralesional injection of triamcinolone acetonide (TAC), and the application of an individual pressure splint. Quality of life (QoL) was assessed using the keloid intervention benefit inventory 21 (KIBI-21). Further analysis was carried out for patients without (group 1) and with (group 2) recurrence of the keloid. Results: In total, 50 keloids with a mean follow-up period of 59months (range 6-137months) could be analyzed. In nine cases (18%), a keloid recurrence was found during the observation period. The assessment of QoL differed significantly between study groups at P = 0.04, as well as for the subcategories General Health (GH) and Physical Health (PH). No differences were found for the categories Social Impact (SI) and Self-Esteem (SE). Conclusions: The multimodal subsequent treatment regimen consisting of surgical resection, intralesional TAC injection, and the application of an individual magnetic pressure splint shows good results concerning long-term recurrence rates. The treatment method shows positive effects on the QoL, especially in the measured categories GH and PH.

State of the Art: onkogen alteriertes nichtkleinzelliges Lungenkarzinom im Stadium IV

BackgroundTwo decades ago, stage IV non-small-cell lung cancer (NSCLC) was associated with a poor median overall survival (mOS) of 7–9 months following chemotherapy. Due to revolutionary developments in recent years and the approval of modern targeted therapies, new therapeutic options with remarkable survival times have broadened the therapeutic armamentarium for patients with NSCLC.ObjectivesThis article provides a systematic overview of the latest therapeutic standards in the treatment of stage IV NSCLC, especially concerning targeted therapies, mechanisms of resistance, and future developments.Materials and methodsAn up-to-date analysis of the literature was performed.ResultsMolecular testing is essential to offer individualized targeted therapies tailored to corresponding genetic alterations. Besides tyrosine kinase inhibitors (TKI) of EGFR and ALK alterations that have been widely adopted in routine practice for at least a decade, new inhibitors for KRAS G12C, ROS1, BRAF V600, MET exon 14 skipping, NTRK or RET alterations were approved in recent years.ConclusionDue to consistent testing and the use of targeted therapies, prolonged overall survival and improvement in quality of life in patients with NSCLC harboring driver alterations could be achieved. Future developments focus on individualization of targeted therapies, optimization of therapeutic concepts, and identification of new targets.

Unravelling the landscape of skin cancer through single-cell transcriptomics

The human skin is a complex organ that forms the first line of defense against pathogens and external injury. It is composed of a wide variety of cells that work together to maintain homeostasis and prevent disease, such as skin cancer. The exponentially rising incidence of skin malignancies poses a growing public health challenge, particularly when the disease course is complicated by metastasis and therapeutic resistance. Recent advances in single-cell transcriptomics have provided a high-resolution view of gene expression heterogeneity that can be applied to skin cancers to define cell types and states, understand disease evolution, and develop new therapeutic concepts. This approach has been particularly valuable in characterizing the contribution of immune cells in skin cancer, an area of great clinical importance given the increasing use of immunotherapy in this setting. In this review, we highlight recent skin cancer studies utilizing bulk RNA sequencing, introduce various single-cell transcriptomics approaches, and summarize key findings obtained by applying single-cell transcriptomics to skin cancer.

OC-058 MORTALITY OF THE ELDERLY: ANALYSIS OF DATA FROM THE LAPARASTOMA REGISTRY

Abstract Aim The therapeutic concept of open abdomen with temporary abdominal wall closure was introduced about 30 years ago. Since that time, various surgical strategies have been tried, continuously developed and established. In May 2015, a laparastoma registry was released in the form of an internet-based online platform. Methods Data from the laparastoma registry were analyzed and evaluated. The focus of the study was on the mortality of patients in the age group 75 years and older who underwent laparastoma treatment. Special attention was paid to the previous diseases, risk factors, MPI. Results 913 patients with open abdomen and subsequent laparastomy treatment were enrolled in the laparastomy registry from 2015 to 2022. 65% of patients were male. 69.6% had secondary diseases. The indications for laparastoma establishment were peritonitis (37.2%, N=340), trauma (9.2%, n=84), abdominal compartment (18.1%, n=165) and others. The overall mortality rate was 28.7%. The mortality rate in the group between 75 and 80 years (n=155) was 36% (OR= 1.445 [CI: 1.002–2.008]; p=0.049). The mortality rate in patients older than 75 years (n=67) was 40.3% (OR 1.680 CI 1.008–2.802; p=0.047). Conclusion In the evaluation, three key questions were raised and analyzed by the study: what is the mortality in the elderly patients under laparastoma treatment, what is the mortality in the patients over 75 years old? What are the leading risk factors in the two groups.