The complex intervention day hospice - a quality-assured study on the implementation, realization, and benefits with model character for Germany (IMPULS) using the example of "Day hospice Adiuvantes".

BACKGROUND: Currently, a conclusive experience on the uniform implementation and benefits of day hospice structures and interventions is lacking in Germany. The following questions should be clarified: (1) Which structural conditions and interventional measures should be established in day hospices from the point of view of patients, relatives, and specialist staff?; (2) Are the planned structures or interventions feasible and implementable under real conditions and accepted by patients, relatives, and staff?; (3) How can a final implementation and intervention catalog for day hospices be designed?; (4) Is this final catalog of services feasible, reasonable, economical, and effective under everyday conditions in day hospices? METHODS: We planned to perform a multistage investigation, guided by the Medical Research Council Framework for the development and evaluation of complex interventions. In Stage 1, an initial theoretical construct on structures and interventions will be established through an extensive literature and guideline review on day hospices and through qualitative interviews. In a nominal group process, we will create a catalog of offers. In Stage 2, feasibility testing is conducted in a single-day hospice under real-life conditions using quantitative quality indicators and qualitative interviews. Structures and interventions can be adapted here if necessary. In a second nominal group process, a final structure and offer catalog is created, which is then implemented in Stage 3 in the day hospice under investigation and evaluated under real daily conditions through a process and effectiveness test. For this purpose, qualitative and quantitative quality indicators will be used and a comparative cohort of patients who are not cared for in the day hospice - but in the same network structure (oncology-palliative care network Lower Bavaria) - is examined. DISCUSSION: Finally, the initial statements on the reasonable and realizable structures or interventions in day hospices and their benefits in daily real-life conditions as well as possible optimization processes shall be made. TRIAL REGISTRATION: The study was retrospectively registered in the German Clinical Trials Register (DRKS-ID DRKS00031613, registration date April 04, 2023) and the display portal of the Center for Clinical Trials of the University Hospital Regensburg (Z-2022-1734-6, registration date July 01, 2023).

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue.

In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called 'master modulators' of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning 'communication' in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control-in contrast to an immediate, 'poisoning' with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.

Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro. Methods: Experiments were performed with different LDL dosages (LDLlow = 50 µg/ml and LDLhigh = 200 µg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade. Results: The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh. Discussion: Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.

Immunometabolic Markers in a Small Patient Cohort Undergoing Immunotherapy.

Although the discovery of immune checkpoints was hailed as a major breakthrough in cancer therapy, generating a sufficient response to immunotherapy is still limited. Thus, the objective of this exploratory, hypothesis-generating study was to identify potentially novel peripheral biomarkers and discuss the possible predictive relevance of combining scarcely investigated metabolic and hormonal markers with immune subsets. Sixteen markers that differed significantly between responders and non-responders were identified. In a further step, the correlation with progression-free survival (PFS) and false discovery correction (Benjamini and Hochberg) revealed potential predictive roles for the immune subset absolute lymphocyte count (rs = 0.51; p = 0.0224 *), absolute basophil count (rs = 0.43; p = 0.04 *), PD-1+ monocytes (rs = -0.49; p = 0.04 *), hemoglobin (rs = 0.44; p = 0.04 *), metabolic markers LDL (rs = 0.53; p = 0.0224 *), free androgen index (rs = 0.57; p = 0.0224 *) and CRP (rs = -0.46; p = 0.0352 *). The absolute lymphocyte count, LDL and free androgen index were the most significant individual markers, and combining the immune subsets with the metabolic markers into a biomarker ratio enhanced correlation with PFS (rs = -0.74; p ≤ 0.0001 ****). In summary, in addition to well-established markers, we identified PD-1+ monocytes and the free androgen index as potentially novel peripheral markers in the context of immunotherapy. Furthermore, the combination of immune subsets with metabolic and hormonal markers may have the potential to enhance the power of future predictive scores and should, therefore, be investigated further in larger trials.

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis.

Classic tumor therapy, consisting of cytotoxic agents and/or targeted therapy, has not overcome therapeutic limitations like poor risk genetic parameters, genetic heterogeneity at different metastatic sites or the problem of undruggable targets. Here we summarize data and trials principally following a completely different treatment concept tackling systems biologic processes: the principle of communicative reprogramming of tumor tissues, i.e., anakoinosis (ancient greek for communication), aims at establishing novel communicative behavior of tumor tissue, the hosting organ and organism via re-modeling gene expression, thus recovering differentiation, and apoptosis competence leading to cancer control - in contrast to an immediate, "poisoning" with maximal tolerable doses of targeted or cytotoxic therapies. Therefore, we introduce the term "Master modulators" for drugs or drug combinations promoting evolutionary processes or regulating homeostatic pathways. These "master modulators" comprise a broad diversity of drugs, characterized by the capacity for reprogramming tumor tissues, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs etc., or for example differentiation inducing therapies. Data on 97 anakoinosis inducing schedules indicate a favorable toxicity profile: The combined administration of master modulators, frequently (with poor or no monoactivity) may even induce continuous complete remission in refractory metastatic neoplasia, irrespectively of the tumor type. That means recessive components of the tumor, successively developing during tumor ontogenesis, are accessible by regulatory active drug combinations in a therapeutically meaningful way. Drug selection is now dependent on situative systems characteristics, to less extent histology dependent. To sum up, anakoinosis represents a new substantive therapy principle besides novel targeted therapies.

Determinants of completion of advance directives: a cross-sectional comparison of 649 outpatients from private practices versus 2158 outpatients from a university clinic.

OBJECTIVES: To compare outpatients from private practices and outpatients from a university clinic regarding the determinants of completion of advance directives (AD) in order to generalise results of studies from one setting to the other. Five determinants of completion of AD were studied: familiarity with AD, source of information about AD, prior experiences with own life-threatening diseases or family members in need of care and motives in favour and against completion of AD. DESIGN: Observational cross-sectional study. SETTING: Private practices and a university clinic in Germany in 2012. PARTICIPANTS: 649 outpatients from private practices and 2158 outpatients from 10 departments of a university clinic. OUTCOME MEASURES: Completion of AD, familiarity with AD, sources of information about AD (consultation), prior experiences (with own life-threatening disease and family members in need of care), motives in favour of or against completion of AD, sociodemographic data. RESULTS: Determinants of completion of AD did not differ between outpatients from private practices versus university clinic outpatients. Prior experience with severe disease led to a significantly higher rate of completion of AD (33%/36% with vs 24%/24% without prior experience). Participants with completion of AD had more often received legal than medical consultation before completion, but participants without completion of AD are rather aiming for medical consultation. The motives in favour of or against completion of AD indicated inconsistent patterns. CONCLUSIONS: Determinants of completion of AD are comparable in outpatients from private practices and outpatients from a university clinic. Generalisations from university clinic samples towards a broader context thus seem to be legitimate. Only one-third of patients with prior experience with own life-threatening diseases or family members in need of care had completed an AD as expression of their autonomous volition. The participants' motives for or against completion of AD indicate that ADs are considered a kind of 'negative autonomy' as instruments to prevent particular forms of therapy. Interactive, repeated and situation-based AD discussions might reach a higher percentage of patients and concurrently enable personal volitions and thereby strengthen individual 'positive autonomy'.

Palliative treatment of presacral recurrence of endometrial cancer using irreversible electroporation: a case report.

INTRODUCTION: Irreversible electroporation (IRE) is a new minimally invasive tumor ablation technique which induces irreversible disruption of cell membrane integrity by changing the transmembrane potential resulting in cell death. Irreversible electroporation is currently undergoing clinical investigation as local tumor therapy for malignant liver and lung lesions. This is the first case report to describe the successful palliative ablation of a presacral recurrence of an endometrial cancer to achieve locoregional tumor control and pain relief. CASE PRESENTATION: A 56-year-old Caucasian woman was referred for interventional treatment of an advanced local recurrence of endometrial cancer (11.9 × 11.6 × 14.9cm) with infiltration of the sacral bone and nerve plexus. Due to the immediate proximity to the sacral plexus, the patient could neither undergo surgical therapy nor a second radiation therapy. Due to its ablation mechanism irreversible electroporation was deemed to be the best therapy option. CONCLUSION: We showed in this case that a large tumor mass adjacent to a bundle of neural structures, the sacral plexus, can be widely ablated by irreversible electroporation with only minor temporary impairment of the neural function, even though a large infiltrating tissue volume (941cm3) was ablated.