Annette Schnell

Background: Nausea is a common and distressing symptom in palliative care, substantially impairing quality of life. Despite guideline-based antiemetic therapy, a considerable proportion of patients continue to experience substantial nausea burden. Evidence guiding personalised management strategies in this setting remains limited. This study aimed to identify routinely available laboratory markers and clinical factors associated with persistent nausea burden at peak antiemetic therapy. Methods: In this retrospective exploratory study, 788 admissions to a specialised palliative care unit (2019–2022) were screened, and 223 cases with documented nausea were included. Nausea burden and associated symptom burdens were assessed at the time of “peak antiemetic therapy”, defined as the highest level of antiemetic treatment reached during admission beyond which therapy was not further escalated. Symptom burden was measured using the staff-completed Integrated Palliative Outcome Scale (IPOS). Baseline demographic, clinical, and laboratory variables were assessed at admission. Patients were stratified according to persistent nausea burden (IPOS ≥ 2 vs. < 2). Univariable analyses were performed to identify a core set of associated factors. Baseline variables meeting significance criteria were entered into complete-case binary logistic regression with bootstrap validation (1,000 samples; N = 143). Multiple testing was addressed using the Benjamini-Hochberg (BH) procedure. Results: Persistent nausea burden at peak antiemetic therapy was observed in 33% of patients with nausea. After BH adjustment, vomiting and poor appetite (both IPOS ≥ 2), cystatin C levels, broad-spectrum antiemetic therapy, in-house mortality, ileus, and peritoneal carcinomatosis were significantly associated with persistent nausea burden at peak antiemetic therapy in univariable analyses (BH-adjusted p < 0.05). Of these, the baseline variables ileus, peritoneal carcinomatosis, and cystatin C levels constituted the core set for multivariable analysis. In logistic regression, higher cystatin C levels were associated with lower odds of persistent nausea burden (OR = 0.235; 95% CI [0.08–0.47]; BH-adjusted p = 0.003), whereas peritoneal carcinomatosis was associated with higher odds (OR = 3.967; 95% CI [1.54–12.29]; BH-adjusted p = 0.005). Conclusions: Persistent nausea burden co-occurred with diverse clinical factors, underscoring its multifactorial nature in advanced disease. Nausea management in palliation remains a major challenge far beyond the application of antiemetics. Prospective studies are warranted.

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 (LDL^low = 50 μg/ml and LDL^high = 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 LDL^high 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 LDL^high.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.

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.

Functional systemic and local immunity is required for effective anti-tumor responses. In addition to an active engagement with cancer cells and tumor stroma, immune cells can be affected and are often found to be dysregulated in cancer patients. The impact of tumors on local and systemic immunity can be assessed using a variety of approaches ranging from low-dimensional analyses that are performed on large patient cohorts to multi-dimensional assays that are technically and logistically challenging and are therefore confined to a limited sample size. Many of these strategies have been established in recent years leading to exciting findings. Not only were analyses of immune cells in tumor patients able to predict the clinical course of the disease and patients’ survival, numerous studies also detected changes in the immune landscape that correlated with responses to novel immunotherapies. This review will provide an overview of established and novel tools for assessing immune cells in tumor patients and will discuss exemplary studies that utilized these techniques to predict patient outcomes.