Evolving insights into the improvement of adoptive T-cell immunotherapy through PD-1/PD-L1 blockade in the clinical spectrum of lung cancer.

Undeniably, cancer immunotherapies have expanded the spectrum of cancer treatment, however, some patients do not respond to immunotherapies. This scenario is no different for lung cancer, whose two main types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), still pose a serious clinical challenge. Adoptive T-cell therapies (ATC), which primarily include cytokine-induced killer (CIK) cell therapy, chimeric antigen receptor T-cell (CAR T-cell) therapy and γδ-T-cell therapy, strengthen the patient's immune system in combating cancer. Combining ATC with immune checkpoint inhibitors (ICI) further enhances the effectiveness of this approach to eradicate cancer. With a particular emphasis on CIK cell therapy, which recently completed 30 years, we highlight the role of the PD-1/PD-L1 axis in NSCLC and SCLC. Besides, we provide insights into the potential synergies of PD-1/PD-L1 inhibitors with adoptive T-cell immunotherapy in reshaping the treatment paradigm for lung cancer.

Cytokine-induced killer (CIK) cells, successes and challenges: report on the first international conference dedicated to the clinical translation of this unique adoptive cell immunotherapy.

On August 30, 2023, experts from Germany and abroad met to discuss the successes and challenges of cytokine-induced killer cell (CIK) therapy, that recently celebrated its 30th anniversary providing treatment for cancer. This first virtual conference was hosted by CIO Bonn, a certified Comprehensive Cancer Center (CCC) funded by German Cancer Aid (DKH). In addition to keynote speakers involved in CIK cell clinical trials or optimized preclinical models to improve this adoptive cell immunotherapy, more than 100 attendees from around the world also participated in this event. Initiatives to establish the International Society of CIK Cells (ISCC) and a stronger CIK cell network guiding preclinical research and future clinical trials were also announced.

Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.

Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".

Developing tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers.

BACKGROUND: To include the patient perspective in the assessment of adverse events in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the US National Cancer Institute, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets for patients with breast cancer (BC), multiple myeloma (MM), and prostate cancer (PC). METHODS: The cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers. RESULTS: 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms (fatigue, muscle pain, insomnia, joint pain, general pain, dizziness, shortness of breath, and swelling) were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by insomnia. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set, and decreased appetite in the MM item set. CONCLUSIONS: Individual PRO-CTCAE item sets for a German patient population were developed for the three tumor entities on the basis of patients' differences in symptom profiles and perceptions. The quality and psychometric criteria of the newly compiled item sets should be evaluated in validation studies.

Regulatory T Cell Inhibition by P60 Combined with Adenoviral AFP Transduced Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma.

BACKGROUND & AIMS: Vaccination with tumor-associated antigen-pulsed dendritic cells leads to specific T-cell response against hepatocellular carcinoma. However, clinical response has been shown to be limited. High regulatory T-cell count is associated with poor prognosis and seems to mediate immune tolerance in hepatocellular carcinoma. Forkhead box P3-peptide inhibitor P60 has been shown to specifically inhibit regulatory T-cell function in murine models. Aim of this study was to investigate whether P60 can improve the immune response induced by vaccination with adenovirus-transduced dendritic cells expressing alpha-fetoprotein in subcutaneous and orthotopic murine models for hepatocellular carcinoma. METHODS: Mice developing subcutaneous or orthotopic HCC received daily treatment with P60 starting at different tumor stages. Additionally, mice were vaccinated twice with dendritic cells expressing alpha-fetoprotein. RESULTS: In a preventive setting prior to tumor engraftment, vaccination with alpha-fetoprotein-expressing dendritic cells significantly decreased tumor growth in a subcutaneous model (p = .0256), but no further effects were achieved by addition of P60. However, P60 enhanced the antitumoral effect of a vaccination with alpha-fetoprotein-expressing dendritic cells in established subcutaneous and orthotopic hepatocellular carcinoma characterized by high Treg levels (p = .011). CONCLUSION: In this study, we showed that vaccination with alpha-fetoprotein-expressing dendritic cells in combination with a specific inhibition of regulatory T-cells by using P60 leads to synergistic tumor inhibition and prolonged survival. This emphasizes the importance of regulatory T-cells inhibition for obtaining an effective antitumoral immune response in hepatocellular carcinoma.

Revising the Landscape of Cytokine-Induced Killer Cell Therapy in Lung Cancer: Focus on Immune Checkpoint Inhibitors.

Undeniably, immunotherapy has markedly improved the survival rate of cancer patients. The scenario is no different in lung cancer, where multiple treatment options are now available and the inclusion of immunotherapy yields better clinical benefits than previously used chemotherapeutic strategies. Of interest, cytokine-induced killer (CIK) cell immunotherapy has also taken a central role in clinical trials for the treatment of lung cancer. Herein, we describe the relative success of CIK cell therapy (alone and combined with dendritic cells as DC/CIKs) in lung cancer clinical trials and discuss its combination with known immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Additionally, we provide insights into the findings of several preclinical in vitro/in vivo studies linked to lung cancer. In our opinion, CIK cell therapy, which recently completed 30 years and has been approved in many countries, including Germany, offers tremendous potential for lung cancer. Foremost, when it is optimized on a patient-by-patient basis with special attention to the patient-specific genomic signature.

Cytokine-Induced Killer Cells in Combination with Heat Shock Protein 90 Inhibitors Functioning via the Fas/FasL Axis Provides Rationale for a Potential Clinical Benefit in Burkitt's lymphoma.

Constant efforts are being made to develop methods for improving cancer immunotherapy, including cytokine-induced killer (CIK) cell therapy. Numerous heat shock protein (HSP) 90 inhibitors have been assessed for antitumor efficacy in preclinical and clinical trials, highlighting their individual prospects for targeted cancer therapy. Therefore, we tested the compatibility of CIK cells with HSP90 inhibitors using Burkitt's lymphoma (BL) cells. Our analysis revealed that CIK cytotoxicity in BL cells was augmented in combination with independent HSP90 inhibitors 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) and ganetespib. Interestingly, CIK cell cytotoxicity did not diminish after blocking with NKG2D (natural killer group 2, member D), which is a prerequisite for their activation. Subsequent analyses revealed that the increased expression of Fas on the surface of BL cells, which induces caspase 3/7-dependent apoptosis, may account for this effect. Thus, we provide evidence that CIK cells, either alone or in combination with HSP90 inhibitors, target BL cells via the Fas-FasL axis rather than the NKG2D pathway. In the context of clinical relevance, we also found that high expression of HSP90 family genes (HSP90AA1, HSP90AB1, and HSP90B1) was significantly associated with the reduced overall survival of BL patients. In addition to HSP90, genes belonging to the Hsp40, Hsp70, and Hsp110 families have also been found to be clinically significant for BL survival. Taken together, the combinatorial therapy of CIK cells with HSP90 inhibitors has the potential to provide clinical benefits to patients with BL.

Identification of the Integrated Prognostic Signature Associated with Immuno-relevant Genes and Long Non-coding RNAs in Acute Myeloid Leukemia.

BACKGROUND: Like other cancers, considerable effort has been made in acute myeloid leukemia (AML) to identify prognostic genes and long noncoding RNAs (lncRNAs) with their potential clinical applications. However, to date, no integrated prognostic model has been developed that combines both gene expression and lncRNAs as a singular approach in AML. METHOD: Comprehensive bioinformatic approaches (Weighted gene co-expression network analysis, Univariate Cox regression analyses, Pearson correlation, LASSO-Cox regression, Wilcoxon test) were used to construct the signature and to define high- and low-risk groups in AML datasets. ESTIMATE and CIBERSORT algorithms were applied to investigate the potential impact of infiltrating immune cells based on the obtained signature in tumor microenvironment. In addition, gene ontology (GO) and KEGG enrichment were applied to explore the potential function of the signature. RESULTS: Herein, we focused on immune-related genes (IRGs) and immune-related long noncoding RNAs (IRlncRNAs) and constructed an integrated prognostic immunorelevant signature in AML. The obtained signature exhibit five IRGs (DAXX, PSMB8, CSRP1, RAC2 and PTPN6) and one IRlncRNA (AC080037.2) and is strictly associated with age and FAB (French-American-British classification). Importantly, the high-risk AML group (defined by the signature) correlated positively with three types of scores (immune score, stroma score, and ESTIMATE score). We also identified a few immune cells (resting mast cells and monocytes) potentially involved in the correlation between signature and survival of AML patients. The prognostic ability of the obtained signature was tested in the training cohort and then validated in both test and total cohorts. The pathway enrichment analysis confirmed the possible immune- related role of the signature. CONCLUSION: We constructed an integrated prognostic signature comprising five immune-related protein-coding genes (IRPCG) (DAXX, PSMB8, CSRP1, RAC2, and PTPN6) and one immune-related lncRNA (AC080037.2) that may serve as potential biomarkers for predicting survival and further stratifying AML patients.

Patient participation in multidisciplinary tumor conferences in breast and gynecological cancer care: How patient-centered is the communication?

OBJECTIVE: Patients' participation is part of patient-centeredness, but it is so far unclear whether providers in multidisciplinary tumor conferences (MTCs) with patient participation communicate in a patient-centered way. Our aim is to explore (a) to what extent providers ask questions to breast and gynecological cancer patients during case discussion in MTCs, (b) how providers respond to patients' expressions of emotions during case discussions, and (c) which patient- and context-related characteristics and responses are associated with patients' trust in the treatment team after the case discussion. METHODS: This observational study included survey data and audio recordings of MTCs with patient participation at three breast and gynecological cancer centers. Providers' questions to patients and responses to patients' emotional expressions were coded using the Verona Coding Definitions of Emotional Sequences. The response can be explicitly or non-explicitly related to the emotion and space-reducing or space-providing. Multiple linear regression analysis was used to determine associations between providers' responses, patient- and context-related characteristics, and patients' trust in the treatment team after the case discussion. RESULTS: We analyzed 82 case discussions (77 breast, 5 breast and gynecological cancer patients). Providers asked a total of 646 questions, of which 86% were polar (yes/no). Providers gave 303 responses to a total of 230 emotional expressions by patients. Non-explicit responses were associated with more trust when they were space-providing, but with less trust when space-reducing. CONCLUSIONS: The frequency of providers' closed questions and space-reducing responses to emotions shows that patient-centered communication rarely takes place in MTCs with patient participation.

How shared is decision-making in multidisciplinary tumour conferences with patient participation? An observational study.

BACKGROUND: In some breast and gynaecologic cancer centres in Germany, patients participate in their own case discussion in multidisciplinary tumour conferences (MTCs), where treatment recommendations are discussed and finalized. However, the extent to which patients in MTCs are involved in decision-making on treatment recommendations remains largely unexplored. Hence, this study investigates how recommendations are communicated to patients and the extent to which the interactions with patients in MTCs are in line with shared decision-making (SDM). METHODS: In this observational study, we audio-recorded MTCs with patient participation in three breast and gynaecologic cancer centres in Germany. We qualitatively analysed the data with regard to content and linguistic aspects. RESULTS: We analysed 82 case discussions. Recommendations made during MTCs were regarding (i) treatment options, (ii) treatment initiation, (iii) next (treatment) steps and (iv) whether a treatment method should be initiated at all. The decision about recommendations depended in part on patients' preferences or further course/further outcomes. Although the purpose of MTCs is to provide recommendations, some recommendations were framed as the final decision. The majority of the decision-making conversation could be characterized as option talk (78%), during which patients were mostly proposed only one (treatment) option. CONCLUSIONS: This study establishes limited SDM in MTCs with patient participation. By indicating choices and thereby creating awareness of choices among patients, MTCs with patient participation could be used to foster SDM implementation. PATIENT OR PUBLIC CONTRIBUTION: Two representatives of a large self-help organization for patients with breast cancer assisted the research project, particularly, in discussing the results.

Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside.

Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.

A Low Dose of Pure Cannabidiol Is Sufficient to Stimulate the Cytotoxic Function of CIK Cells without Exerting the Downstream Mediators in Pancreatic Cancer Cells.

Despite numerous studies conducted over the past decade, the exact role of the cannabinoid system in cancer development remains unclear. Though research has focused on two cannabinoid receptors (CB1, CB2) activated by most cannabinoids, CB2 holds greater attention due to its expression in cells of the immune system. In particular, cytokine-induced killer cells (CIKs), which are pivotal cytotoxic immunological effector cells, express a high-level of CB2 receptors. Herein, we sought to investigate whether inducing CIK cells with cannabidiol can enhance their cytotoxicity and if there are any possible counter effects in its downstream cascade of phosphorylated p38 and CREB using a pancreatic ductal adenocarcinoma cell line (PANC-1). Our results showed that IL-2 modulates primarily the expression of the CB2 receptor on CIK cells used during ex vivo CIK expansion. The autophagosomal-associated scaffold protein p62 was found to co-localize with CB2 receptors in CIK cells and the PANC-1 cell line. CIK cells showed a low level of intracellular phospho-p38 and, when stimulated with cannabidiol (CBD), a donor specific variability in phospho-CREB. CBD significantly decreases the viability of PANC-1 cells presumably by increasing the cytotoxicity of CIK cells. Taken together, in our preclinical in vitro study, we propose that a low effective dose of CBD is sufficient to stimulate the cytotoxic function of CIK without exerting any associated mediator. Thus, the combinatorial approach of non-psychoactive CBD and CIK cells appears to be safe and can be considered for a clinical perspective in pancreatic cancer.

Improvements in Flow Cytometry-Based Cytotoxicity Assay.

The flow cytometry-based assay has been increasingly used to assess the cell-mediated cytotoxicity since the 1980s due to its advantages over the conventional radioactive 51 Cr release assay (CRA), such as higher sensitivity at the single-cell level and nonradioactivity. The basic principle of this assay is the usage of two dyes, one nontoxic dye for labeling targets or effector cells to distinguish one from another, one viability dye for discrimination of dead from live cells. Due to the problem of spontaneous release or leakage of the nontoxic dye, the concern about the cross-staining has not yet been clearly elucidated. In this study, carboxyfluorescein diacetate succinimidyl ester (CFSE) was utilized to label target cells and Hoechst 33258 was used as the viability dye. We confirmed that no cross-staining occurred between the effector and target cells after 4 h of coculture. We also found that the cytotoxicity would be overestimated if effector cells instead of target cells were labeled due to the exclusion of viable targets in effector-target conjugates. Using EDTA at the end of culture or labeling targets can solve this problem. Furthermore, the gating strategy could be improved by plotting CFSE against forward scatter (FSC) to discriminate some early apoptotic events. Due to the loss of target cells lysed by effector cells, counting beads are normally preferable in this assay. Here, we found an alternative to the use of beads in standardizing the flow cytometry-based assay. Instead of using beads, sample acquisition in a fixed time was shown to have the same effect in specific lysis evaluation as the beads application but have a greater stability than the latter. With a good quality control, the acquisition time for each sample could be shortened to 15 s, thus making this work to be done efficiently, especially in the case of larger sample sizes. Collectively, the findings in this study can improve the flow cytometric cytotoxicity assay to be carried out in a more accurate, efficient, and cost-effective way. © 2020 International Society for Advancement of Cytometry.

Epigenetic Regulatory Enzymes: mutation Prevalence and Coexistence in Cancers.

Epigenetic regulation is an important layer of transcriptional control with the particularity to affect the broad spectrum of genome. Over the years, largely due to the substantial number of recurrent mutations, there have been hundreds of novel driver genes characterized in various cancers. Additionally, the relative contribution of two dysregulated epigenomic entities (DNA methylation and histone modifications) that gradually drive the cancer phenotype remains in the research focus. However, a complex scenario arises when the disease phenotype does not harbor any relevant mutation or an abnormal transcription level. Although the cancer landscape involves the contribution of multiple genetic and non-genetic factors, herein, we discuss specifically the mutation spectrum of epigenetically-related enzymes in cancer. In addition, we address the coexistence of these two epigenetic entities in malignant human diseases, especially cancer. We suggest that the study of epigenetically-related somatic mutations in the early cellular differentiation stage of embryonic development might help to understand their later-staged footprints in the cancer genome. Furthermore, understanding the co-occurrence and/or inverse association of different disease types and redefining the general definition of "healthy" controls could provide insights into the genome reorganization.

No evidence to support the impact of migration background on treatment response rates and cancer survival: a retrospective matched-pair analysis in Germany.

BACKGROUND: Immigration has taken the central stage in world politics, especially in the developed countries like Germany, where the continuous flow of immigrants has been well documented since 1960s. Strikingly, emerging data suggest that migrant patients have a poorer response to the treatment and lower survival rates in their new host country, raising concerns about health disparities. Herein, we present our investigation on the treatment response rate and cancer survival in German patients with and without an immigrant background that were treated at our comprehensive cancer center in Germany. METHODS: Initially, we considered 8162 cancer patients treated at the Center for Integrated Oncology (CIO), University Hospital Bonn, Germany (April 2002-December 2015) for matched-pair analysis. Subsequently, the German patients with a migration background and those from the native German population were manually identified and catalogued using a highly specific name-based algorithm. The clinical parameters such as demographic characteristics, tumor characteristics, defined staging criteria, and primary therapy were further adjusted. Using these stringent criteria, a total of 422 patients (n = 211, Germans with migration background; n = 211, native German population) were screened to compare for the treatment response and survival rates (i.e., 5-year overall survival, progression-free survival, and time to progression). RESULTS: Compared to the cohort with migration background, the cohort without migration background was slightly older (54.9 vs. 57.9 years) while having the same sex distribution (54.5% vs. 55.0% female) and longer follow-up time (36.9 vs. 42.6 months). We did not find significant differences in cancer survival (5-year overall survival, P = 0.771) and the response rates (Overall Remission Rate; McNemar's test, P = 0.346) between both collectives. CONCLUSION: Contrary to prior reports, we found no significant differences in cancer survival between German patients with immigrant background and native German patients. Nevertheless, the advanced treatment protocols implemented at our comprehensive cancer center may possibly account for the low variance in outcome. To conduct similar studies with a broader perspective, we propose that certain risk factors (country-of-origin-specific infections, dietary habits, epigenetics for chronic diseases etc.) should be considered, specially in the future studies that will recruit new arrivals from the 2015 German refugee crisis.

Drug-related problems in head and neck cancer patients identified by repeated medication reviews on consecutive therapy cycles.

BACKGROUND: Head and neck cancer (HNC) patients are particularly vulnerable to drug-related problems (DRPs) given the toxicity of concomitant chemoradiotherapy (CCRT). OBJECTIVE: To investigate the number and type of potential DRPs (pDRPs) in HNC outpatients undergoing five consecutive cycles of CCRT. METHODS: A single-centre, non-randomized, non-interventional, observational study was conducted at the Oncological Outpatient Clinic of the Center for Integrated Oncology at the University Hospital Bonn, Germany. Clinical pharmacists took a comprehensive medication history, documented laboratory data, assessed patients' symptom burden, and retrospectively performed medication reviews at study entry and on the first day of each therapy cycle without any clinical intervention. RESULTS: In 26 patients, the mean number of pDRPs continuously increased during therapy course, from 4.8 (SD 2.7, range 2-12) at cycle 1 to 6.9 (SD 2.6, range 2-12) at cycle 5, with drug-drug interactions, adverse drug reactions, inappropriate durations of use, and inappropriate dosage intervals being the most common. Considering only new and recurrent pDRPs, the mean number was 4.3 (SD 2.3, range 2-9) at cycle 1 and lower in the further therapy course with an average of 1.3 (SD 1.7, range 0-7) at cycle 2 and 1.9 (SD 1.5, range 0-5) at cycle 5. The number of pDRPs was found to be associated with medication regimen complexity and health-related quality of life assessed in the first therapy cycle. CONCLUSION: pDRPs frequently occurred in HNC outpatients demonstrating the need for pharmaceutical care. A methodological framework for repeated medication reviews was established, facilitating implementation into routine healthcare practice.

[Development and Implementation of a Nutrition Medicine Strategy to optimize Medical Service for Malnourished Patients at a Tertiary Referral Centre]. / Entwicklung und Implementierung einer ernährungsmedizinischen Strategie zur optimierten Versorgung von Patienten mit Mangelernährung in einem Großklinikum.

BACKGROUND: Malnutrition in hospitalised patients is an important and underestimated problem, with a negative impact on outcome and survival - not only in surgical patients. There is a discrepancy between optimal treatment as defined in relevant guidelines on clinical nutrition and the clinical reality. The Main reason for this discrepancy is the lack of established structures for nutrition medicine as an integral part of clinical routines. The necessary structural development is impaired mainly by the lack of resources, but in isolated cases also by the lack of appreciation of the problem. Therefore, practicability and feasibility with regard to local conditions are pivotal for sustainable improvement in a nutrition strategy in hospitalised patients. METHODS: We describe the institutional and procedural measures taken at a tertiary referral centre to implement a nutrition medicine strategy. The underlying nutrition medicine methodology and definitions are introduced and practical implementation at our centre is illustrated by four examples of ongoing projects. RESULTS: Using the described systematics, structural changes were implemented at our centre within one year that allowed malnutrition screening, the treatment of patients with complex nutritional care and improvements in the nutritive status of hospitalised patients by ongoing and future project initiatives. SUMMARY: The successfully implemented structural change at the University Hospital of Bonn described here may serve as a modular example for other hospitals striving to improve clinical nutrition and outcome in hospitalised patients.

Ten-year update of the international registry on cytokine-induced killer cells in cancer immunotherapy.

Cytokine-induced killer (CIK) cells represent an exceptional T-cell population uniting a T cell and natural killer cell-like phenotype in their terminally differentiated CD3+ CD56+ subset, which features non-MHC-restricted tumor-killing activity. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures. We established the international registry on CIK cells (IRCC) to collect and evaluate clinical trials for the treatment of cancer patients in 2010. Moreover, our registry set new standards on the reporting of results from clinical trials using CIK cells. In the present update, a total of 106 clinical trials including 10,225 patients were enrolled in IRCC, of which 4,889 patients in over 30 distinct tumor entities were treated with CIK cells alone or in combination with conventional or novel therapies. Significantly improved median progression-free survival and overall survival were shown in 27 trials, and 9 trials reported a significantly increased 5-year survival rate. Mild adverse effects and graft-versus-host diseases were also observed in the studies. Recently, more efforts have been put into the improvement of antitumoral efficacy by CIK cells including the administration of immune checkpoint inhibitors and modification with chimeric antigen receptorc. The minimal toxicity and multiple improvements on their tumor-killing activity both make CIK cells a favorable therapeutic tool in the clinical practice of cancer immunotherapy.

Integrative analysis of key candidate genes and signaling pathways in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy by bioinformatics.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), the first immune checkpoint to be targeted clinically, has provided an effective treatment option for various malignancies. However, the clinical advantages associated with CTLA-4 inhibitors can be offset by the potentially severe immune-related adverse events (IRAEs), including autoimmune thyroid dysfunction. To investigate the candidate genes and signaling pathways involving in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy, integrated differentially expressed genes (DEGs) were extracted from the intersection of genes from Gene Expression Omnibus (GEO) datasets and text mining. The functional enrichment was performed by gene ontology (GO) annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Protein-protein interaction (PPI) network, module enrichment, and hub gene identification were constructed and visualized by the online Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. A total of 22 and 17 integrated human DEGs in hypothyroidism and hyperthyroidism group related to anti-CTLA-4 therapy were identified, respectively. Functional enrichment analysis revealed 24 GO terms and 1 KEGG pathways in the hypothyroid group and 21 GO terms and 2 KEGG pathways in the hyperthyroid group. After PPI network construction, the top five hub genes associated with hypothyroidism were extracted, including ALB, MAPK1, SPP1, PPARG, and MIF, whereas those associated with hyperthyroidism were ALB, FCGR2B, CD44, LCN2, and CD74. The identification of the candidate key genes and enriched signaling pathways provides potential biomarkers for autoimmune thyroid dysfunction related to anti-CTLA-4 therapy and might contribute to the future diagnosis and management of IRAEs for cancer patients.

Higher number of multidisciplinary tumor board meetings per case leads to improved clinical outcome.

BACKGROUND: This analysis aims at evaluating the impact of multidisciplinary tumor boards on clinical outcome of multiple tumor entities, the effect of the specific number of multidisciplinary tumor boards and potential differences between the tumor entities. METHODS: By a matched-pair analysis we compared the response to treatment, overall survival, relapse or disease free survival and progression free survival of patients whose cases were discussed in a tumor board meeting with patients whose cases were not. It was performed with patients registered in the cancer registry of the University of Bonn and diagnosed between 2010 and 2016. After the matching process with a pool of 7262 patients a total of 454 patients with 66 different tumor types were included in this study. RESULTS: First, patients with three or more multidisciplinary tumor board meetings in their history show a significantly better overall survival than patients with no tumor board meeting. Second, response to treatment, relapse free survival and time to progression were not found to be significantly different. Third, there was no significant difference for a specific tumor entity. CONCLUSION: This study revealed a positive impact of a higher number of multidisciplinary tumor boards on the clinical outcome. Also, our analysis hints towards a positive effect of multidisciplinary tumor boards on overall survival.