Modulation of Breast Cancer Cell Apoptosis and Macrophage Polarization by Mistletoe Lectin in 2D and 3D Models.

Korean mistletoe (Viscum album L. var. coloratum) is renowned for its medicinal properties, including anti-cancer and immunoadjuvant effects. This study aimed to elucidate the mechanisms by which Korean mistletoe lectin (V. album L. var. coloratum agglutinin; VCA) modulates breast cancer cell apoptosis and macrophage polarization. The specific objectives were to (1) investigate the direct effects of VCA on MCF-7 breast cancer cells and THP-1-derived M1/M2 macrophages; (2) analyze the impact of VCA on the paracrine interactions between these cell types; and (3) compare the efficacy of VCA in 2D vs. 3D co-culture models to bridge the gap between in vitro and in vivo studies. We employed both 2D and 3D models, co-culturing human M1/M2 macrophages with human MCF-7 breast cancer cells in a Transwell system. Our research demonstrated that M1 and M2 macrophages significantly influenced the immune and apoptotic responses of breast cancer cells when exposed to VCA. M1 macrophages exhibited cytotoxic characteristics and enhanced VCA-induced apoptosis in both 2D and 3D co-culture models. Conversely, M2 macrophages initially displayed a protective effect by reducing apoptosis in breast cancer cells, but this protective effect was reversed upon exposure to VCA. Furthermore, our findings illustrate VCA's ability to modulate M1 and M2 polarization in breast cancer cells. Finally, the use of magnetic 3D cell cultures suggests their potential to yield results comparable to conventional 2D cultures, bridging the gap between in vitro and in vivo studies.

Chronobiology of Viscum album L.: a time series of daily metabolomic fingerprints spanning 27 years.

Introduction: European mistletoe (Viscum album L.) has been gaining increasing interest in the field of oncology as a clinically relevant adjunctive treatment in many forms of cancer. In the field of phytopharmacology, harvesting time is pivotal. In the last century, a form of metabolomic fingerprinting based on pattern formation was proposed as a way to determine optimal harvesting times to ensure high quality of mistletoe as raw material for pharmaceutical use. In order to further evaluate the information obtained with this metabolomic fingerprinting method, we analysed a large time series of previously undigitised daily mistletoe chromatograms dating back to the 1950s. Methods: These chromatograms were scanned and evaluated using computerized image analysis, resulting in 12 descriptors for each individual chromatogram. We performed a statistical analysis of the data obtained, investigating statistical distributions, cross-correlations and time self-correlations. Results: The analysed dataset spanning about 27 years, contains 19,037 evaluable chromatograms in daily resolution. Based on the distribution and cross-correlation analyses, the 12 descriptors could be clustered into six independent groups describing different aspects of the chromatograms. One descriptor was found to mirror the annual rhythm being well correlated with temperature and a phase shift of 10 days. The time self-correlation analysis showed that most other descriptors had a characteristic self-correlation of ∼50 days, which points to further infradian rhythms (i.e., more than 24 h). Discussion: To our knowledge, this dataset is the largest of its type. The combination of this form of metabolomic fingerprinting with the proposed computer analysis seems to be a promising tool to characterise biological variations of mistletoe. Additional research is underway to further analyse the different rhythms present in this dataset.

Self-Nanoemulsifying Drug Delivery System (SNEDDS) Using Lipophilic Extract of Viscum album subsp. austriacum (Wiesb.) Vollm.

Background and Purpose: Natural products are potential sources of anticancer components. Among various species, the lipophilic extract of the Viscum album subsp. austriacum (Wiesb.) Vollm. (VALE) has shown promising therapeutic potential. The present work aimed to qualify the plant source and characterize the extract's chemical profile. In addition, a self-nanoemulsifying drug delivery system (SNEDDS) containing VALE (SNEDDS-VALE) was developed. Methods: V. album subsp. austriacum histochemistry was performed, and the chemical profile of VALE was analyzed by GC-MS. After the SNEEDS-VALE development, its morphology was visualized by transmission electron microscopy (TEM), while its stability was evaluated by the average droplet size, polydispersity index (PdI) and pH. Lastly, SNEDDS-VALE chemical stability was evaluated by LC-DAD-MS. Results: The histochemical analysis showed the presence of lipophilic compounds in the leaves and stems. The major compound in the VALE was oleanolic acid, followed by lupeol acetate and ursolic acid. SNEDDS was composed of medium chain triglyceride and Kolliphor® RH 40 (PEG-40 hydrogenated castor oil). A homogeneous, isotropic and stable nanoemulsion was obtained, with an average size of 36.87 ± 1.04 nm and PdI of 0.14 ± 0.02, for 14 weeks. Conclusion: This is the first histochemistry analysis of V. album subsp. austriacum growing on Pinus sylvestris L. which provided detailed information regarding its lipophilic compounds. A homogeneous, isotropic and stable SNEDDS-VALE was obtained to improve the low water solubility of VALE. Further, in vitro and in vivo experiments should be performed, in order to evaluate the antitumoral potential of SNEDDS-VALE.

Efficacy of quercetin-like compounds from the mistletoe plant of Dendrophthoe pentandra L. Miq, as oral random blood sugar lowering treatment in diabetic rats.

Background: Mistletoe is an herb that grows on duku plants (Lancium demosticum) and is known as benalu duku (BD) in Indonesia. It is predicted to have benefits such as anticancer or antiviral properties, and it is also thought to have anti-diabetic pharmacological activity. Quercetin-like compounds (QLCs) are secondary metabolites with antidiabetic activity that are expected to lower blood sugar levels in animals after oral administration.Objective: This study aimed to analyze the ability of QLCs to reduce random blood sugar levels using experimental animals as clinical models.Material and methods: The research method used was exploratory, which used a before-after test model, and observations were made on the random blood sugar levels after treatment. Secondary metabolites were extracted from BD leaves, which were then screened. Diabetes was induced in 30 rats (Rattus norvegicus) by the administration of streptozotocin at 0.045 mg/g body weight daily for 2 days. The antidiabetic effects of the secondary metabolite at doses of 0.5 mg/kg body weight (twice a day) when administered orally for up to 5 days were tested in diabetic rats. The random sugar levels (mg/dL) were measured using a One Touch Ultra Plus medical device for observation of randomized blood sugar levels. Results and novelty: The results revealed that the secondary metabolite, as an analyte from the BD leaf extract, can significantly reduce random blood sugar levels.Conclusion: The secondary metabolite extracted from BD, could be used to treat diabetes in rats.

Isolation of a Marker Olean-12-en-28-butanol Derivative from Viscum continuum E. Mey. Ex Sprague and the Evaluation of Its Antioxidant and Antimicrobial Potentials.

Viscum continuum E. Mey. Ex Sprague (Mistletoe) is a semi-parasitic plant that grows on the branches of other trees with reported numerous biological activities. This study was aimed at isolating a compound/s that will be used as a standard reference for quality control of South African-based commercialized mistletoe products and to further perform antioxidant and antimicrobial tests on the isolated compound. A dried sample of mistletoe was ground and extracted successively with hexane, dichloromethane (DCM), acetone and methanol using a serial exhaustive cold maceration procedure. The compound was isolated using column chromatography, and its chemical structure was elucidated using two-dimensional nuclear magnetic resonance (2D NMR) and ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS). The antioxidant activity of the compound was determined using DPPH, hydrogen radical scavenging activity and reducing power assays, whereas antimicrobial activity was assessed using the minimum inhibitory concentration (MIC) method. Subjection of the DCM extract to column chromatography resulted in the isolation of a compound elucidated as olean-12-en-28-butanol-1-one, 3-hydroxy-4,4,10, 14, 20-pentamethyl (D4). Both the DPPH, H2O2 radical scavenging activity and reducing power assays revealed a significant antioxidant potential of compound D4 with an IC50 of 0.701 mg/mL, lower than that of gallic acid (0.793 mg/mL) for the H2O2 radical scavenging assay. The results also indicated good antibacterial activity of D4 with an IC50 of 0.25 mg/mL, compared to ciprofloxacin with an IC50 of 0.0039 mg/mL, against two Gram-negative (Pseudomonas aeruginosa, Escherichia coli) and three Gram-positive (Streptococcus pyogenes, Bacillus cereus and Staphylococcus aureus) bacteria. This study is the first to report on the isolation of the olean-12-en-28-butanol derivative from mistletoe of the South African ecotype.

Ecological aspects and relationships of the emblematic Vachellia spp. exposed to anthropic pressures and parasitism in natural hyper-arid ecosystems: ethnobotanical elements, morphology, and biological nitrogen fixation.

MAIN CONCLUSION: Emblematic Vachellia spp. naturally exposed to hyper-arid conditions, intensive grazing, and parasitism maintain a high nitrogen content and functional mutualistic nitrogen-fixing symbioses. AlUla region in Saudi Arabia has a rich history regarding mankind, local wildlife, and fertility islands suitable for leguminous species, such as the emblematic Vachellia spp. desert trees. In this region, we investigated the characteristics of desert legumes in two nature reserves (Sharaan and Madakhil), at one archaeological site (Hegra), and in open public domains et al. Ward and Jabal Abu Oud. Biological nitrogen fixation (BNF), isotopes, and N and C contents were investigated through multiple lenses, including parasitism, plant tissues, species identification, plant maturity, health status, and plant growth. The average BNF rates of 19 Vachellia gerrardii and 21 Vachellia tortilis trees were respectively 39 and 67%, with low signs of inner N content fluctuations (2.10-2.63% N) compared to other co-occurring plants. The BNF of 23 R. raetam was just as high, with an average of 65% and steady inner N contents of 2.25 ± 0.30%. Regarding parasitism, infected Vachellia trees were unfazed compared to uninfected trees, thereby challenging the commonly accepted detrimental role of parasites. Overall, these results suggest that Vachellia trees and R. raetam shrubs exploit BNF in hyper-arid environments to maintain a high N content when exposed to parasitism and grazing. These findings underline the pivotal role of plant-bacteria mutualistic symbioses in desert environments. All ecological traits and relationships mentioned are further arguments in favor of these legumes serving as keystone species for ecological restoration and agro-silvo-pastoralism in the AlUla region.

The cardioprotective potential of selected species of mistletoe.

Mistletoe is an evergreen woody shrub with stems measuring 30-100 cm. It has leathery, yellowish-green strap-shaped leaves, yellowish-green flowers, and bears typical berries. The most common species is Viscum album L., mainly present in Europe and Asia. It is commonly known as European mistletoe or simply, mistletoe. Scientific interest in mistletoe was awakened in the XX century. Mistletoe, especially V. album L., has historically been used in the treatment and prophylaxis of CVD, with its properties being confirmed in recent studies. This mini-review describes new aspects of the cardioprotective properties of various species of mistletoe, especially V. album L. The effect of oral and subcutaneous application of fresh V. album L. extracts on blood pressure has been studied in various models; while the data suggests that mistletoe may be a promising herbal extract with cardioprotective properties, the species has only been tested in vitro and in vivo, on animals. In addition, it is unclear whether the cardioprotective activity of mistletoe may be due to particular chemical components, as the chemical composition of mistletoe extracts can vary depending on inter alia the time of harvest, extraction method and plant part. Hence, this activity may instead result from synergistic interactions between various secondary metabolites. Therefore, further studies are needed to identify the mechanisms of action of mistletoe compounds on CVDs, and determine their interactions with other cardioprotective drugs, their metabolic mechanisms, pharamacokinetics and adverse effects. More research is also needed to determine the therapeutic doses of active ingredients for use in clinical trials; this would require an accurate understanding of the chemical composition of extracts from different species of mistletoe (not only V. album L.) and from various host trees.

Systematic assessment of the influence of quality of studies on mistletoe in cancer care on the results of a meta-analysis on overall survival.

PURPOSE: Mistletoe treatment in cancer patients is controversial, and a Cochrane review concluded that due to heterogeneity, performing a meta-analysis was not suitable. However, several systematic reviews included meta-analyses in favor of mistletoe. The aim of this work was to assess the influence of the methodological quality of controlled studies on the results of a meta-analysis regarding overall survival. METHODS: Between April and August 2022, Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, CINAHL and Web of Science were systematically searched. In addition, reference lists of previously published meta-analyses were checked for relevant publications. A random effects meta-analysis with clustering was performed. The risk of bias within the studies was assessed using ROB 2.0 and ROBINS-I. RESULTS: The search identified 4685 hits, and 28 publications reporting on 28 298 patients were included in the quantitative analysis. Overall, the analysis led to a significant result in favor of mistletoe therapy (overall HR = 0.61 with 95% CI [0.53;0.7]). According to our subgroup analysis of randomized studies, studies of higher quality (lower risk of bias) did not lead to a significant result in favor of mistletoe therapy (HR = 0.78; CI = [0.30; 2.00]). CONCLUSIONS: In the case of mistletoe therapy, the results of the meta-analysis strongly depended on the methodological quality of the included studies. Calculating meta-analyses that include low-quality studies may lead to severe misinterpretation of the data.

A randomized placebo-controlled double-blinded study comparing oral and subcutaneous administration of mistletoe extract for the treatment of equine sarcoid disease.

BACKGROUND: Equine sarcoids (ES) are the most common cutaneous tumors in equids. Systemic treatment options are sparse. Subcutaneous (SC) injections of Viscum album extract (VAE) demonstrate efficacy as a systemic treatment directed against ES. OBJECTIVES/AIM: To critically assess the therapeutic efficacy of orally administered VAE. ANIMALS: Forty-five ES-affected, privately owned, 3-12 year-old horses. METHODS: A 3-armed randomized placebo-controlled, double-blinded study was conducted in a double-dummy design. Horses were subjected to oral administration and SC injections of either VAE or placebo (VAE oral/placebo SC, VAE SC/placebo oral, placebo oral/placebo SC) over a 7-month treatment period. Primary endpoint was the change of baseline of a composite index of ES number and ES area after 14 months. Second endpoint was the clinical response. RESULTS: No statistically significant difference in the composite endpoint between the 3 study arms was found. The primary endpoint showed 4 (27%) horses in the VAE oral group with complete ES regression, 3 (21%) in the VAE SC injection group, and 2 (13%) in the placebo group. The clinical response revealed complete or partial regression in 6 horses of the oral VAE group (40%), 4 of the SC injection group (29%), and 4 of the placebo group (25%). Direct comparison of oral VAE and placebo showed an odds ratio, stratified for prognosis of 2.16 (95%-CI: 0.45-10.42) and a P-value of 0.336. CONCLUSION AND CLINICAL IMPORTANCE: Oral administration of VAE is well tolerated. No statistically significant difference in the effectiveness of systemic VAE versus placebo against ES was found.

Arceuthobium Species (Viscaceae) Parasitizing an Angiosperm: The Unique Case of A. azoricum in the Azores Islands.

Arceuthobium azoricum Wiens & Hawksw. is a rare Azorean endemic epiphytic hemiparasite (mistletoe), which typically parasitizes branches of the gymnosperm Juniperus brevifolia (Hochst. ex Seub.) Antoine (Cupressaceae), which is also an Azorean endemic. Here, we describe a population of A. azoricum, on Pico Island, parasitizing Erica azorica Hochst. ex Seub. (Ericaceae), which is also an Azorean endemic. Our molecular analysis (using nuclear ribosomal internal transcribed spacer) showed no differences between individuals parasitizing Erica and Juniperus species. Moreover, a preliminary analysis showed no differences in morphological characteristics between accessions sampled from different hosts. Given that this is the first bona fide record of Arceuthobium sp. parasitizing an angiosperm, this population represents a unique host-shifting event, and its conservation is important because it may allow new insights into host recognition mechanisms in mistletoes. Immediate attention should be given to characterizing this Pico Island population using appropriate molecular methods and additional morphological analyses.

Pharmakokinetics of Mistletoe Lectins after Intravenous Application of a Mistletoe Product in Healthy Subjects.

Mistletoe lectins (ML) have cytotoxic and immunomodulating properties, and subcutaneously applied mistletoe products (MP) containing ML have approval for supportive cancer treatment. MP are also given off-label intravenously, but data about pharmacokinetics are widely lacking. Therefore, the aim of our phase I trial was to evaluate the pharmacokinetics and safety of intravenously applied natural ML. Initially, 12 healthy male volunteers were planned to receive a single infusion of 2000 mg Helixor® P. We had to terminate the study prematurely after the inclusion of eight subjects due to elevation of all subjects' liver enzymes. ML was detected in all subjects after infusion. The mean half-life of serum ML was 7.02 ± 2.01 h. Mean alanine transaminase increased from 23 ± 6 to a maximum of 445 ± 260 U/L, and mean aspartate aminotransferase increased from 24 ± 3 to a maximum of 318 ± 33 U/L 72 h after infusion. Severity grading for drug-induced liver injury was mild. Participants did not suffer from any liver-specific symptoms and recovered completely. As a conclusion, the dose of 2000 mg Helixor® P caused transient liver injury in healthy subjects and should, therefore, not be used for initial patient treatment. Liver enzymes should be monitored in patients receiving intravenous treatment with Helixor® P.

The associational effects of host plant and mistletoe functional traits on leaf herbivory in mistletoe.

Associational effects are a phenomenon in which herbivore damage on co-occurring plant species is influenced by neighboring plants. Mistletoes are a group of shrubs that obtain nutrients from host plants through haustoria. Despite the potential for mistletoe herbivory to be affected by associational effects with their hosts, the effects of host and mistletoe functional traits on mistletoe herbivory have been largely overlooked. This study aimed to evaluate the associational effects of host plants and the direct effects of mistletoe functional traits on mistletoe herbivory. To achieve this, we measured leaf herbivory and leaf traits of three mistletoe species (Dendrophthoe pentandra, Scurrula chingii var. yunnanensis, and Helixanthera parasitica) and their associated 11 host species during both dry and wet seasons. Our results showed that leaf herbivory of D. pentandra and S. chingii var. yunnanensis differed significantly on their respective host species, but H. parasitica did not. The relationships between mistletoe and the paired host herbivory differed between seasons, with a stronger positive relationship observed during the dry season. Furthermore, significant relationships were observed between paired leaf carbon, leaf nitrogen, and condensed tannin in mistletoes and their host plants, indicating that host plants can affect mistletoes' leaf functional traits. A group of mistletoe leaf traits provided significant predictions for leaf herbivory: leaves with higher leaf thickness and leaf total nitrogen showed higher herbivory. Overall, our study reveals that mistletoe leaf herbivory is directly affected by its leaf traits and indirectly affected by host associational effects, primarily through changes in mistletoes' leaf traits.

Integrated metabolomics and transcriptomic analysis reveals metabolic changes of flavor compounds of Camellia assamica host plant after parasitized by Viscumarticulatum.

Tea is one of the most popular beverages, it has many health benefits and flavor properties due to the presence of numerous secondary metabolites. Camellia assamica is also a main source of tea, which is mainly planted in the regions of southwest China. In this study, a non-targeted and targeted metabolomics analysis and sensory evaluation on tea leaves with and without mistletoe (Viscum articulatum) was carried out using liquid chromatography-mass spectrometry. RNA-seq-based transcriptomic analysis was conducted in parallel on the same samples, subsequently gene expression and metabolic differentiation were also investigated. Tea leaves with mistletoe presented much lower contents of (-)-catechin, (-)-epicatechin, (-)-gallocatechin gallate and (-)-epicatechin gallate, but significantly higher levels of free amino acids including Arg, Asp, GABA and Gln than that without mistletoe. Transcriptomic analysis also confirmed the main differentially expressed genes (DEGs) containing phenylpropanoid and flavonoid biosynthesis were down-regulated, but genes of amino acid biosynthesis were up-regulated. qRT-PCR analysis further revealed that the relative expression of CsCHS, CsC4H, CsANS, CsLAR, and CsF3H was hindered, while CsglyA and CsilvE expression was increased.

Clinical characteristics and therapeutic behavior of breast cancer patients using mistletoe therapy consulting a clinic offering integrative oncology: a registry data analysis.

MOTIVATION: Cancer patients often use complementary and/or alternative medicine, such as mistletoe therapy, alongside conventional cancer therapies. In Switzerland, so far not much is known about treatment patterns of breast cancer patients using integrative oncology. Solid knowledge on complementary care utilization may help to enhance integrative oncology care in Switzerland. METHODS: In this exploratory, descriptive database study, we investigated the treatment pathways of a cohort of breast cancer patients who received mistletoe therapy and were documented in the cancer registry of an anthroposophic Swiss hospital offering integrative oncology treatments. RESULTS: Patients treated with mistletoe in this cohort are in median 10 years younger than Swiss breast cancer patients as a whole. Only 5.8% of these patients were treated with mistletoe alone, while 60.5% of them supplemented chemotherapy and/or hormone therapy and/or surgery and/or radiation with mistletoe therapy. Nearly 80% of patients started conventional therapy followed by additional mistletoe therapy or started mono mistletoe therapy after completion of conventional therapies. The median time from initial diagnosis to hospital admission (inpatient and/or outpatient) was less than one year. Almost ¾ of the patients were treated in an outpatient setting only. CONCLUSION: From our data, it appears that younger breast cancer patients are more likely to use mistletoe therapy simultaneously with or following their conventional medical therapies. The extent to which these patients discuss their mistletoe therapy and eventually other complementary and/or alternative therapies with their primary oncologists is not clear from the data. We therefore recommend that (Swiss) oncologists should openly discuss the desire for integrative oncology therapies, especially with their younger breast cancer patients, in order to find the best holistic care pattern for these patients.

Exposing the error hidden in plain sight: A critique of Calder's (1983) group selectionist seed-dispersal hypothesis for mistletoe "mimicry" of host plants.

Some mistletoe species (Loranthaceae) resemble their host plants to a striking degree. Various mechanisms have been proposed for the developmental origins of novel traits that cause mistletoes to appear similar to their hosts, as well as for the adaptive phenotypic evolution of such traits. Calder (1983) proposed a logically flawed group selectionist seed-dispersal hypothesis for mistletoes to resemble their hosts. Calder's (1983) hypothesis does not provide a viable potential explanation for mistletoe resemblance to hosts.

Quality of Life in Breast Cancer Patients Treated With Mistletoe Extracts: A Systematic Review and Meta-Analysis.

BACKGROUND: Breast cancer is the most common cancer type in women and quality of life an essential part of patients' well-being. Although the treatment with mistletoe extracts is covered by multiple cancer guidelines and reviews, it is uncertain whether mistletoe extracts can improve the quality of life in breast cancer patients. We therefore performed a systematic review and meta-analysis on this topic. METHODS: This systematic review included randomized clinical trials (RCTs) and non-randomized studies of intervention (NRSIs) comparing the quality of life in breast cancer patients treated with mistletoe extracts as add-on therapy to control groups treated conventionally. We searched previous systematic reviews and multiple databases until January 2023. We conducted a meta-analysis and assessed the risk of bias according to the Cochrane Handbook via RoB 2 and ROBINS-I and the certainty of evidence via GRADE, respectively. RESULTS: Nine RCTs and 7 NRSIs with 833 and 2831 participants, respectively, were included. The pre-post changes for the quality of life resulted in a pooled standardized mean difference for RCTs of SMD = 0.61 (95% CI 0.47-0.75; P < .0001) and for retrospective NRSIs of SMD = 0.46 (95% CI 0.10-0.82; P = .01). The risk of bias was low to high for the RCTs and serious for all NRSIs. The certainty of evidence was moderate for RCTs and very low for NRSIs. DISCUSSION: Our results indicate a clinically relevant, medium-sized effect of mistletoe extracts on the quality of life in breast cancer patients which may be based on the immunomodulating effects of mistletoe extracts during chemotherapy. The limitations of evidence include the risk of bias which is mainly caused by the difficulty of blinding. Further RCTs and real-world evidence need to confirm this result, especially in the setting of neoadjuvant chemotherapy and in breast cancer survivors.

Patients with Advanced Pancreatic Cancer Treated with Mistletoe and Hyperthermia in Addition to Palliative Chemotherapy: A Retrospective Single-Center Analysis.

This retrospective analysis investigated the influence of integrative therapies in addition to palliative chemotherapy in patients with advanced pancreatic cancer, treated at a single institution specialized in integrative oncology between January 2015 and December 2019. In total, 206 consecutive patients were included in the study, whereof 142 patients (68.9%) received palliative chemotherapy (gemcitabine/nab-paclitaxel 33.8%; FOLFIRINOX 35.9%; gemcitabine 30.3%) while the remainder were treated with best supportive and integrative care. Integrative therapies were used in 117 of 142 patients (82.4%) in addition to conventional chemotherapy, whereby mistletoe was used in 117 patients (82.4%) and hyperthermia in 74 patients (52.1%). A total of 107/142 patients (86.3%) died during the observation period, whereby survival times differed significantly depending on the additional use of integrative mistletoe or hyperthermia: chemotherapy alone 8.6 months (95% CI 4.7-15.4), chemotherapy and only mistletoe therapy 11.2 months (95% CI 7.1-14.2), or a combination of chemotherapy with mistletoe and hyperthermia 18.9 months (95% CI 15.2-24.5). While the survival times observed for patients with advanced pancreatic cancer receiving chemotherapy alone are consistent with pivotal phase-III studies and German registry data, we found significantly improved survival using additional mistletoe and/or hyperthermia.

Mistletoe Extracts from Different Host Trees Disparately Inhibit Bladder Cancer Cell Growth and Proliferation.

Extracts of European mistletoe (Viscum album) are popular as a complementary treatment for patients with many different cancer types. However, whether these extracts actually block bladder cancer progression remains unknown. The influence of different mistletoe extracts on bladder cancer cell growth and proliferation was investigated by exposing RT112, UMUC3, and TCCSup cells to mistletoe from hawthorn (Crataegi), lime trees (Tiliae), willow trees (Salicis), or poplar trees (Populi). The tumor cell growth and proliferation, apoptosis induction, and cell cycle progression were then evaluated. Alterations in integrin α and ß subtype expression as well as CD44 standard (CD44s) and CD44 variant (CD44v) expressions were evaluated. Cell cycle-regulating proteins (CDK1 and 2, Cyclin A and B) were also investigated. Blocking and knock-down studies served to correlate protein alterations with cell growth. All extracts significantly down-regulated the growth and proliferation of all bladder cancer cell lines, most strongly in RT112 and UMUC3 cells. Alterations in CD44 expression were not homogeneous but rather depended on the extract and the cell line. Integrin α3 was, likewise, differently modified. Integrin α5 was diminished in RT112 and UMUC3 cells (significantly) and TCCSup (trend) by Populi and Salicis. Populi and Salicis arrested UMUC3 in G0/G1 to a similar extent, whereas apoptosis was induced most efficiently by Salicis. Examination of cell cycle-regulating proteins revealed down-regulation of CDK1 and 2 and Cyclin A by Salicis but down-regulation of CDK2 and Cyclin A by Populi. Blocking and knock-down studies pointed to the influence of integrin α5, CD44, and the Cyclin-CDK axis in regulating bladder cancer growth. Mistletoe extracts do block bladder cancer growth in vitro, with the molecular action differing according to the cell line and the host tree of the mistletoe. Integrating mistletoe into a guideline-based treatment regimen might optimize bladder cancer therapy.

The Introspective Patient Experience of Mistletoe Therapy in Cancer: A Qualitative Study.

INTRODUCTION: The introspective experience of cancer patients using mistletoe therapy has received little scientific interest, although it is crucial for a holistic understanding of this therapy. This study contributes to patient-centered research and treatment by documenting the subjective experiences of individuals undergoing mistletoe therapy. METHODS: In this qualitative, explorative study, 20 outpatients with a history of various cancer types were recruited from Arlesheim Hospital (Arlesheim, Switzerland). All patients received subcutaneous mistletoe therapy for at least 2 years (median 7.5 years). Data was collected through 2 semi-structured, in-depth interviews per patient. Qualitative content analysis was applied to examine the data. The individual experience of mistletoe therapy was analyzed in relation to 6 predefined levels of human experience: physical, vital, emotional, mental, spiritual and social. In addition, 3 further aspects, considered as cross-dimensional perspectives, emerged out of the material: warmth, immune strengthening, and general wellbeing. RESULTS: Data analysis revealed considerable heterogeneity among patients' experiences with mistletoe therapy. The importance of specific aspects became apparent, such as increased vitality to manage daily life, greater emotional and mental stability, warmth as a multidimensional phenomenon, feelings of safety and protection through mistletoe therapy, heightened self-awareness and improved self-care, as well as sensations of spiritual connectedness. CONCLUSIONS: Prior to this study it had not been shown that cancer patients using mistletoe therapy do have observations on different levels of experience. These results may lead to a deeper understanding of patients receiving mistletoe therapy, enabling them to be supported in a more holistic way both during mistletoe treatment and on their life path. Further investigations into the effects of mistletoe therapy on the emotional, mental, and spiritual level are warranted.

Mistletoe Extracts during the Oncological Perioperative Period: A Systematic Review and Meta-Analysis of Human Randomized Controlled Trials.

BACKGROUND: We aim to evaluate the safety and efficacy of mistletoe extract (ME) use during the oncological perioperative period. METHODS: Details registered a priori on PROSPERO (CRD42018086168). RESULTS: Seven RCTs (comprising 663 participants in nine reports) and three nonrandomized studies were included. In five RCTs, ME was evaluated as adjunctive care and the control group had no additional intervention, whereas in two RCTs, ME was compared head-to-head against common cancer treatments (i.e., etoposide or bacillus Calmette-Guérin) with the intervention groups not receiving standard care. Meta-analyses found no evidence for a difference between ME and no added therapy for mortality and recurrence (RR, 95% CI: 1.00, 0.79-1.27; and 1.03, 0.79-1.33, respectively). Two RCTs reported beneficial effects of ME on immune cells, specifically natural killer cells, in colorectal cancer, and one RCT reported quality of life improvement. Two RCTs reported ME discontinuations due to adverse events and grade 3/4 toxicities. Nevertheless, no safety signals were detected from these 10 studies. Quality appraisal revealed a substantial risk of bias. CONCLUSIONS: Preliminary data are encouraging for mistletoe extracts, particularly in the context of colorectal cancer. However, the evidence is limited by the number of studies, an evaluation of different outcomes, and methodological limitations. Further high-quality research is warranted.