Antiproliferative and immunomodulative potential of Citrullus colocynthis and its bioactive compounds in human lymphocytes and lung cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Citrullus colocynthis (L.) Schrad is a member of the Cucurbitaceae plant family which has been used in traditional medicine for the treatment of lung diseases such as asthma and bronchitis. AIM OF THE STUDY: The study was conducted to investigate antiproliferative and immunomodulating effects of C. colocynthis and isolated cucurbitacins on human T lymphocytes and lung epithelial cells in order to evaluate their potential in the treatment of airway diseases. MATERIALS AND METHODS: Different concentrations of an ethanolic extract of C. colocynthis fruits and cucurbitacins B (CuB), E (CuE) and E-glucopyranoside (CuE-Glu) were analysed for their cytotoxicity and immunomodulatory potential on Peripheral Blood Mononuclear Cells (PBMCs) of healthy donors and on the epithelial lung cancer cell line A549. Viability and proliferation were tested using WST1 and CFSE assays. Flow cytometric analysis of AnnexinV/PI staining was used to investigate cell death through apoptosis/necrosis. Effects on regulatory mechanisms of T lymphocytes, such as CD69 and CD25 marker activation, cytokine production of the cytokines interleukin 2 (IL2), tumor necrosis factor α (TNFα) and interferon γ (IFNy) were also analysed via flow cytometry. Influences on the activator protein 1 (AP1), nuclear factor of activated T-cells (NFAT) or nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB) pathways were analysed in the Jurkat reporter cell line. Cytokine secretion in A549 cells stimulated with virus-like particles was analysed using the bead-based Legendplex™ assay. RESULTS: Non-toxic concentrations of C. colocynthis and CuE-Glu showed dose-dependent effects on viability and proliferation in both T lymphocytes and A549 cells. The extracts inhibited lymphocyte activation and suppressed T cell effector functions, which was also shown by lower production of cytokines IL2, TNFα and IFNy. A dose dependent inhibition of the pathways NFκB, NFAT and AP1 in Jurkat cells could be observed. In A549 cells, especially CuE and CuE-Glu showed inhibitory effects on cytokine production following a simulated viral infection. Unglycosylated cucurbitacins were more effective in suppressing the immune function in lymphocytes than glycosylated cucurbitacins, however this activity is limited to cytotoxic concentrations. CONCLUSION: In our study we could confirm the immunmodulating effect of C. colocynthis and cucurbitacins B, E and E-glucopyranoside in vitro by suppression of different pathways of inflammation and T cell proliferation. Activity in a lung cell model using a virus-like stimulation shows promise for further research regarding cucurbitacins in airway diseases.

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.

Gut Microbiota in Diagnosis, Therapy and Prognosis of Cholangiocarcinoma and Gallbladder Carcinoma-A Scoping Review.

Cancers of the biliary tract are more common in Asia than in Europe, but are highly lethal due to delayed diagnosis and aggressive tumor biology. Since the biliary tract is in direct contact with the gut via the enterohepatic circulation, this suggests a potential role of gut microbiota, but to date, the role of gut microbiota in biliary tract cancers has not been elucidated. This scoping review compiles recent data on the associations between the gut microbiota and diagnosis, progression and prognosis of biliary tract cancer patients. Systematic review of the literature yielded 154 results, of which 12 studies and one systematic review were eligible for evaluation. The analyses of microbiota diversity indices were inconsistent across the included studies. In-depth analyses revealed differences between gut microbiota of biliary tract cancer patients and healthy controls, but without a clear tendency towards particular species in the studies. Additionally, most of the studies showed methodological flaws, for example non-controlling of factors that affect gut microbiota. At the current stage, there is a lack of evidence to support a general utility of gut microbiota diagnostics in biliary tract cancers. Therefore, no recommendation can be made at this time to include gut microbiota analyses in the management of biliary tract cancer patients.

Characterization of Viscum album L. Effect on Immune Escape Proteins PD-L1, PD-L2, and MHC-I in the Prostate, Colon, Lung, and Breast Cancer Cells.

BACKGROUND: Viscum album L. (VA) preparations possess immunomodulatory properties and are used in complementary medicine to support cancer therapy. It is unclear if there is an impact of VA on the expression of immune checkpoint proteins on the surface of cancer cells. This study was designed to investigate the role of commercially available VA preparations on checkpoint programmed death ligand 1, 2 (PD-L1, PD-L2) and on major histocompatibility complex class I (MHC-I). METHODS: Four human cancer cell lines (prostate, colon, lung, and breast) were assayed for their PD-L1, PD-L2, and MHC-I level after stimulation with interferon-gamma (IFN-γ). The toxicity of mistletoe preparations for the cells was analysed. Afterwards, the effect of mistletoe preparations on the PD ligands and MHC-I was investigated. RESULTS: Surface protein analysis demonstrated that all tested tumour cell lines increased the PD-L1, PD-L2, and MHC-I-expression, but to different extents, after IFN-γ stimulation. Treatment with VA extracts did not influence the viability of the cells. The expression of PD ligands and MHC-I was not affected by incubation with the VA preparations. CONCLUSION: Our investigation concludes that VA treatment does not interfere with the expression of PD ligands or MHC-I among selected cancer cells.Viscum album L. (VA)-Präparate besitzen immunmodulatorische Eigenschaften und werden in der Komplementärmedizin zur Unterstützung in der Krebstherapie eingesetzt. Es ist jedoch unklar, ob VA einen Einfluss auf die Expression von Immuncheckpoint-Proteinen auf Krebszellen hat. In der vorliegenden Arbeit wurde ein Einfluss von handelsüblichen VA-Präparaten auf die Checkpoint-Proteine programmed death ligand 1, 2 (PD-L1, PD-L2) und major histocompatibility complex class I (MHC-I) untersucht.Vier humane Krebszelllinien der Prostata, des Dickdarms, der Lunge und Brust wurden nach Stimulation mit Interferon-gamma (IFN-γ) auf ihre PD-L1, PD-L2 und MHC-I Konzentration untersucht. Zunächst wurde die Toxizität von Mistelpräparaten auf die Tumorzellen analysiert. Anschließend erfolgte eine Charakterisierung der Wirkung von Mistelpräparaten auf die PD-Liganden und MHC-I.Die Oberflächenproteinanalysen zeigten, dass alle getesteten Tumorzelllinien nach einer IFN-γ-Stimulation die PD-L1, PD-L2 und MHC-I Expression in unterschiedlichem Ausmaß erhöhten. Die Behandlung mit verschiedenen VA-Extrakten hatte keinen Einfluss auf die Viabilität der Zellen, sowie auf die Expression der PD-Liganden und MHC-I.Unsere Untersuchung kommt zu dem Schluss, dass eine VA-Behandlung die Expression von PD-Liganden oder MHC-I in den untersuchten Krebszellen nicht beeinflusst.

Longitudinal dynamics of gut bacteriome and mycobiome interactions pre- and post-visceral surgery in Crohn's disease.

Introduction: Alterations of the gut microbiome are involved in the pathogenesis of Crohn's disease (CD). The role of fungi in this context is unclear. This study aimed to determine postoperative changes in the bacterial and fungal gut communities of CD patients undergoing intestinal resection, and to evaluate interactions between the bacteriome and mycobiome and their impact on the patients' outcome. Methods: We report a subgroup analysis of a prospective cohort study, focusing on 10 CD patients whose fecal samples were collected for bacterial 16S rRNA and fungal ITS2 genes next-generation sequencing the day before surgery and on the 5th or 6th postoperative day. Results: No significant differences in bacterial and fungal diversity were observed between preoperative and postoperative stool samples. By in-depth analysis, significant postoperative abundance changes of bacteria and fungi and 17 interkingdom correlations were detected. Network analysis identified 13 microbial clusters in the perioperative gut communities, revealing symbiotic and competitive interactions. Relevant factors were gender, age, BMI, lifestyle habits (smoking, alcohol consumption) and surgical technique. Postoperative abundance changes and identified clusters were associated with clinical outcomes (length of hospital stay, complications) and levels of inflammatory markers. Conclusions: Our findings highlight the importance of dissecting the interactions of gut bacterial and fungal communities in CD patients and their potential influence on postoperative and disease outcomes.

Complementary medicine usage in surgery: a cross-sectional survey in Germany.

BACKGROUND: Complementary medicine (CM) is frequently used by patients, but little is known about the usage of CM in surgical patients. The study aimed to elucidate the relevance of CM in surgery. METHODS: This cross-sectional, multi-center survey utilized a paper-based questionnaire consisting of 21 questions to capture CM usage and interest as well as CM communication in visceral and thoracic surgical patients being hospitalized at the corresponding departments of surgery at the University Medical Centers in Freiburg, Heidelberg und Ulm, Germany. RESULTS: Overall, 151 patients consented to the survey. On average, current CM usage was stated by 44% of patients. Most frequently used CM approaches were physical exercise (63%), nutritional supplements (59%) and herbal medicine (56%). Strong interest in CM counselling was stated by 51% of patients. Almost 80% of patients wanted to be treated in a holistic manner and desired for reliable information about CM as well as CM informed physicians. Only 12% of patients communicated CM usage and interest with their attending physician. Review of literature revealed similar results showing an overall CM usage of 43%, preferring nutritional supplements and herbal medicine. CONCLUSION: The results of our cross-sectional study indicate a high percentage of CM users and a strong interest in CM among surgical patients. Indeed, the current communication about CM between patients and surgeons is poor. With respect to safety and quality reasons, but also to pay attention to patients' demands, physicians should be aware of patients' CM usage in surgery. TRIAL REGISTRATION: German Clinical Trial register (DRKS00015445).

Surgery as an Emotional Strain: An Observational Study in Patients Undergoing Elective Colorectal Surgery.

Recent research suggests an impact of psychological distress on postoperative outcomes in orthopedic and neurosurgery. It is widely unknown whether patients' mood might affect the postoperative outcome and complication rate in colorectal surgery. Over a period of 22 months, a monocentric, observational study among patients undergoing elective colorectal surgery without the creation of an ostomy was conducted. Patients were asked to fill in a standardized multi-dimensional mood questionnaire (MDMQ) preoperatively as well as on the third, sixth, and ninth postoperative days to assess mood, wakefulness, and arousal. The results of 80 patients (51% male, mean age 59 years) were analyzed. Almost half of the patients (58%) developed postoperative complications according to the Clavien-Dindo classification (Grade I 14%, Grade II 30%, Grade III 9%, Grade IV 3%). Patients' mood increased continually from the preoperative day to the ninth postoperative day. Patients' wakefulness decreased initially (pre- to third postoperative day) and increased again in the further course. Patients' arousal decreased pre- to postoperatively. Neither preoperative mood, nor arousal or wakefulness of patients showed a clear association with the development of postoperative complications. In conclusion, preoperative psychological distress measured by MDMQ did not affect the postoperative complication rate of patients undergoing elective colorectal surgery.

Analysis of S-Adenosylmethionine and S-Adenosylhomocysteine: Method Optimisation and Profiling in Healthy Adults upon Short-Term Dietary Intervention.

S-adenosylmethionine (SAM) is essential for methyl transfer reactions. All SAM is produced de novo via the methionine cycle. The demethylation of SAM produces S-adenosylhomocysteine (SAH), an inhibitor of methyltransferases and the precursor of homocysteine (Hcy). The measurement of SAM and SAH in plasma has value in the diagnosis of inborn errors of metabolism (IEM) and in research to assess methyl group homeostasis. The determination of SAM and SAH is complicated by the instability of SAM under neutral and alkaline conditions and the naturally low concentration of both SAM and SAH in plasma (nM range). Herein, we describe an optimised LC-MS/MS method for the determination of SAM and SAH in plasma, urine, and cells. The method is based on isotopic dilution and employs 20 µL of plasma or urine, or 500,000 cells, and has an instrumental running time of 5 min. The reference ranges for plasma SAM and SAH in a cohort of 33 healthy individuals (age: 19-60 years old; mean ± 2 SD) were 120 ± 36 nM and 21.5 ± 6.5 nM, respectively, in accordance with independent studies and diagnostic determinations. The method detected abnormal concentrations of SAM and SAH in patients with inborn errors of methyl group metabolism. Plasma and urinary SAM and SAH concentrations were determined for the first time in a randomised controlled trial of 53 healthy adult omnivores (age: 18-60 years old), before and after a 4 week intervention with a vegan or meat-rich diet, and revealed preserved variations of both metabolites and the SAM/SAH index.

Valerian and postoperative sleep: a retrospective cohort analysis of gynecological, urologic, and general surgical patients.

STUDY OBJECTIVES: Postoperative sleep disturbances appear to be a common complication after surgery being treated with sleep-promoting medication such as valerian, but robust data and evidence of medicinal approaches are lacking. METHODS: We performed a retrospective cohort analysis of all 21 168 urological, gynecological, and general surgical patients of the University Medical Center Freiburg, Germany, who underwent surgery between 2015 and 2020. Target parameters were the usage of sleep-promoting medication to estimate the occurrence of postoperative sleep disturbances as well as the kind of sleep medication with a special focus on herbal medication such as valerian. RESULTS: Drug-treated sleep disturbances occurred in 15% (n = 3083) of the patients. Valerian was the second most applied drug (n = 814, 26.4%) after classic benzodiazepines (n = 1 138, 36.9%). The majority of patients got valerian as monotherapy. Age, length of stay, and comorbidities were associated with demand for sleep medication in general (p < .001). Valerian monotherapy was more common in women (OR 1.53, 95% CI: 1.33-1.77, p < .001), elderly patients (OR 1.50, 95% CI: 1.29-1.75, p < .001), and patients with prolonged hospital stay (OR 2.23, 95% CI: 1.91-2.61, p < .001). CONCLUSIONS: Valerian plays an important role in the treatment of postoperative sleep disturbances clinically, and it appears to be a promising therapeutic approach especially in women, older and sicker patients, and those with prolonged hospital stay. Further research has to clarify the efficacy of valerian postoperatively. CLINICAL TRIAL REGISTRATION: DRKS00027903, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027903.

Current Insights: The Impact of Gut Microbiota on Postoperative Complications in Visceral Surgery-A Narrative Review.

Postoperative complications are a major problem occurring in up to 50% of patients undergoing major abdominal surgery. Occurrence of postoperative complications is associated with a significantly higher morbidity and mortality in affected patients. The most common postoperative complications are caused by an infectious genesis and include anastomotic leakage in case of gastrointestinal anastomosis and surgical site infections. Recent research highlighted the importance of gut microbiota in health and disease. It is plausible that the gut microbiota also plays a pivotal role in the development of postoperative complications. This narrative review critically summarizes results of recent research in this particular field. The review evaluates the role of gut microbiota alteration in postoperative complications, including postoperative ileus, anastomotic leakage, and surgical site infections in visceral surgery. We tried to put a special focus on a potential diagnostic value of pre- and post-operative gut microbiota sampling showing that recent data are inhomogeneous to identify a high-risk microbial profile for development of postoperative complications.

Complementary medicine in Germany: a multi-centre cross-sectional survey on the usage by and the needs of patients hospitalized in university medical centers.

BACKGROUND: The results of recent surveys indicate that more than 50% of the German population has experience with complementary and alternative medicine (CAM) or uses CAM regularly. This study investigated the CAM usage and CAM-related needs of hospitalized patients at university medical centres in the state of Baden-Württemberg, Germany. METHODS: A multi-centre, paper-based, pseudonymous survey was carried out by the members of the Academic Centre for Complementary and Integrative Medicine. Patients of all ages, regardless of sex, diagnosis and treatment, who were hospitalized in the Department of Cardiology, Gastroenterology, Oncology, Gynaecology or Surgery at the university medical centres in Freiburg, Heidelberg, Tübingen and Ulm were eligible for inclusion. RESULTS: Of the 1275 eligible patients, 67% (n = 854) consented to participate in the survey. Forty-eight percent of the study participants stated that they were currently using CAM. The most frequently used therapies were exercise (63%), herbal medicine (54%) and dietary supplements (53%). Only 16% of the patients discussed CAM usage with their attending physician. Half of the patients (48%) were interested in CAM consultations. More than 80% of the patients desired reliable CAM information and stated that physicians should be better informed about CAM. CONCLUSIONS: The frequency of CAM usage and the need for CAM counselling among hospitalized patients at university medical centres in Baden-Württemberg are high. To better meet patients' needs, CAM research and physician education should be intensified. TRIAL REGISTRATION: German Clinical Trial register ( DRKS00015445 ).

Complementary medicine in orthopaedic and trauma surgery: a cross-sectional survey on usage and needs.

OBJECTIVES: Complementary and alternative medicine (CAM) is frequently used in Western countries within general medicine and internal medicine. Information on the use in orthopaedic and trauma surgery is widely lacking. The aim of this study was to investigate usage and needs regarding CAM for these patients. DESIGN: Prospective paper-based, pseudoanonymous, cross-sectional survey. SETTING: From August to December 2018, a questionnaire composed of 17 questions was distributed to all eligible patients. PARTICIPANTS: In-house patients in orthopaedic and trauma surgery at a high-volume medical centre in Germany. PRIMARY AND SECONDARY OUTCOME MEASURES: Previous or current usage of CAM, interest and requests towards CAM as well as communication about CAM. RESULTS: Overall, 457 orthopaedic and trauma surgical patients took part in the survey. They were on average 52 years old and 54% were male. Most of the patients were admitted due to bone fractures and most underwent operative therapy. Previous or current CAM usage was stated by 76% and 30% of patients, respectively. Most of the patients stated to be interested in usage of CAM and demanded for more clinical usage of CAM and reliable information about CAM. More than 90% of patients did not discuss CAM interest or usage with their treating physicians. Patients stated that physicians should have knowledge about CAM. They wish to be treated in a holistic manner and want to strengthen self-efficacy. CONCLUSIONS: Usage of CAM of patients in orthopaedic and trauma surgery appears to be high. Only a few patients discuss their interest and usage of CAM with their treating physician. Therefore, surgeons should ask their patients about CAM and should consider evidence-based CAM approaches for complementary treatment. TRIAL REGISTRATION NUMBER: DRKS0001544.

Vegan diet reduces neutrophils, monocytes and platelets related to branched-chain amino acids - A randomized, controlled trial.

BACKGROUND: Vegan diet (VD) has improved inflammatory activity in patients with rheumatoid arthritis (RA) in several small controlled trials. The underlying mechanism remains widely unclear. We investigated the effect of a VD in comparison to a meat-rich diet (MD) on markers of inflammation (which have been shown to be relevant in patients with RA) in healthy volunteers. METHODS: 53 healthy, omnivore subjects were randomized to a controlled VD (n = 26) or MD (n = 27) for 4 weeks following a pre-treatment phase of a one week controlled mixed diet. Primary parameters of interest were sialylation of immunoglobulins, percentage of regulatory T-cells and level of interleukin 10 (IL10). Usual care immune parameters used in patients with RA and amino acid serum levels as well as granulocytes and monocytes colony stimulating factor (GM-CSF) serum levels were secondary parameters. RESULTS: In the VD group, total leukocyte, neutrophil, monocyte and platelet counts decreased and after four weeks they were significantly lower compared to the MD group (ANCOVA: leukocytes p = 0.003, neutrophils p = 0.001, monocytes p = 0.032, platelets p = 0.004). Leukocytes, neutrophils, monocytes, and platelets correlated with each other and likewise conform with serum levels of branched-chain amino acids, which were significantly lower in the VD compared to the MD group. The primary parameters did not differ between the groups and BMI remained stable in the two groups. CONCLUSION: Four weeks of a controlled VD affected the number of neutrophils, monocytes and platelets but not the number or function of lymphocytes. The relation with branched-chain amino acids and GM-CSF suggests a mode of action via the mTOR signaling pathway. REGISTERED AT: http://www.drks.de (German Clinical Trial register) at DRKS00011963.

Statement to an Insufficient Systematic Review on Viscum album L. Therapy.

BACKGROUND: Up to 88% of oncological patients apply complementary therapies and up to 77% apply complementary mistletoe therapy in the context of integrative oncological approaches. An evidence-based consultation of oncological health professionals regarding complementary therapies used in Germany is missing. Therefore, a new S3-Guideline for Complementary Medicine in the Treatment of Oncological Patients is under development and is anticipated to be finalized in November 2020. It will be based on evidence-based publications and systematic reviews on complementary therapies in oncology. A recently published two-part systematic review on mistletoe treatment in oncology has been reevaluated. METHODS: The latest published systematic two-part review on mistletoe has been systematically proofread and checked in compliance with the Cochrane Handbook for Systematic Reviews of Intervention and the AMSTAR 2 (A MeaSurement Tool to Assess Systematic Reviews) tool. RESULTS: The here discussed two-part review is incomplete, lacks sound accuracy including insufficient assessment of the risk of bias, and contains imprecise statements. In addition, it does not sufficiently comply with the Cochrane Handbook for Systematic Reviews of Intervention and the AMSTAR 2 tool. CONCLUSION: In view of the approaching release of a new guideline in the field of complementary therapies in oncology, the present statement draws attention to a lack of profound methodology of conductance of a recently released systematic review on mistletoe. In consequence, a comprehensive overview of published mistletoe studies, i.e., a meta-analysis with a sound methodology of conductance, is necessary.

Hapalindoles from the Cyanobacterium Hapalosiphon sp. Inhibit T Cell Proliferation.

Novel immunomodulating agents are currently sought after for the treatment of autoimmune diseases and cancers. In this context, a screening campaign of a collection of 575 cyanobacteria extracts for immunomodulatory effects has been conducted. The screening resulted in several active extracts. Here we report the results of subsequent studies on an extract from the cyanobacterium Hapalosiphon sp. CBT1235. We identified 5 hapalindoles as the compounds responsible for the observed immunomodulatory effect. These indole alkaloids are produced by several strains of the cyanobacterial family Hapalosiphonaceae. They are known for their anti-infective, cytotoxic, and other bioactivities. Modulation of the activity of human immune cells has not yet been described. The immunomodulatory activity of the hapalindoles was characterized in vitro using flow cytometry-based measurements of T cell proliferation after carboxyfluorescein diacetate succinimidyl ester staining, and apoptosis and necrosis induction after annexin V/propidium iodide staining. The most potent compound, hapalindole A, reduced T cell proliferation with an IC50 of 1.56 µM, while relevant levels of apoptosis were measurable only at 10-fold higher concentrations. Hapalindole A-formamide and hapalindole J-formamide, isolated for the first time from a natural source, had much lower activity than the nonformylated derivatives while, at the same time, being less selective for antiproliferative over apoptotic effects.

The impact of immunosuppression on postoperative graft function after graft-unrelated surgery: a retrospective controlled cohort study.

BACKGROUND: Physicians are faced with a growing number of patients after renal transplantation undergoing graft-unrelated surgery. So far, little is known about the postoperative restitution of graft function and the risk factors for a poor outcome. METHODS: One hundred one kidney transplant recipients undergoing graft-unrelated surgery between 2005 and 2015 were reviewed retrospectively. A risk analysis was performed and differences in creatinine, GFR and immunosuppressive treatment were evaluated. Additional, a comparison with a case-matched non-transplanted control group were performed. RESULTS: Preoperative creatinine averaged 1.88 mg / dl [0.62-5.22 mg / dl] and increased to 2.49 mg / dl [0.69-8.30 mg / dl] postoperatively. Acute kidney failure occurred in 18 patients and 14 patients had a permanent renal failure. Significant risk factors for the development of postoperative renal dysfunction were female gender, a preoperative creatinine above 2.0 mg / dl as well as a GFR below 40 ml / min and emergency surgery. Patients with tacrolimus and mycophenolate mofetil treatment showed a significant lower risk of renal dysfunction than patients with other immunosuppressants postoperatively. Contrary to that, the risk of patients with cyclosporine treatment was significantly increased. Transplanted patients showed a significantly increased rate of postoperative renal dysfunction. CONCLUSIONS: The choice of immunosuppressant might have an impact on graft function and survival of kidney transplant recipients after graft-unrelated surgery. Further investigations are needed.

Antitumor activity of an Artemisia annua herbal preparation and identification of active ingredients.

BACKGROUND: Artemisia annua L. has gained increasing attention for its anticancer activity. However, beside artemisinin, less is known about the possible bioactive ingredients of Artemisia annua and respective herbal preparations. We hypothesized that, in addition to artemisinin, Artemisia annua preparations might contain multiple ingredients with potential anticancer activity. METHODS: MDA-MB-231 triple negative human breast cancer (TNBC) cells along with other treatment resistant, metastatic cancer cell lines were used to investigate in vitro and in vivo the anticancer efficacy of an Artemisia annua extract marketed as a herbal preparation, which contained no detectable artemisinin (limit of detection = 0.2 ng/mg). The extract was characterized by HPLC-DAD and the most abundant compounds were identified by 1H- and 13C NMR spectroscopy and quantified by UHPLC-MS/MS. Cell viability and various apoptotic parameters were quantified by flow cytometry. In vitro data were validated in two in vivo cancer models, the chick chorioallantoic membrane (CAM) assay and in orthotopic breast cancer xenografts in nude mice. RESULTS: The Artemisia annua extract, the activity of which could be enhanced by acetonitrile maceration, inhibited the viability of breast (MDA-MB-231 and MCF-7), pancreas (MIA PaCa-2), prostate (PC-3), non-small cell lung cancer (A459) cells, whereas normal mammary epithelial cells, lymphocytes, and PBMC were relatively resistant to extract treatment. Likewise, the extract's most abundant ingredients, chrysosplenol D, arteannuin B, and casticin, but not arteannuic acid or 6,7-dimethoxycoumarin, inhibited the viability of MDA-MB-231 breast cancer cells. The extract induced accumulation of multinucleated cancer cells within 24 h of treatment, increased the number of cells in the S and G2/M phases of the cell cycle, followed by loss of mitochondrial membrane potential, caspase 3 activation, and formation of an apoptotic hypodiploid cell population. Further, the extract inhibited cancer cell proliferation, decreased tumor growth, and induced apoptosis in vivo in TNBC MDA-MB-231 xenografts grown on CAM as well as in nude mice. CONCLUSION: An extract of an artemisinin-deficient Artemisia annua herbal preparation exhibits potent anticancer activity against triple negative human breast cancer. New active ingredients of Artemisia annua extract with potential anticancer activity have been identified.

Surgical outcomes of renal transplant recipients after abdominal surgery not connected with transplantation. A retrospective case-control study.

BACKGROUND: Due to the increasing number of patients after kidney transplantation, elective and emergency surgery of transplanted patients is becoming a relevant challenge in clinical routine. The current data on complication rate of patients after kidney transplantation, which must undergo another elective or emergency abdominal surgery, is inhomogeneous. Therefore, the aim of our study was to evaluate the outcome of renal transplant patients undergoing abdominal and abdominal wall surgery. MATERIAL AND METHODS: We performed an observational study of patients after kidney transplantation undergoing graft-unrelated abdominal surgery between 2005 and 2015. We randomly created a non-transplanted control for a case-matched controlled analysis. Primary endpoint was the comparison of complication rate. Secondary, a risk analysis of all patients was performed and differences in mortality, length of hospital stay and reoperation rates were calculated. RESULTS: Overall 101 kidney transplanted patients were eligible for inclusion. 20 (19.8%) died after graft-unrelated surgery and 60 (59.4%) suffered from postoperative complications. Case-matched analysis could be performed for 84 out of these 101 patients. We found no significant difference in morbidity rate (58.3% vs. 45.2%, p = 0.090). Transplanted patients had, however, a significantly higher mortality (19% vs. 2.4%, p = 0.001), a longer hospital stay (28.2 vs. 16.9 days, p = 0.020) and a higher rate of re-operations (38.1% vs. 20.2%, p = 0.017). . CONCLUSIONS: Patients after renal transplantation undergoing graft-unrelated abdominal surgery have a significantly increased mortality risk, are more frequently re-operated and have to stay significantly longer in hospital than non-transplanted patients.

Durable clinical remission of a skull metastasis under intralesional Viscum album extract therapy: Case report.

BACKGROUND: Skull metastases are rare, they can eventually cause pain, and can invade the brain. Viscum album extracts (VAEs) are used as an adjuvant treatment in cancer. METHODS AND RESULTS: A 68-year-old patient with rectal cancer presented with lung metastases, and metastases to multiple bone sites, the chest wall, and the liver were later identified. Histological examination of one of the bone lesions revealed an additional thyroid carcinoma. An osteolytic parietal bone lesion progressed to a painful metastasis of the skull despite radiotherapy and chemotherapy. The VAEs were applied weekly into the metastasis, followed by pain relief and softening of the lesion. The lesion partially regressed (>50%) after 8 months of continued VAE treatment and remained stable for 2 years. CONCLUSION: This case shows a durable clinical remission of a skull metastasis under VAE. Further investigations of intratumoral VAE treatment seem worthwhile-especially in symptomatic skull metastases not responding to radiotherapy or systemic therapies.