Impact of complementary treatment of breast cancer patients with standardized mistletoe extract during aftercare: a controlled multicenter comparative epidemiological cohort study.

OBJECTIVES: To investigate the safety and efficacy of complementary treatment of breast cancer patients with the standardized mistletoe extract (sME) HELIXOR in routine practice during aftercare through a multicenter comparative epidemiological cohort study with 53 randomly selected hospitals/practices representatively distributed in Germany, including oncologists, gynaecologists and general practitioners. PATIENTS AND METHODS: Data from 741 screened patients fulfilling the inclusion/exclusion criteria were checked. Of these, 681 patients were eligible for the final analysis of the study group (with sME n = 167) and the control group (n = 514). Efficacy (development of disease/therapy-induced signs and symptoms; quality of life) and safety (number and severity of adverse events) of complementary treatment in breast cancer patients treated with sME in the aftercare period were determined. RESULTS: Complementary treatment of breast cancer patients with sME during the aftercare period of approximately 5 years after terminating recommended standard therapies resulted in significantly fewer (p < 0.001) complaints of patients (56.3% study group versus 70.0% control group). The reduced number of disease/therapy-related sign/symptoms (e.g. mucositis, fatigue, pain, headache) correlated to a significantly improved quality of life. Adverse drug reactions to the sME treatment were mostly mild and self limiting. CONCLUSION: Complementary treatment with the sME HELIXOR proved to be beneficial for breast cancer patients since it significantly improved quality of life and significantly reduced persistant signs/symptoms of the disease/treatment during the validated aftercare period of approximately five years.

Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model.

The cytotoxic in vitro activity of standardized mistletoe extracts (ME) was examined by established assays towards the human ductal breast carcinoma cell line BT474. A dose-dependent (optimum 25 mg/mL medium) and significantly (p < 0.05) enhanced cytotoxic activity towards the BT474 cells was demonstrated. In vivo experiments on the antitumor activity of ME-A and ME-M were performed in a BALB/c-mouse / BT474 ductal breast carcinoma model. ME-A and ME-M were intratumorally administered according to an application schedule which was found to be optimal concerning dosage and time of administration. Standardized intratumoral application of ME-A and ME-M induced a significantly (p < 0.05) decreased tumor weight in experimental mice. Histological investigations were performed comprising analysis of mitosis and proliferation rates (Ki67 expression), as well as necrosis and apoptosis induction (ssDNA detection). As compared to tumors of control mice with intratumoral phosphate-buffered saline (PBS) injections, tumors of the ME-A and ME-M treated groups showed a decreased cell proliferation rate, as well as an increased cell necrosis and apoptosis rate. Standardized mistletoe extracts, interfering with defined tumor cell functions, e.g., proliferation, necrosis and apoptosis, may have an impact on local cancer treatment.

Local administration of TGF-beta1 to reinforce the anterior abdominal wall in a rat model of incisional hernia.

The purpose of this study was to investigate different forms of the local application of TGF-beta(1) for augmentation of the anterior abdominal wall in an appropriate model of an incisional hernia. Sixty male Sprague-Dawley rats were divided into six groups. Artificial defects of the anterior abdominal wall were closed with one of the following methods: running Prolene suture, Vicryl mesh, prolene suture followed by an intramuscular injection of 1 mug TGF-beta(1), Vicryl mesh coated with 1 mug TGF-beta(1), and prolene suture coated with 1 mug TGF-beta(1). A control group did not receive any defect and treatment. Six weeks after operation, tensile strength, collagen content, gene expression of collagen I and III, blood vessels, and thickness of collagen fibres were evaluated. Tensile strength was strongest in the controls (14.2 (10.5-18 N)). There was no increase in tensile strength due to the administration of TGF-beta(1). On the contrary, bolus injection of the growth factor resulted in a significantly decreased strength of the wound tissue when compared to the groups 1, 4, 5, and 6 (9.1 (4.2-9.1 N)). These results correlated with the gene expression of collagen I and III. Local application of TGF-beta(1) did not augment the strength of the abdominal wall after 6 weeks.

Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth.

The dental follicle is an ectomesenchymal tissue surrounding the developing tooth germ. It is believed that this tissue contains stem cells and lineage committed progenitor cells or precursor cells (PCs) for cementoblasts, periodontal ligament cells, and osteoblasts. In this study, we report the isolation of PCs derived from dental follicle of human third molar teeth. These fibroblast-like, colony forming and plastic adherent cells expressed putative stem cell markers Notch-1 and Nestin. We compared gene expressions of PCs, human mesenchymal stem cells (hMSCs), periodontal ligament cells (PDL-cells) and osteoblasts (MG63) for delimitation of PCs. Interestingly, PCs expressed higher amounts of insulin-like growth factor-2 (IGF-2) transcripts than hMSCs. Differentiation capacity was demonstrated under in vitro conditions for PCs. Long-term cultures with dexamethasone produced compact calcified nodules or appeared as plain membrane structures of different dimensions consisting of a connective tissue like matrix encapsulated by a mesothelium-like cellular structure. PCs differentially express osteocalcin (OCN) and bone sialoprotein (BS) after transplantation in immunocompromised mice but without any sign of cementum or bone formation. Therefore, our results demonstrate that cultured PCs are unique undifferentiated lineage committed cells residing in the periodontium prior or during tooth eruption.

[Is implant removal after percutaneous iliosacral screw fixation of unstable posterior pelvic ring disruptions indicated?]. / Ist die Entfernung des Osteosynthesematerials nach perkutaner iliosakraler Verschraubung bei iliosakraler Sprengung oder Sakrumfraktur indiziert?

The aim of this study was to examine the indication for implant removal (IR) after percutaneous iliosacral screw fixation of unstable posterior pelvic ring disruptions by systematic literature analysis and clinical follow-up examination. Retrospective identification revealed 27 operatively stabilized patients [12 females, mean age: 35 years, ISS 22 points (range: 14-37)] between January 1996 and July 2001. Patient characteristics, AO classification, Hannover fracture scale pelvis, ISS, and DGU pelvis score points were analyzed. All cases showed a C-type lesion (C1:67%, C2:33%). A total of 21 patients were seen at follow-up, 12 with and 9 without IR. In ten cases with IR, clinical outcome improved after surgery according to the DGU pelvis score ( p=0.001, Wilcoxon's test). These mostly young patients also showed a better outcome compared with those cases without IR. Due to the good clinical results, implant removal seems to be beneficial for selected individual patients, especially when pain is present.

[Special aspects of implant-associated infection in orthopedic surgery. From the pathophysiology to custom-tailored prevention strategies]. / Besonderheiten der implantatassoziierten Infektion in der orthopädischen Chirurgie. Von der Pathophysiologie zu massgeschneiderten Präventionsstrategien.

One of the most important risk factors in orthopedic surgery is implant-associated infection. Adhesion and colonization mediated implant infections are extremely resistant to antibiotics and host defences and frequently persist until the biomaterial or foreign body is removed, which is standard therapy. Tissue damage caused by surgery and foreign body implantation increases the susceptibility to infections, activates host defences and stimulates the generation of inflammatory mediators including radicals that are further aggravated by bacterial activity and toxins. Nearly one third of implant-related infections can be prevented by strictly following established infection control guidelines. However, a significant number of implant-associated infections remains. The escape of bacteria from host defence and antibiotic therapy makes the development of infection-resistant materials as anti-microbial drug delivery systems feasible. This concept consists of the sustained delivery of antimicrobial drugs into the local microenvironment of implants avoiding systemic side effects exceeding usual systemic concentrations by magnitudes of order.

[Psoas abscesses. Genesis, diagnosis, and therapy]. / Psoasabszesse. Entstehung, Diagnostik, Therapie.

BACKGROUND: A psoas abscess is a rarely encountered entity with various etiologies and nonspecific clinical presentation, frequently resulting in delayed diagnosis, increased morbidity, and prolonged or recurrent hospitalization. PATIENTS AND METHODS: Between January 1996 and January 2002 we treated ten patients (approximately 54.8, 5 males,5 females). These cases were analyzed retrospectively relative to a review of the literature. RESULTS: CT scanning was decisive in the final diagnosis of psoas abscess. Primary psoas abscess occurred in four cases and six patients had secondary abscesses. In all except one case, the psoas abscess was located on the right side. The causes of primary abscesses were retroperitoneal perforated appendicitis, paravertebral injections for lumboischialgia, Pott's disease, and repeated intravenous drug application in the groin. Five patients underwent retroperitoneal open drainage and four patients CT-guided drainage. One patient with retroperitoneal perforated appendicitis was treated by laparotomy. Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli were the most common infective agents. There was no postoperative mortality and no cases of abscess recurred. CONCLUSIONS: CT scan is a diagnostic "gold standard" for psoas abscess. CT-guided drainage is the method of first choice, but is not possible in all cases. Open retroperitoneal drainage is a standard method of treatment. Postoperative antibiotic therapy is obligatory and should be adapted individually.

Port function after laparoscopic adjustable gastric banding for morbid obesity.

BACKGROUND: Laparoscopic adjustable gastric banding (LGB) has gained wide popularity, but information on port function is limited. METHODS: In a prospective nonrandomized study, we analyzed port function and related symptoms in 50 consecutive patients with severe obesity. All patients underwent LGP in a five trocar technique. In 11 patients, the port was placed subcutaneously in the subxiphoid region. In 39 patients, the port was implanted in the left upper abdomen. Mean duration of follow-up was 2.8 years. RESULTS: Patients (12 males and 38 females) had an initial body mass index (BMI) of 47.1 kg/m2. Puncturing the subxiphoidal port was without problems in all 11 patients. However, seven women reported pain and inconvenience when wearing a brassiere. Two underwent port reimplantation in the left upper abdomen (one due to infection; one due to pain). Among the 39 patients with abdominal port implantation, nine patients required port correction (two of them twice). The causes were port dislocation (four cases), difficult puncturing (three), tube leakage (three), and infection (one). CONCLUSION: The high number of complications suggests that the port is the Achilles' heel of LGB. Ports at the subxiphoid site were easier to puncture, but frequently caused pain in female patients.

Pharmacokinetics of the antimicrobial agents rifampicin and miconazole released from a loaded central venous catheter.

The time course of rifampicin and miconazole concentrations after insertion of a polyurethane catheter loaded with these antibiotics were studied. Data from controlled release experiments in vitro were used, and the concentration time courses of the antimicrobials in serum were calculated by pharmacokinetic simulations. Systemic therapy using typical dosages (rifampicin 600 mg/day iv, miconazole 3 x 200 mg/day iv) results in rifampicin concentrations between 54 and 8424 microg/L, and miconazole concentrations between 3567 and 4676 microg/L. After insertion of a polyurethane catheter loaded with these antibiotics, the maximal concentrations after catheter placement were determined as 6 microg/L at 10.7h for rifampicin, and 13 microg/L at 28.6 h for miconazole. Assuming that the total amount of antibiotics incorporated in the catheter matrix were bioavailable ('worst case'), the resulting maximal concentrations calculated by simulation are 10 microg/L for rifampicin and 65 microg/L for miconazole. Maximal concentrations of rifampicin or miconazole resulting from the insertion of a polyurethane catheter loaded with these antibiotics are, therefore, far below the concentrations resulting from a systemic therapy with the same antimicrobial agents. Even in the worst case, the danger of selecting resistant bacterial strains seems remote because the systemic drug levels are magnitudes of order below subinhibitory concentrations.

Standardized mistletoe extract augments immune response and down-regulates local and metastatic tumor growth in murine models.

The immunomodulatory and antimetastatic activity of standardized aqueous mistletoe extract (sME) was evaluated in BALB/c-mice. Regular subcutaneous (s.c.) applications (three times per week for 14 consecutive days; 2, 20, 100 and 500 micrograms per injection and mouse) up-regulated thymocyte and peripheral blood leukocyte counts in tumor-bearing mice. Tumor weight and tumor volume were significantly down-regulated after application of sME doses greater than 20 micrograms per injection. To check the influence of sME treatment on growth of experimental metastases, RAW 117 H 10 lymphosarcoma cells and L-1 sarcoma cells were intravenously inoculated into BALB/c-mice to establish liver and lung colonization, respectively. sME was regularly administered starting 24 hours after tumor cell challenge. Organ colonization was investigated on day 14 after tumor cell inoculation and demonstrated statistically significant (p < 0.05) reductions of experimental liver and lung metastases for sME-treated mice.

Application-dependent immunomodulating and antimetastatic efficacy of thymic peptides in BALB/c-mice.

The immunomodulating and antimetastatic activity of clinically approved, low molecular weight, standardized thymic peptide (TP) preparations was evaluated in BALB/c-mice. Daily applications (subcutaneously, s.c.; intraperitoneally, i.p.; intramusculary, i.m.) of two commercially available TP preparations (7 consecutive days, 10, 50 and 100 micrograms per mouse and injection) up-regulated the thymus weight and thymocyte counts as well as peripheral blood leukocyte and lymphocyte counts in liver metastases-bearing mice. The immunomodulating activity of TP application was most pronounced and statistically significant for thymus weight and counts of thymocytes, leukocytes and lymphocytes after s.c. administration of both TP preparations and concentrations. I.p. and i.m. TP-injections were less effective at reaching statistical significance, however, for defined dosages and parameters, only. To evaluate the influence of TP on experimental liver metastases, RAW 117 lymphosarcoma cells were intravenously inoculated into BALB/c-mice. TP (10, 50, 100 micrograms/mouse) were s.c., i.p. and i.m. administered daily for 7 consecutive days starting 24 hours after tumor cell challenge. Liver colonization was investigated on day 14 after tumor cell inoculation and demonstrated a statistically significant (p < 0.05) reduction of experimental liver metastases for s.c. (both preparations and concentrations) as well as i.p. and i.m. (dose-dependent) TP-treated mice.

In vitro adherence and accumulation of Staphylococcus epidermidis RP 62 A and Staphylococcus epidermidis M7 on four different bone cements.

Bacterial resistance of Staphylococcus epidermidis, a serious pathogen of implant-related infections, to antibiotics is related to the production of a glycocalyx slime that impairs antibiotic access and the killing by host defense mechanisms. In vitro studies of different bone cements containing antibiotics, developed for the prevention of biomaterial-associated infection, could not always demonstrate complete eradication of biomaterial-adherent bacteria. We have investigated four different bone cements in regard to bacterial accumulation of a slime-producing strain RP 62 A and its isogenic mutant M7 lacking the ability to produce exopolysaccharide slime using a bacterial adhesion assay and modified Kirby-Bauer technique. A significant effect of exopolysaccharide production for the accumulation on bone cement could be demonstrated. The gentamicin/clindamycin bone cement was the only tested biomaterial that produced a large zone of bacterial inhibition in the inoculated area adjacent to the biomaterial. The bacterial adhesion was not reduced significantly and there was no correlation between zones of inhibition on blood agar plates and the quantitative adhesion assay. The clinical efficacy of the gentamicin/clindamycin bone cement must be proven in vivo.

Implant infections: a haven for opportunistic bacteria.

The insertion of implants and medical devices has emerged as a common and often life-saving procedure. A current estimate of the rate of total hip replacement in the world is approximately one million a year, and knee replacements more than 250000. More than 30% of hospitalized patients have one or more vascular catheters in place. More than 10% of hospitalized patients have an indwelling urinary catheter. Some patients require multiple joint replacements. In the United States, approximately 2 million nosocomial infections cost nearly $11 billion annually. Exposure to invasive medical devices is one of the most important risk factors.(1)Devices predispose to infection by damaging or invading epithelial or mucosal barriers and by supporting growth of micro-organisms, thus serving as reservoirs. Invasive medical devices impair host defence mechanisms and, when contaminated, can result in resistant chronic infection or tissue necrosis, the major objections to extended use of implant devices. Implant devices today account for approximately 45% of all nosocomial infections.(2)Implant infections are extremely resistant to antibiotics and host defences and frequently persist until the implant is removed, which is the standard therapy. Tissue damage caused by surgery and foreign body implantation further increases the susceptibility to infections, activates host defences and stimulates the generation of inflammatory mediators; these are enhanced by bacterial activity and toxins.(3)The ability of bacteria such as Staphylococcus epidermidis, which are otherwise virtually avirulent, to escape from host defences and antibiotic therapy, has led to the development of alternative methods of control such as infection-resistant materials acting as antimicrobial drug-delivery systems. By these methods, there is a sustained delivery of antimicrobial drugs into the local micro-environment of implants, which avoids systemic side-effects and exceeds usual systemic concentrations by several orders of magnitude. Bioengineering of hybrid implant materials in order to achieve optimal performance and to prevent inflammatory reactions and interface cellular disorganization is a field undergoing rapid development. Hybrid materials that slowly deliver antimicrobial drugs may reduce implant infections in the future.

Application of standardized mistletoe extracts augment immune response and down regulates metastatic organ colonization in murine models.

The immunomodulatory and antimetastatic activity of standardized aqueous mistletoe extracts from plants grown on fir trees (ME-A) and pine trees (ME-P) were evaluated in BALB/c-mice. Regular subcutaneous (s.c.) and intraperitoneal (i.p.) applications (three times per week for 14 consecutive days; 5 and 50 microg per injection and mouse) upregulated thymus weight and peripheral blood leukocyte counts in tumor bearing mice. To check the influence of ME-A and ME-P treatment on growth of experimental metastases, RAW 117 H 10 lymphosarcoma cells and L-1 sarcoma cells were intravenously inoculated into BALB/c-mice to establish liver and lung colonization. ME-A and ME-P were regularly administered starting 24 h after tumor cell challenge. Organ colonization was investigated on day 14 after tumor cell inoculation and demonstrated statistically significant (P<0.05) reductions of experimental liver and lung metastases for ME-A and ME-P treated mice.

Treatment of staphylococcal implant infection with rifampicin-ciprofloxacin in stable implants.

Infection following total joint replacement remains a problem that has not been solved so far. The treatment options include removal of the implant and a delayed reconstruction or a direct exchange operation. Among patients with stable implants and short duration of infection as well as in patients who for certain reasons are inoperable, antibiotic therapy with a combination of rifampicin-ciprofloxacin may be a reasonable treatment option for curing staphyloccocal infection without removal of the implant. A case study of a Staphylococcus epidermidis (coagulase-negative) infection following delayed revision total knee replacement after septic loosening of a knee arthroplasty and its successful conservative treatment with rifampicin-ciprofloxacin is described. Alternative rifampicin combinations are discussed with respect to recently developed pharmacodynamical and pharmacokinetical findings of biofilm active drugs.

Studies on the role of superoxide anion radicals for the cardiotoxicity of adrenochrome.

Adrenochrome is an oxidative product of adrenaline and possesses cardiotoxic properties. As oxygen free radicals play a role in the cytotoxic effects of catecholamines, the role of superoxide anion radicals, as mediators of adrenochrome toxicity, was investigated using electrically-driven Langendorff rabbit hearts with depleted catecholamine stores. Repetitive regional myocardial ischemia (MI) was induced by coronary artery branch ligature, and MI was quantitated from epicardial NADH-fluorescence photography. Adrenochrome (10(-6) mol/l) was added to the perfusion solution after a reperfusion period of 20 min, 30 min before the 2nd coronary occlusion, with or without the additional application of SOD (30 U/ml). Left ventricular pressure was significantly enhanced by adrenochrome (p < 0.05), but it fell rapidly down below its initial value (p < 0.05). Coronary flow was significantly decreased by adrenochrome (p < 0.05). Whereas epicardial NADH-fluorescence was similar after repetitive coronary occlusions in untreated controls, it was significantly enhanced by adrenochrome (p < 0.05). The deleterious effects of adrenochrome on MI were not inhibited by SOD. Thus, there is no evidence for superoxide anion radicals as mediators of the deleterious effects of adrenochrome on MI in isolated rabbit hearts. The deleterious effects of adrenochrome on MI in isolated rabbit hearts might be caused by functional effects, impairing the oxygen consumption/oxygen supply balance.

Studies of the toxic effects of norepinephrine on isolated cardiomyocytes of guinea-pigs.

Catecholamines have been demonstrated to possess direct cardiotoxic effects mediated by oxygen free radicals in isolated organ preparations. In order to assess direct cytotoxic properties, the influence of exogenous noradrenaline (norepinephrine, CAS 51-41-2) (10(-6) mol/l) on isolated guinea-pigs cardiomyocytes was examined, in the presence of propranolol (10(-6) mol/l) and phentolamine (10(-6) mol/l) to inhibit adrenoceptor-mediated effects. Cell viability was assessed by morphologic examination (% of striated, rod-shaped cells), before and after a treatment period of 15 and 60 min by the measurement of intracellular enzyme activities in the supernatant of the suspension (lactate dehydrogenase, creatine kinase, aspartate aminotransferase, alanine aminotransferase, glutamate dehydrogenase). The proportion of viable, rod-shaped cardiomyocytes (21.6% +/- 7.6% after preparation, before starting the treatments) significantly decreased over the experimental time (p < 0.05) and, concomitantly, the activity of intracellular enzymes in the supernatant increased. There was no difference between controls and treated suspensions. Thus, there is no evidence for direct toxic effects of norepinephrine in micromolar concentration on isolated cardiomyocytes of guinea-pigs. However, cytoprotective effects by propranolol and/or phentolamine cannot be excluded in this model.

Novel strategies to prevent catheter-associated infections in oncology patients.

Aggressive cytotoxic treatment of cancer contributes to the growing number of life-threatening infections. Vascular catheters create predominant risks for staphylococcal, enterococcal and candida blood stream infections. Although the contaminating microorganisms may be few in number, the altered host immune response in the presence of such implants as well as disease-associated immunosuppression implies that even small bacterial counts have to be regarded as highly virulent species. Diagnosis of catheter-related infection (CRI) remains difficult before withdrawal of the suspected catheter. Positive culture of catheter surface, lumen and hub and positive peripheral blood probes (paired quantitative blood culture) are predictive for catheter related bacteremia (CRB). Diligent catheter care and effective antimicrobial catheters may reduce prolonged hospital stay, increased morbidity or mortality and serious economical consequences. The most promising approach features the incorporation of antimicrobial drugs into the polymer matrices that entrap but do not bind the drugs, allowing for extended release. For the efficacious prevention of colonization in the microenvironment of the implantable device the concentration of the antimicrobial substances must exceed usual antibiotic concentrations by a thousand-fold. This is the desired effect--high concentration near the device surface and very low systemic concentration. Incorporation of antimicrobials in the bulk material that constitutes a device can be effective as shown in several in vitro and in vivo studies. In the future, modification of both short-term and long-term catheters by biofilm-active antimicrobials creating slow delivery systems may provide an effective method to protect patients from nosocomial infection in oncology.