Objectives/Hypothesis: Superficial parotidectomy dramatically reduced the high rates of tumor recurrence that occurred with simple enucleation of parotid pleomorphic adenoma (PPA). However, there is not agreement in the medical literature confirming the exact margin of parotid tissue to be resected to avoid recurrence. Worldwide, SP and/or partial superficial parotidectomy (PSP) is commonly practiced for the treatment of PPA. In Europe and Asia, reports covering a spectrum from total parotidectomy (TP) to extracapsular dissection (ECD) are common. The outcomes (capsular exposure, tumor-facial nerve interface, capsular rupture, recurrence, facial nerve dysfunction, and Frey syndrome) from surgical treatment of mobile, superficial PPA smaller than 4 cm are not significantly altered by surgical approach (TP, PSP, or ECD). Study Design: Retrospective series of pathological specimens were correlated with their clinical outcomes to compare TP, PSP, and ECD. Historical data review and meta-analysis were also performed. Methods: Matched pairs of 60 pathological specimens of PPA (20 cases treated by TP, PSP, and ECD, respectively) were compared for capsular exposure and the degree of cellularity of tumors. Statistical analysis of the respective rates of tumor-facial nerve interface, capsular rupture, recurrence, permanent and transient facial nerve dysfunction, and Frey syndrome was performed. Results: Focal capsular exposure occurs in virtually all parotid surgery for PPA, regardless of the type of operation (margin). Dissecting PPA from the facial nerve led to a positive margin in 25% of cases. Capsular rupture does result in a significantly higher rate of recurrence and did not vary among surgical approaches (TP, PSP, and ECD). Tumor-facial nerve interface did not vary significantly by surgical approach. A less complete parotidectomy did not result in a higher rate of recurrence. Less parotid tissue sacrifice did not result in a lower rate of permanent facial nerve dysfunction, although it did result in significantly less transient facial nerve dysfunction and Frey syndrome. Hypocellular tumors did not have a higher incidence of capsular rupture or recurrence. Multicentric PPA was not identified in the clinically negative deep lobe for TP specimens. The most common cause of recurrence for PPA today is enucleation. Conclusions: The major outcomes of surgical treatment for small PPA (capsular exposure, tumor-facial nerve interface, capsular rupture, recurrence, and permanent facial nerve dysfunction) are not significantly altered by the amount of parotid tissue sacrifice (TP, PSP, or ECD). More complete parotidectomy results in higher rates of transient facial nerve dysfunction and Frey syndrome. Focal capsular exposure occurs in virtually all cases of parotid surgery for PPA. Dissecting PPA from the facial nerve results in cases with positive margins because of incomplete capsule or perforating pseudopodia. Few separations of pseudopodia from the main tumor occur with expertly performed contemporary parotid surgery because most of the PPA has a margin of normal parotid tissue. Minimal margin surgery in ECD is not recommended.

The significance of the margin in parotid surgery for pleomorphic adenoma.

Breast cancer is among the most frequent types of cancer in women worldwide. Current conventional treatment options are accompanied by side effects. Mistletoe is amongst the important herbal medicines traditionally used as complementary remedies. An increasing number of studies have reported anticancer activity of mistletoe extracts on breast cancer cells and animal models. Some recent evidence suggests that cytotoxic activity of mistletoe may be mediated through different mechanisms. These findings provide a good base for clinical trials. Various studies on mistletoe therapy for breast cancer patients revealed similar findings concerning possible benefits on survival time, health-related quality of life (HRQoL), remission rate, and alleviating adverse reactions to conventional therapy. This review provides an overview of the recent findings on preclinical experiments and clinical trials of mistletoe for its cytotoxic and antitumor activity and its effect on HRQoL in breast cancer patients. Moreover, studies investigating molecular and cellular mechanisms underlying antitumor activity of mistletoe are discussed in this paper. The analyzed trials provided evidence that there might be a combination of pharmacological and motivational aspects mediated by the mistletoe extract application which may contribute to the clinical benefit and positive outcome such as improved HRQoL and self-regulation in breast cancer patients.

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Preclinical and Clinical Effects of Mistletoe against Breast Cancer

An old goal of natural complementary medical therapy has been to aim at a long-term stimulation of natural resistance in order to restrain cancer progression or improve defective immunological conditions without toxic side effects. Mistletoe extracts were applied to a large number of cancer patients because of their modulatory effect on the natural immune system. By carefully removing lectins, an essential group of components, from mistletoe extracts, a significant reduction of their effectiveness on several cellular immune parameters could be observed in vivo (1). That is the reason why, for the last 14 years, biological research of mistletoe extracts has focused on lectins. Meanwhile, the quantitatively dominant lectin, Viscum album agglutinin (VAA)-I has become available in a recombinant form (rVAA). Other constitiuents of plant extracts such as viscotoxins (2,3), poly- and oligosaccharides (4), flavonoids (5,6), chitin-binding mistletoe lectin (7) and arginine have also been investigated in connection with the effects of mistletoe extracts on the host defense. However, little evidence has been found that these substances contribute to the effects of mistletoe in vivo (8).

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Oncopharmacological Perspectives of a Plant Lectin (Viscum album Agglutinin-I): Overview of Recent Results from In vitro Experiments and In vivo Animal Models, and Their Possible Relevance for Clinical Applications.

Viscum album L. or European mistletoe (Loranthaceae), a semi-parasitic shrub, has been used as a traditional medicine in Europe for centuries to treat various diseases like cancer, cardiovascular disorder, epilepsy, infertility, hypertension and arthritis. V. album contains diverse phytochemicals, which exert a large number of biological and pharmacological activities. The aim of this review is to compile the developments in the domain of V. album and research trends, with a focus on ethnopharmacology, phytochemistry and pharmacological properties, to illustrate the potential of this phytotherapeutic as an attractive commercial herbal medicine. Crude extracts and isolated chemical constituents from V. album have exhibited significant medicinal effects in experimental models and in patients with cancer, autoimmune and inflammatory conditions. Importantly, recent randomized clinical trials have suggested improved overall survival and quality of life in cancer patients treated with different mistletoe preparations. The current phytochemical studies have shown that lectins, hetero-dimeric glycoproteins, polysaccharides, viscotoxins, alkaloids, lipids, triterpenes, peptides, vesicles, flavonoids, cyclitols and amines are principal bioactive phytochemicals of V. album. Clinical studies and experimental models have revealed that V. album exhibits several pharmacological functions such as immunomodulatory, anti-hypertensive, anti-oxidant, cytotoxicity, anti-tumor, anti-inflammation, anti-diabetic, anti-microbial and sedative activities. It is conceivable that the heterogenous profile of biochemical compounds provides the basis for the broad diversity of pharmacological activities of mistletoe, as each single component contributes diverse modes of action in addition to imparting a synergistic beneficial action in conjunction with other molecules.

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European Viscum album: a potent phytotherapeutic agent with multifarious phytochemicals, pharmacological properties and clinical evidence

Background and Objectives: Mistletoe preparations, which are widely used among patients with cancer in Germany, have immunomodulating properties in vitro and in vivo. The aim of this evaluation was to determine and compare the effects of a lectin-rich (Iscador Qu [IQ] special, Weleda Company, Schwabisch, Gmund, Germany.) and a lectin-poor but viscotoxin-rich (Iscador Pini [IP] Weleda Company) mistletoe preparation on clinical and hematologic parameters in healthy subjects. Design: In a double-blinded study, 48 volunteers were randomized to one of three groups: 16 received IQ or IP in increasing doses or placebo twice per week subcutaneously for 12 weeks. The differential blood count and the acute phase markers haptoglobin and C-reactive protein were examined weekly and the symptoms were scored using standardized questionnaires. Results: IQ resulted in significant eosinophilia (315 ± 109) beginning at week 5 (until week 12) compared to IP (183 ± 120) or placebo (200 ± 179). Furthermore, the acute phase mar...

Effects of a lectin- and a viscotoxin-rich mistletoe preparation on clinical and hematologic parameters: a placebo-controlled evaluation in healthy subjects.

The influence of galactoside-specific mistletoe lectin (ML-1) administration on defined acute phase reactants in the serum of cancer patients (mammary carcinoma, n = 4; larynx carcinoma, n = 11; TNM-stages II to IV; after appropriate surgery, chemotherapy, radiation) was studied. Regular subcutaneous injections of the optimal doses of ML-1 (1 mg/kg body weight, twice a week) yielded statistically significant increases of certain acute phase reactants (C-reactive protein, haptoglobin, coeruloplasmin, C3-complement, albumin, immunoglobulin IgM) after four weeks of treatment. However, serum concentrations of transferrin, C4-complement and the immunoglobulins IgG and IgA were found within the biological range (means +/- 2 s). The increase of acute phase reactants after administration of ML-1 correlates positively with the activity of lymphatic cells (e.g. expression of IL-2 and HLA-DR receptors) in FACS (fluorescence-activated cell sorter) staining experiments and indicates the immunoreactive potency of this substance which may be speculated to be cytokine-induced.

Effect of mistletoe lectin therapy on serum level of defined serum proteins (acute phase proteins) in tumor patients

Will neoadjuvant chemotherapy affect the capacity of head and neck squamous cell carcinoma to bind neoglycoproteins

Recognition of the carbohydrate part of cellular glycoconjugates by sugar receptors like lectins may contribute to biosignaling and interactions between normal and transformed cells. Such recognitions may be essential for establishing phenotypic characteristics in neoplastic cells, including metastasis-associated properties. To evaluate various glycoconjugates in tumor diagnosis and clinical therapy, a panel of 18 biotinylated neoglycoproteins was prepared. This included conjugates of a histochemically inert carrier protein and crucial sugar moieties such as D-glucuronic acid, alpha- and beta-N-acetyl-galactosamine, beta-N-acetyl-glucosamine, melibiose, lactose, maltose, cellobiose, mannose, mannose-6-phosphate, fucose, rhamnose, and xylose. In so doing the diazo derivative of the respective p-aminophenyl glycosides was coupled with galactose, beta-N-acetyl-galactosamine or beta-N-acetyl-glucosamine via an epoxy group-containing aliphatic spacer. Other glycoconjugates used were the proteoglycan heparin and the sulfated fucan fucoidan. Labeling was effected with cyanogen bromide activation and aminoalkylation for specific detection of endogeneous sugar receptors, especially lectins. Tissues studied were paraformaldehyde-fixed, paraffin-embedded surgical biopsies from patients with different stages of squamous cell carcinomas (SCCs) of the oral cavity (n = 16) and oropharynx (n = 17), including three lymph node metastases from oropharyngeal primary tumors. Semiquantitative binding differences of probes to tumor stages were evaluated statistically by the Mann-Whitney U-Wilcoxon rank sum W test. Specific binding of a probe to cytoplasmic and nuclear structures was detected with apparent quantitative differences. Overall, the cytoplasmic compartment revealed a higher intensity of histochemical reaction than did nuclear structures, indicating a comparatively higher density of specific carbohydrate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of sugar receptor expression by neoglycoproteins in oral and oropharyngeal squamous cell carcinomas.

Are differences in the expression of carbohydrate-binding sites (endogenous lectins) responsible for recurrences of benign tumours of the parotid gland?

Michael Steuer

Papers

Effect of mistletoe lectin therapy on serum level of defined serum proteins (acute phase proteins) in tumor patients

Will neoadjuvant chemotherapy affect the capacity of head and neck squamous cell carcinoma to bind neoglycoproteins

Characterization of sugar receptor expression by neoglycoproteins in oral and oropharyngeal squamous cell carcinomas.

Are differences in the expression of carbohydrate-binding sites (endogenous lectins) responsible for recurrences of benign tumours of the parotid gland?