Medizin - Open Access LMU - Teil 15/22 Archiv

The revised 11th edition of the Manual of Recommendations for the Diagnosis, Therapy, and Follow-Up of Patients with Breast Cancer of the publications series of the Tumor Center Munich (Tumorzentrum Munchen, TZM) is an excellent example of a regional hands-on publication which, while based on national and international guidelines, does not replace these. By virtue of countless additions and revisions in the course of 10 editions, the `blue tumor manual for breast cancer' has matured into a hands-on reference work which throughout Germany has found its place on the desks of physicians, and has thus gained a reputation reaching far beyond the TZM. The reputation of this manual is on the one hand founded on the professional competence of the individual authors and project group members. The great strength of the project group, however, surely lies in the broad spectrum of expertise of more than 180 experts of all kinds of specialties, whose continuing interdisciplinary exchange in the course of the present revision has again led to a result which is arousing interest far beyond Munich. This article summarizes some of the TZM project group's own positions on data collection, prevention, adjuvant systemic therapy, and follow-up treatment in an exemplary fashion.

Breast cancer-associated mortality has been significantly reduced since the 1990s, mainly because of early diagnosis and systemic therapeutic interventions. All three therapy components-cytostatic therapy, endocrine therapy and targeted antibody therapy-are at present necessary tools for the curative treatment of primary breast cancer. This article reviews the evidence base for the use of various chemotherapy schedules in patients with primary, node-positive breast cancer, including schedules in combination with targeted HER2/neu therapy.

Background: Folic acid plays a fundamental role in cell division and differentiation. Docosahexaenoic acid (DHA) has been associated with infantile neurological and cognitive development. Thus, optimal intrauterine development and growth requires adequate supply of these nutrients during pregnancy. Methods: Healthy pregnant women, aged 18-41 years, were recruited in Granada (Spain; n = 62), Munich (Germany; n = 97) and Pecs (Hungary; n = 152). We estimated dietary DHA and folate intake in weeks 20 (w20) and 30 of gestation (w30) using a food frequency questionnaire with specific focus on the dietary sources of folate and DHA. Results: Both w20 and w30 Spanish participants had significantly higher daily DHA intakes (155 +/- 13 and 161 +/- 9 mg/1,000 kcal) than the German (119 +/- 9 and 124 +/- 12 mg/1,000 kcal; p = 0.002) and Hungarian participants (122 +/- 8 and 125 +/- 10 mg/1,000 kcal; p = 0.005). Hungarian women had higher folate intakes in w20 and w30 (149 +/- 5 and 147 +/- 6 mu g/1,000 kcal) than Spanish (112 +/- 2 and 110 +/- 2 mu g/1,000 kcal; p < 0.001) and German participants (126 +/- 4 and 120 +/- 6 mu g/1,000 kcal; p < 0.001), respectively. Conclusion: Dietary DHA and folate intake of pregnant women differs significantly across the three European cohorts. Only 7% of the participants reached the recommended folate intake during pregnancy, whereas nearly 90% reached the DHA recommended intake of 200 mg per day. Copyright (C) 2008 S. Karger AG, Basel

Background: Pluripotent embryonic stem (ES) cells that can differentiate into functional cardiomyocytes as well as vascular cells in cell culture may open the door to cardiovascular cell transplantation. However, the percentage of ES cells in embryoid bodies (EBs) which spontaneously undergo cardiovascular differentiation is low (< 10%), making strategies for their specific labeling and purification indispensable. Methods: The human connexin 40 (Cx40) promoter was isolated and cloned in the vector pEGFP. The specificity of the construct was initially assessed in Xenopus embryos injected with Cx40-EGFP plasmid DNA. Stable Cx40-EGFP ES cell clones were differentiated and fluorescent cells were enriched manually as well as via fluorescence-activated cell sorting. Characterization of these cells was performed with respect to spontaneous beating as well as via RT-PCRs and immunofluorescent stainings. Results: Cx40-EGFP reporter plasmid injection led to EGFP fluorescence specifically in the abdominal aorta of frog tadpoles. After crude manual enrichment of highly Cx40-EGFP- positive EBs, the appearance of cardiac and vascular structures was increased approximately 3-fold. Immuno fluorescent stainings showed EGFP expression exclusively in vascular-like structures simultaneously expressing von Willebrand factor and in formerly beating areas expressing alpha-actinin. Cx40-EGFP-expressing EBs revealed significantly higher numbers of beating cardiomyocytes and vascular-like structures. Semiquantitative RT-PCRs confirmed an enhanced cardiovascular differentiation as shown for the cardiac markers Nkx2.5 and MLC2v, as well as the endothelial marker vascular endothelial cadherin. Conclusions: Our work shows the feasibility of specific labeling and purification of cardiovascular progenitor cells from differentiating EBs based on the Cx40 promoter. We provide proof of principle that the deleted CD4 (Delta CD4) surface marker-based method for magnetic cell sorting developed by our group will be ideally suitable for transference to this promoter. Copyright (c) 2008 S. Karger AG, Basel.

Background and Purpose: Oxidative stress has been proposed as a major contributing factor for vascular disease, that acts independently from its participation in predisposing disorders such as diabetes and arterial hypertension. A functionally relevant C242T polymorphism of the CYBA gene encoding the NAD(P)H oxidase p22(phox) subunit, is supposed to lead to an abnormal reduction in the generation of reactive oxygen species in vascular smooth-muscle and endothelial cells. Methods: We investigated the p22(phox) C242T single-nucleotide polymorphism by polymerase chain reaction in consecutive patients with ischemic stroke or transient ischemic attack under the age of 50 (n = 161) and in population-based control subjects (n = 136). Results: Homozygosity for the T variant was associated with an enhanced risk for cerebral ischemia (odds ratio 3.85, confidence interval 1.39-10.64) after adjusting for classical risk factors. Risk for cerebral ischemia was not increased in heterozygous subjects. Conclusion: The p22(phox) C242T single-nucleotide polymorphism is associated with stroke risk. This finding supports the hypothesis that oxidative stress may contribute to stroke pathogenesis. Copyright (C) 2008 S. Karger AG, Basel.

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths. Difficulties to diagnose HCC at early stages remain the major obstacle to curative (surgical) therapy. Therapy in advanced stages has to be considered palliative. In this situation, a considerable amount of attention should be paid to innovative treatment strategies, e. g. including antiangiogenetic drugs. Results: We report on the successful treatment of a patient suffering from progressive HCC with a novel drug (EndoTAG (R)-1, formerly named LipoPac (R)) currently investigated in phase II studies. This drug consists of liposomally encapsulated paclitaxel. Its liposomal formulation favors the drug's adherence to the tumor neovasculature, in effect starving the tumor. Conclusions: EndoTAG (R)-1 stopped tumor progression for 9 months in our patient. This, along with successes observed testing this drug against other indications, makes it a suitable candidate for future clinical trials. Copyright (C) 2008 S. Karger AG, Basel.

Background: In contrast to the increasing numbers of agents for the treatment of invasive fungal infections, discoveries of new antifungal agents with therapeutic value in dermatomycoses are reported only rarely. Methods: Abafungin (chemical abstracts service registry No. 129639-79/8) is the first member of a novel class of synthetic antifungal compounds, the arylguanidines. It was first synthesized at Bayer AG, Leverkusen, Germany, and its antifungal action was discovered during the screening of H-2-receptor antagonists based on the structure of famotidine. To obtain insight into its mode of action and antifungal activity, various tests were carried out with different fungal pathogens in vitro. Results: Abafungin was found to have potent antifungal activity. Furthermore, mode-of-action studies suggested that abafungin exerts its antifungal activity regardless of whether the pathogens are growing or in a resting state. One target of abafungin was found to be the inhibition of transmethylation at the C-24 position of the sterol side chain, catalyzed by the enzyme sterol-C-24-methyltransferase. A second action of abafungin seems to be a direct effect on the fungal cell membrane. Conclusion: The observed characteristics of abafungin indicate that abafungin might be a promising antifungal agent defining a new class of antimycotics. Copyright (C) 2008 S. Karger AG, Basel.

The taurine and zebuine cattle breeds comprise the majority of the world cattle population but their taxonomic status is still controversial. The two forms of cattle are currently classified as Bos taurus and Bos indicus species and are differentiated primarily by the presence or absence of a hump. However, these two species hybridize readily, producing fully fertile offspring. We have determined and analyzed complete B. taurus and B. indicus mitochondrial genome sequences to investigate the extent of sequence divergences and to study their taxonomic status by molecular dating. The sequences encompassed 16,338 and 16,339 nucleotides, respectively, and differed at 237 positions. Estimated divergence times indicated that the two cattle lineages separated 1.7-2.0 million years ago. Combined phylogenetic analyses of 18 new and 130 previously reported extant B. taurus and B. indicus control region sequences with data from 32 archaeological specimens of the extinct wild aurochs (Bos primigenius) identified four major maternal lineages. B. primigenius haplotypes were present in all but the B. indicus lineage, and one B. taurus sequence clustered with B. primigenius P haplotypes that were not previously linked with domestic cattle. The B. indicus cluster and a recently reported new B. primigenius haplotype that represents a new lineage were approximately equidistant from the B. taurus cluster. These data suggest domestications from several differentiated populations of B. primigenius and a subspecies status for taurine (B. primigenius taurus) and zebuine (B. primigenius indicus) cattle. Copyright (C) 2008 S. Karger AG, Basel.

Several new genomic disorders caused by copy number variation (CNV) of genes whose dosage is critical for the physiological function of the nervous system have been recently identified. Dup(7)(q11.23) patients carry duplications of the genomic region deleted in Williams-Beuren syndrome, they are characterized by prominent speech delay. The phenotypes of Potocki-Lupski syndrome and MECP2 duplication syndrome were neuropsychologically examined in detail, which revealed autism as an endophenotype and a prominent behavioral feature of these disorders. Tandem duplication of LMNB1 was reported to cause adult-onset autosomal dominant leukodystrophy. PAFAH1B1/LIS1 and YWHAE, which were deleted in isolated lissencephaly (PAFAH1B1/LIS1 alone) and Miller-Dieker syndrome (both genes), were found to be duplicated in patients with developmental delay. Finally, two novel microdeletion syndromes affecting 17q21.31 and 15q13.3, as well as their reciprocal duplications, were also identified. In this review, we provide an overview of the phenotypic manifestation of these syndromes and the rearrangements causing them. Copyright (C) 2009 S. Karger AG, Basel

Background: Dementia results from heterogeneous diseases of the brain. Mixed disease forms are increasingly recognized. Methods: We performed a survey within brain banks of BrainNet Europe to estimate the proportion of mixed disease forms underlying dementia and age- and gender-specific influences. Results: Data collected in 9 centres from 3,303 individuals were analysed. The proportion of patients with mixed diagnoses among all cases with Alzheimer disease (AD), vascular pathology (VP), argyrophilic grain dementia (AGD), and synucleinopathies, such as Lewy body dementia (LBD), Parkinson disease (PD) and synuclein pathology only in the amygdala, was 53.3%. Mixed pathology was more frequently reported with LBD, PD, AGD, and VP than with AD. The percentage of mixed diagnoses for AGD and VP significantly differed between centres. In patients younger than 75 years, synucleinopathies, and pure forms of AD, VP, and AGD were more frequent in men. Above 75 years of age, more women had pure AD and pure AGD. Conclusions: The most obvious neuropathological alteration should not terminate the diagnostic procedure since copathology is likely to be found. Neuropathological interpretation of AGD and VP has not been sufficiently established in a consensus. Pure forms of synucleinopathies are unlikely sole substrates for dementia. Copyright (C) 2008 S. Karger AG, Basel

Background: Eccrine porocarcinoma is a rare malignant tumor of the sweat gland, characterized by a broad spectrum of clinicopathologic presentations. Surprisingly, unlike its benign counterpart eccrine poroma, eccrine porocarcinoma is seldom found in areas with a high density of eccrine sweat glands, like the palms or soles. Instead, eccrine porocarcinoma frequently occurs on the lower extremities, trunk and abdomen, but also on the head, resembling various other skin tumors, as illustrated in the patients described herein. Observations: We report 5 cases of eccrine porocarcinoma of the head. All patients were initially diagnosed as having epidermal or melanocytic skin tumors. Only after histopathologic examination were they classified as eccrine porocarcinoma, showing features of epithelial tumors with abortive ductal differentiation. Characteristic clinical, histopathologic and immunohistochemical findings of eccrine porocarcinomas are illustrated. Conclusion: Eccrine porocarcinomas are potentially fatal adnexal malignancies, in which extensive metastatic dissemination may occur. Porocarcinomas are commonly overlooked, or misinterpreted as squamous or basal cell carcinomas as well as other common malignant and even benign skin tumors. Knowledge of the clinical pattern and histologic findings, therefore, is crucial for an early therapeutic intervention, which can reduce the risk of tumor recurrence and serious complications. Copyright (c) 2008 S. Karger AG, Basel.

Objective: We evaluated whether immunoblotting is capable of substantiating the posttreatment clinical assessment of patients with erythema migrans ( EM), the hallmark of early Lyme borreliosis. Methods: In 50 patients, seroreactivity to different antigens of Borrelia burgdorferi sensu lato was analyzed by a recombinant immunoblot test (IB) in consecutive serum samples from a minimum follow-up period of 1 year. Antigens in the IgG test were decorin- binding protein A, internal fragment of p41 (p41i), outer surface protein C (OspC), p39, variable major protein-like sequence expressed (VlsE), p58 and p100; those in the IgM test were p41i, OspC and p39. Immune responses were correlated with clinical and treatment-related parameters. Results: Positive IB results were found in 50% before, in 57% directly after therapy and in 44% by the end of the follow-up for the IgG class, and in 36, 43 and 12% for the IgM class. In acute and convalescence phase sera, VlsE was most immunogenic on IgG testing 60 and 70%), and p41i (46 and 57%) and OspC (40 and 57%) for the IgM class. By the end of the follow-up, only the anti-p41i lgM response was significantly decreased to 24%. Conclusions: No correlation was found between IB results and treatment-related parameters. Thus, immunoblotting does not add to the clinical assessment of EM patients after treatment. Copyright (c) 2008 S. Karger AG, Basel.

Granuloma annulare (GA) is a benign granulomatous and inflammatory skin disorder. The pathogenesis remains enigmatic and convincingly effective treatment options are not available. Inspired by a report showing photodynamic therapy (PDT) to be effective in a single patient with GA, we sought to evaluate this benefit in a series of patients with GA. Observations: PDT was performed in 7 consecutive patients with histologically confirmed GA located at the extremities. First, 20% ALA gel was applied under an occlusive dressing for 5 h, followed by illumination with 100 J/cm(2) by a standard red-light source. In total, 2-3 PDT sessions were performed, with an interval of 2-4 weeks between each session. Treatment was stopped when complete remission was achieved or when GA lesions remained unchanged after 2 consecutive PDT sessions. The overall response rate was 57%. In 2 patients (29%), GA cleared completely, in 2 patients ( 29%) the skin lesions improved markedly and in 3 patients (43%) no clinical response could be observed. Conclusion: These promising results should be evaluated in larger controlled studies. In selected patients, PDT might be a valuable recruit for the sparse armory available to treat GA. Copyright (c) 2008 S. Karger AG, Basel

Molluscum contagiosum is a common viral skin infection in children with atopic diathesis and not rare in HIV patients. We report a 45-year-old psoriasis patient who developed eruptive mollusca contagiosa during an antipsoriatic treatment with efalizumab. Copyright (C) 2008 S. Karger AG, Basel.