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Regulatory T cells (Treg) and dendritic cells (DC) play an important role in tumor immunity and immune escape. However, their interplay and the effects of anti-cancer therapy on the human immune system are largely unknown. For DC generation, CD14+monocytes were enriched by immunomagnetic selection from peripheral blood of advanced head and neck squamous cell carcinoma (HNSCC) patients and differentiated into immature DC using GM-SCF and IL-4. DC maturation was induced by addition of TNFα. The frequency of CD4+CD25highF0XP3+Treg in HNSCC patients was analyzed before and after radio-chemotherapy (RCT) by four-color flow cytometry. In HNSCC patients, the frequency of Treg (0.33 ± 0.06%) was significantly (p = 0.001) increased compared to healthy controls (0.11 ± 0.02%), whereas RCT had variable effects on the Treg frequency inducing its increase in some patients and decrease in others. After six days in culture, monocytes of all patients had differentiated into immature DC. However, DC maturation indicated by CD83 up-regulation (70.7 ± 5.5%) was successful only in a subgroup of patients and correlated well with lower frequencies of peripheral blood Treg in those patients. The frequency of regulatory T cells is elevated in HNSCC patients and may be modulated by RCT. Monocyte-derived DC in HNSCC patients show a maturation deficiency ex vivo. Those preliminary data may have an impact on multimodality clinical trials integrating cellular immune modulation in patients with advanced HNSCC.

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemoradiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.

Pyoderma gangrenosum is a non-infectious neutrophilic skin disease commonly associated with underlying systemic diseases. Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture. Here, we report the case of a 69-year old man with progredient pyoderma gangrenosum-like ulcerations under treatment with sunitinib due to hepatocellular carcinoma. A conventional ulcer therapy did not lead to a regression of the lesions. Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations. Sunitinib is a multikinase inhibitor that targets the PDGF-α - and -β-, VEGF-1-3-, KIT-, FLT3-, CSF-1- and RET-receptor, thereby impairing tumour proliferation, pathological angiogenesis and metastasation. Here, we demonstrate that pyoderma gangrenosum-like ulcers may represent a serious side effect of sunitinib-based anti-cancer treatment.

Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the IGF-system can serve as a tumor marker in neoplasms. In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.

Patients with ESCC (squamous cell carcinoma of the esophagus) are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.

For head and neck as well as for oromaxillofacial surgery, the use of the pectoralis major myocutaneous (PMMC) flap is a standard reconstructive technique after radical surgery for cancers in this region. We report to our knowledge for the first development of breast cancer in the PMMC flap in a 79 year old patient, who had undergone several operations in the past for recurring squamous cell carcinoma of the jaw. The occurrence of a secondary malignancy within the donor tissue after flap transfer is rare, but especially in the case of transferred breast tissue and the currently high incidence of breast cancer theoretically possible. Therefore preoperative screening mammography seems advisable to exclude a preexisting breast cancer in female patients undergoing such reconstruction surgery. Therapy for breast cancer under these circumstances is individual and consists of radical tumor resection followed by radiation if applicable and a standard systemic therapeutic regimen on the background of the patients individual prognosis due to the primary cancer.

Tumor-related methylated DNA and circulating tumor cells (CTC) in the peripheral blood might be of prognostic importance in breast cancer. Thus, the aim of our study was to examine free methylated DNA and CTC in the blood from breast cancer patients and to correlate it with clinicopathological features known to influence prognosis. We prospectively obtained serum samples from 85 patients with breast cancer and 22 healthy volunteers. Sera were analysed by methylation specific PCR (MethyLight PCR) for five genes: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A), estrogen receptor 1 (ESR1), CDKN2A (p16) and glutathione s-transferase pi 1 (GSTP1). Beta actin (ACTB) served as control. In parallel matched peripheral blood of 63 patients was used to assay for circulating tumor cells in the peripheral blood by a modified immunomagnetic AdnaTest BreastCancerSelect with PCR detection for EPCAM, MUC1, MGB1 and SPDEF. We found a hypermethylation in the APC gene in 29% (25/85), in RASSF1A in 26% (22/85), in GSTP1 in 18% (14/76) and in ESR1 in 38% (32/85) of all breast cancer patients. No hypermethylation of CDKN2A was found (0/25). Blood samples of patients were defined CTC positive by detecting the EPCAM 13% (8/63), MUC1 16% (10/63), MGB 9% (5/55), SPDEF 12% (7/58) and in 27% detecting one or more genes (15/55). A significant difference was seen in methylated APC DNA between cancer patients and healthy volunteers. Moreover, methylated APC, RASSF1 and CTC were significantly different in metastatic versus non-metastatic disease. In addition, the presence of methylated APC, RASSF1A and CTC correlated significantly with AJCC-staging (p = 0.001, p = 0.031 and 0.002, respectively). High incidences of methylations were found for the genes RASSF1 and ESR1 in healthy individuals (both 23% 5/22). Methylated GSTP1 was predominantly found in the serum of patients with large primaries (p = 0.023) and was highly significantly correlated with positive Her2/neustatus (p = 0.003). Elevated serum CA15.3 was strongly correlated with methylated APC and CTC detection (both p = 0.000). Methylated ESR1 failed to exhibit significant correlations with any of the above mentioned parameters. The presence of CTC in peripheral blood was significantly associated with methylated APC (p = 0.012) and methylated GSTP1 (p = 0.001). The detection of methylated APC and GSTP1 DNA in serum correlated with the presence of CTC in the blood of breast cancer patients. Both methylated DNA and CTC correlated with a more aggressive tumor biology and advanced disease.

Antiseptics are frequently used for the prophylaxis and treatment of local infections of chronic wounds. Whereas local antiseptics in general have a positive effect on wound healing an uncritical use may impair wound healing due to toxic side effects. We sought to assess the vascular irritation potential of different antiseptic solutions and ointments commonly used for short and long term application as a measure of tissue toxicity. The vascular irritation was evaluated by the hen's egg test (HET) on the chorioallantoic membrane (CAM). The effects on the vessels of a mucous membrane were directly assessed by stereomicroscopic observation in vivo. Severe CAM irritation was observed after short-term applications of 1% octenidin-2HCl (Octeni sept™), 72% isopropanol (Cutasept™), 0.35% chloroxylenol (Dettol™) and 10% PVP-I ointment (Betaisodona™). Medium irritations were observed for 10% PVP-I solution (Betaisodona™), 3% lysosomal PVP-I ointment (Repithel™), 1.8% cadexomer-iodine ointment (Iodosorb™) and 1% cadexomer-iodine pellets (Iodosorb™). Finally, slight irritations were observed for 1% PVP-I solution (Betaisodona™), 0.1% polyhexanid plus betain (Prontosan™) and 1% silver-sulfadiazine ointment (Flammazine™), whereas 0.04% polyhexanid solution (Lavanid™), washings from sterile maggots of Lucilia sericata and filtrated enzymes from Clostridium histolyticum (Iruxol-N™) showed no effects of irritation. In the long-term approaches, no vascular irritations were found for polyhexanid, washings from Lucilia sericata and enzyme filtrations from Clostridium histolyticum. The vascular injuries caused by the studied antiseptics are an indirect indicator of their tissue toxicity. Strikingly, even therapeutic substances, which have been regarded as safe in their application for the treatment of chronic wounds in clinical studies, showed severe irritations on the CAM. We suggest that agents with no or low irritation potential on the CAM should be preferred in the clinical practice in order to obtain optimal results.

The sequences of many genomes are available; therefore, relevant methods are needed for rapid and efficient identification of functional genes. The ability of tumour cells to resist apoptosis induced by anticancer agents may decide the success of failure of tumour elimination. Although the CD95-signalling pathway is functional in tumour cells, the increased resistance of tumour cells to CD95-mediated apoptosis has been widely reported. In order to identify genes that might determine the response of tumour cells to CD95-mediated apoptosis, we modified the conventional technical knock out (TKO) strategy for isolation of genes that function in CD95-mediated apoptosis. Due to the fact that multiple different plasmids are usually introduced into the same cells, the effectiveness of the conventional TKO strategies is low. To overcome this obstacle, we replaced the conventional TKO strategy (based on stably expressed randomly fragmented cDNA libraries) with a multi-cycle selection procedure (based on transiently expressed randomly fragmented cDNA libraries with multi-cycle selection). Using this approach we could rapidly and significantly identify small numbers of antisense mRNA molecules, whose re-introduction into different tumour types confirmed their ability to block the pro-apoptotic function of their cognate genes. Thus, our modified TKO strategy provides a generally applicable procedure for the identification of functional genes with pro-apoptotic properties that may be clinically relevant to tumor therapy.

Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2), previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi-or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2.

Desmoid tumors are fibroblastic/myofibroblastic neoplasms, which originate from musculo-aponeurotic structures and are classified as deep fibromatoses. Despite their benign histologic appearance and lack of metastatic potential, desmoid tumors may cause aggressive local infiltrations and compression of surrounding structures. They are often associated with female gender, familial adenomatous polyposis (FAP) and sporadically may occur at sites of previous trauma, scars or irradiation. Molecular studies have demonstrated that these patients are associated with a bi-allelic APC mutation in the affected tissue. Radical tumor resection with free margins remains the first therapy of choice. In cases with anatomical or technical limitations for a wide excision, radiation therapy represents a proven and effective alternative or supplementary treatment.

Stereotactic radiosurgery is related to the history of "radiotherapy" and "stereotactic neurosurgery". The concepts for neurosurgeons and radiooncologists have been changed during the last decade and have also transformed neurosurgery. The gamma knife and the stereotactically modified linear accelerator (LINAC) are radiosurgical equipments to treat predetermined intracranial targets through the intact skull without damaging the surrounding normal brain tissue. These technical developments allow a more precise intracranial lesion control and offer even more conformal dose plans for irregularly shaped lesions. Histological determination by stereotactic biopsy remains the basis for any otherwise undefined intracranial lesion. As a minimal approach, it allows functional preservation, low risk and high sensitivity. Long-term results have been published for various indications. The impact of radiosurgery is presented for the management of gliomas, metastases, brain stem lesions, benign tumours and vascular malformations and selected functional disorders such as trigeminal neuralgia. In AVM's it can be performed as part of a multimodality strategy including resection or endovascular embolisation. Finally, the technological advances in radiation oncology as well as stereotactic neurosurgery have led to significant improvements in radiosurgical treatment opportunities. Novel indications are currently under investigation. The combination of both, the neurosurgical and the radiooncological expertise, will help to minimize the risk for the patient while achieving a greater treatment success.

Breast cancer (BC) represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting. Circulating tumour cells (CTC) of 63 BC patients were isolated from peripheral blood (PB) through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes ga733.2, muc-1, c-erbB2, mgb-1, spdefand c-erbB2were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls. Significant correlations with tumour stages were found in single gene analyses of ga733.2, muc-1and in multi-gene analyses of ga733.2/muc-1/mgb1/spdef. Furthermore, a significant correlation of Ca 15-3and all studied genes was also observed. Herein, we demonstrated a positive correlation of a gene signature consisting of ga733.2, muc-1, mgb1and spdefand advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with Ca 15-3positive cases.

The diagnostic tools to predict the prognosis in patients suffering from breast cancer (BC) need further improvements. New technological achievements like the gene profiling of circulating tumour cells (CTC) could help identify new prognostic markers in the clinical setting. Furthermore, gene expression patterns of CTC might provide important informations on the mechanisms of tumour cell metastasation. We performed realtime-PCR and multiplex-PCR analyses following immunomagnetic separation of CTC. Peripheral blood (PB) samples of 63 patients with breast cancer of various stages were analyzed and compared to a control group of 14 healthy individuals. After reverse-transcription, we performed multiplex PCR using primers for the genes ga733.3, muc-1and c-erbB2. Mammaglobin1, spdefand c-erbB2were analyzed applying realtime-PCR. ga733.2overexpression was found in 12.7% of breast cancer cases, muc-1in 15.9%, mgb1in 9.1% and spdefin 12.1%. In this study, c-erbB2did not show any significant correlation to BC, possibly due to a highly ambient expression. Besides single gene analyses, gene profiles were additionally evaluated. Highly significant correlations to BC were found in single gene analyses of ga733.2and muc-1and in gene profile analyses of ga733.3*muc-1and GA7 ga733.3*muc-1*mgb1*spdef. Our study reveals that the single genes ga733.3, muc-1and the gene profiles ga733.3*muc-1and ga733.3*3muc-1*mgb1*spdefcan serve as markers for the detection of CTC in BC. The multigene analyses found highly positive levels in BC patients. Our study indicates that not single gene analyses but subtle patterns of multiple genes lead to rising accuracy and low loss of specificity in detection of breast cancer cases.

Background: The current two studies evaluate the feasibility, toxicity and efficacy of an adjuvant combined modality treatment strategy containing a three to four-drug chemotherapy regimen plus 5-fluorouracil (FU)-based radiochemotherapy.

The primary chemosensitivity of 16 highly malignant xenografted human soft-tissue sarcomas to ifosfamide, dacarbazine, adriamycin and cisplatin and the development of secondary drug resistance in two chemosensitive sarcoma cell lines was tested in the xenograft system. Single-dose, single-agent treatments with 350 mg kg-1 ifosfamide, 200 mg kg-1 dacarbazine, 10 mg kg-1 doxorubicin and 6.6 mg kg-1 cisplatin were administered and response measured as specific growth delay. Since ifosfamide induced unexpectedly higher toxicity, response was corrected based on the shape of the dose-response curve for ifosfamide. Taking a specific growth delay > 3 as the cut-off point for chemosensitivity, ifosfamide, dacarbazine, doxorubicin and cisplatin were effective in 10/16, 4/16, 2/16 and 1/16 sarcoma cell lines respectively. Five out of 16 sarcoma cell lines were resistant to all tested drugs. Ifosfamide-resistant sarcoma lines were also resistant to doxorubicin and cisplatin, indicating a high degree of cross-resistance. Dacarbazine was still effective in 1/6 ifosfamide-resistant sarcoma cell lines. Secondary drug resistance developed slowly after doxorubicin and ifosfamide pretreatments at moderate selection pressure and developed rapidly after dacarbazine pretreatment at high selection pressure.

Zusammenfassung: Hintergrund: Untersuchungen von Normalgeweben haben gezeigt, daß erhebliche Unterschiede in der individuellen Strahlenempfindlichkeit bestehen. Eine Reihe genetischer Syndrome, die mit einer veränderten Strahlenempfindlichkeit einhergehen, wurden bereits beschrieben. Aber auch zufällig ausgewählte Probanden ohne erkennbare Erberkrankungen unterscheiden sich signifikant in ihrer Strahlensensitivität. Die vorliegende Arbeit geht der Frage nach, ob sich die individuellen Unterschiede der Strahlenempfindlichkeit der Normalgewebe in gleicher Weise auch in den in diesen Normalgeweben entstehenden Tumoren nachweisen lassen. Methode: Die experimentellen und klinischen Daten, die aus eigenen Untersuchungen und aus einer intensiven Literatursuche verfügbar waren, wurden zur Beantwortung der Fragestellung herangezogen. Ergebnisse: Experimentelle Untersuchungen an Normal- und Tumorgeweben von SCID- und C3H-Mäusen konnten zeigen, daß die etwa um den Faktor 2,7 gegenüber C3H-Mäusen erhöhte Strahlenempfindlichkeit der SCID-Normalgewebe sich in quantitativ gleicher Weise auch in den Tumorgeweben nachweisen ließ. Klinische Untersuchungen an Patientinnen mit Zervixkarzinomen und Mammakarzinomen konnten höhere lokale Tumorkontrollraten bei Patientinnen mit starken Akutreaktionen nachweisen. Bei Patienten mit Kopf-Hals-Tumoren war dieser Effekt nicht eindeutig darstellbar. Einzelfallberichte über Patienten mit sehr außergewöhnlichen Akutreaktionen oder unerwarteten Tumorrückbildungen sowie die Berichte über die Strahlenbehandlung von Patienten mit Ataxia teleangiectatica (AT) belegen ebenfalls die Hypothese einer Korrelation von Normalgewebs-und Tumorsensitivität. Untersuchungen von Fibroblasten und Tumorzellen vom gleichen Patienten unterstützen die Hypothese bei Weichteilsarkomen, nicht jedoch bei Kopf-Hals-Tumoren. Das Spektrum der Strahlensensitivitäten weist bei Tumoren eine deutlich höhere Streuung auf als bei Normalgeweben. Schlußfolgerung en: Die experimentellen und klinischen Daten sind größtenteils mit der Vorstellung vereinbar, daß die Strahlenempfindlichkeit von Tumoren mit der Strahlenempfindlichkeit von Normalgeweben korreliert. Die größere Heterogenität der Strahlenempfindlichkeiten von Tumoren läßt die Entwicklung prädiktiver Tests für die individuelle Sensitivität des Tumors auf Basis von Normalgewebsuntersuchungen des Patienten unrealistisch erscheinen.

Zusammenfassung: Grundlagen: Die unbefriedigenden Ergebnisse und die schlechten berlebensraten nach alleiniger chirurgischer Behandlung lokal fortgeschrittener nichtkleinzelliger Bronchialkarzinome (Stadium IIIa und IIIb), haben dazu gefhrt, da weltweit der Einflu einer systemischen Chemotherapie bzw. Chemo-/Strahlentherapie properativ berprft werden sollte. Die meisten Studien betrafen Patienten im Stadium IIIa, einige wenige schlossen beide Stadien IIIa und IIIb ein. Methodik: Die hier vorgestellte Studie beinhaltete eine properative Chemotherapie mit Cisplatin/Etoposid und hyperfraktionierte Strahlentherapie mit 45 Gy, gefolgt von der Resektion. Ergebnisse: Die multimodale Therapie war tolerable, die Remissionsraten hoch (66,7%), die Toxizitt niedrig. Eine R0-Resektion konnte bei 82% der operierten Patienten erzielt werden. Die mediane berlebenszeit lag bei 20 Monate fr das Stadium IIIa und 21 Monate fr das Stadium IIIb. Schlufolgerungen: Diese intensive properative neoadjuvante Therapie fr das lokal fortgeschrittene NSCLC erwies sich so effektiv, da bereits eine randomisierte, prospektive Studie fr das Stadium IIIa begonnen wurde.

Interaction of sodium pyrene-3-sulfonate (NaPyS) with different lipid monolayers has been studied by fluorescence and reflection spectroscopy, surface pressure measurements, and electrochemical methods. NaPyS interacts with dioctadecyldimethylammonium bromide (DOMA) monolayers at the air/water interface due to the Coulombic interaction with the positively charged head groups, while no interaction with dipalmitoylphosphatidylcholine (DPPC) monolayers has been noticed. NaPyS from solution also influenced DOMA monolayers which were transferred from the air/water interface to the mercury surface. The enhancement of the transport of cadmium ions across a DOMA film modified by NaPyS adsorption was observed.

Diffuse large B-cell lymphoma usually starts as a rapidly growing mass in an internal lymph node and can grow in other areas such as the bone or intestines. About 1/3 of these lymphomas are confined to one part of the body when they are localized. In the case of a 78-year-old man, an extensive tumour was located on the right thigh. Biopsies of the tumour revealed diffuse proliferation of large lymphoid cells which have totally affected the normal architecture of striated muscle. The patient received multimodality treatment including chemotherapy of the CHOP regimen and adjuvant radiotherapy. Despite this being a fast growing lymphoma, about 3 out of 4 people will have no signs of disease after initial treatment, and about half of all people with this lymphoma are cured with therapy.