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BACKGROUND: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS: 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.

At present five mono-ocular hand-held dermoscopes, which are most commonly used worldwide, are available on the market. With the exception of the first two case reports, no larger systematic study comparing these five hand-held dermoscopes has been performed so far to reveal possible differences in light spreading, brightness, reproduction of colour and differential structures. Using a digital camera (Nikon Coolpix 995®) test images were taken with five hand-held dermoscopes (Heine Delta 10®, Heine Delta 20®, Dermogenius® and DermLite FOTO37® with and without glass plate) each with 10fold magnification. We determined brightness and sharpness with white rough structured office paper. Millimeter paper was used in order to define the deformation and a test image with 14 different colourfields to qualify the colour. We compared symmetry, sharpness and quotient of boundary, differences and distribution of colours, diameter and area using a program for digital image analysis in 57 epithelial and melanocytic benign and malignant skin tumours of 46 patients. In the newer dermoscopes (Heine Delta 20®, Dermogenius® and DermLite FOTO37® with and without glass plate) the light sources were clearly improved, as now 6 respectively 24 LEDs are employed, a technology which leads to better image quality concerning brightness, sharpness, colours and visible differential structures compared to the images of the dermoscope with only one light source (Heine Delta 10®). The deformation was identical for all dermoscopes. In the digital image analysis of the 57 skin tumours, minor differences with variable distribution were observed in symmetry, sharpness and quotient of boundary, diameter and area. Major differences were revealed in colour differences and distribution in Heine Delta 10® compared to the other dermoscopes. For further improvement of the diagnostic of benign and malignant skin tumours only hand-held dermoscopes with multiple light sources as well with glass plate should be used. Thus reproduces the colours and differential structures in the best manner. For further improvement of the diagnostic of benign and malignant skin tumours only hand-held dermoscopes with multiple light sources as well with glass plate should be used. Thus the colours and differential structures are reproduced in the best manner.

A comprehensive review of physics at an \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$e^+e^-$$\end{document}e+e- linear collider in the energy range of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}=92$$\end{document}s=92 GeV–3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

Background The clinical history of a given pigmented lesion could influence the therapeutic decision. Teledermatology and automated image analysis also hold great potential for revolutionizing dermatology services. Aim The aim of this retrospective study was to evaluate the diagnostic accuracy of users with different experiences in dermoscopy with and without information about patients and their history compared with classification by an automated analysing system. Setting One hundred and fifty-seven dermoscopic images of pigmented lesions, taken and proved by histopathology at the Pigmented Lesions Clinic of the Department of Dermatology of the University Tuebingen, Germany, were included. Methods All images were viewed by three investigators with different experience: excellent (A), average (B) and beginner (C). In the first dermoscopic classification, no information was available. After 3 months the same images were once more classified by the three investigators, now with the information about the patients and their history. The melanocytic lesions were tested by the Tuebinger Mole Analyser. Results For user A the sensitivity, specificity and diagnostic accuracy revealed no improvement on including the history (81.3% to 84.4%, 94.6% to 92.3% and 92.0% to 90.7%), whereas user B clearly improved his results (75.0% to 87.5%, 76.9% to 88.5% and 76.5% to 88.3%). No change in the sensitivity was seen by user C (84.4%), but there was a clear improvement in the specificity (69.2% to 87.7%) and diagnostic accuracy (72.2% to 87.0%). Using the computer algorithm, a sensitivity of 100%, a specificity of 76.9% and a diagnostic accuracy of 81.9% were achieved. Conclusions The study revealed results relevant to the use of dermoscopy: (1) continuing dermoscopic education influences the diagnostic accuracy; (2) the history is helpful for averaged users and beginners in dermoscopy; (3) digital image analysis has the highest sensitivity, but a lower specificity compared to the clinicians; and (4) digital dermoscopy could be used for store-and-forward systems in teledermoscopy.

Summary Background Digital image analysis has been introduced into the diagnosis of skin lesions based on dermoscopic pictures. Objectives To develop a computer algorithm for the diagnosis of melanocytic lesions and to compare its diagnostic accuracy with the results of established dermoscopic classification rules. Methods In the Department of Dermatology, University of Tuebingen, Germany, 837 melanocytic skin lesions were prospectively imaged by a dermoscopy video system in consecutive patients. Of these lesions, 269 were excised and examined by histopathology: 84 were classified as cutaneous melanomas and 185 as benign melanocytic naevi. The remaining 568 lesions were diagnosed by dermoscopy as benign. Digital image analysis was performed in all 837 benign and malignant melanocytic lesions using 64 different analytical parameters. Results For lesions imaged completely (diameter ≤ 12 mm), three analytical parameters were found to distinguish clearly between benign and malignant lesions, while in incompletely imaged lesions six parameters enabled differentiation. Based on the respective parameters and logistic regression analysis, a diagnostic computer algorithm for melanocytic lesions was developed. Its diagnostic accuracy was 82% for completely imaged and 84% for partially imaged lesions. All 837 melanocytic lesions were classified by established dermoscopic algorithms and the diagnostic accuracy was found to be in the same range (ABCD rule 78%, Menzies' score 83%, seven-point checklist 88%, and seven features for melanoma 81%). Conclusions A diagnostic algorithm for digital image analysis of melanocytic lesions can achieve the same range of diagnostic accuracy as the application of dermoscopic classification rules by experts. The present diagnostic algorithm, however, still requires a medical expert who is qualified to recognize cutaneous lesions as being of melanocytic origin.

Purpose: The finding of melanoma cells in the peripheral blood, thus far mainly inferred from the PCR-based demonstration of tyrosinase mRNA, has been associated with metastatic melanoma. Neither the malignant nature nor the prognostic significance of circulating cells could be established. To address this question, we analyzed immunomagnetically isolated circulating melanoma cells for chromosomal aberrations and performed a clinical follow-up study of the enrolled patients. Experimental Design: In a prospective study, blood samples were taken from 164 melanoma patients and 50 donors without malignant disease. Circulating melanoma cells were enriched by immunomagnetic cell sorting using a murine monoclonal antibody against the melanoma-associated chondroitin sulfate proteoglycan. To prove the malignant origin of the positive cells and to define their chromosomal aberrations, we analyzed the genomes of 15 individually isolated cells from seven patients by single-cell comparative genomic hybridization (SCOMP). Results: Absolute and relative frequencies of circulating melanoma cells were associated with stage and with the presence or absence of detectable tumor. The detection of two or more cells correlated significantly with a reduced survival of patients with metastatic melanoma. All of the cells that were analyzed by SCOMP displayed multiple chromosomal changes and carried aberrations typical for melanoma. Conclusions: Immunomagnetic enrichment enables isolation and genomic characterization of circulating melanoma cells. The prognostic impact on survival of metastatic patients apparently reflects the aggressiveness of an ongoing tumor spread. Direct genomic analysis of the enriched and isolated cells will help to clarify the molecular-genetic basis of the establishment of generalized melanoma.

Malignant melanomas of the skin are distinguished by their propensity for early metastatic spread via lymphatic vessels to regional lymph nodes, and lymph node metastasis is a major determinant for the staging and clinical management of melanoma. However, the importance of tumor-induced lymphangiogenesis for lymphatic melanoma spread has remained unclear. We investigated whether tumor lymphangiogenesis occurs in human malignant melanomas of the skin and whether the extent of tumor lymphangiogenesis may be related to the risk for lymph node metastasis and to patient survival, using double immunostains for the novel lymphatic endothelial marker LYVE-1 and for the panvascular marker CD31. Tumor samples were obtained from clinically and histologically closely matched cases of primary melanomas with early lymph node metastasis (n = 18) and from nonmetastatic melanomas (n = 19). Hot spots of proliferating intratumoral and peritumoral lymphatic vessels were detected in a large number of melanomas. The incidence of intratumoral lymphatics was significantly higher in metastatic melanomas and correlated with poor disease-free survival. Metastatic melanomas had significantly more and larger tumor-associated lymphatic vessels, and a relative lymphatic vessel area of >1.5% was significantly associated with poor disease-free and overall survival. In contrast, no differences in the density of tumor-associated blood vessels were found. Vascular endothelial growth factor and vascular endothelial growth factor-C expression was equally detected in a minority of cases in both groups. Our results reveal tumor lymphangiogenesis as a novel prognostic indicator for the risk of lymph node metastasis in cutaneous melanoma.

BACKGROUND Cutaneous melanoma is the most aggressive form of skin carcinoma in humans, frequently with a rapid progression of disease. To detect early developing metastasis, laboratory tests to determine levels of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) form part of the regular follow-up, but often cannot discover recurrent disease at a sufficiently early stage. METHODS To evaluate the diagnostic accuracy of protein S-100β (S-100β), melanoma-inhibitory activity (MIA), LDH, AP, and tyrosinase/MART-1 reverse transcription-polymerase chain reaction (RT-PCR), the authors included 296 consecutive AJCC Stage II or III clinically disease-free melanoma patients. Follow-up examinations were performed every 3 months and blood samples were drawn to determine the levels of these tumor markers. RESULTS Metastasis occurred in 41 of the 296 patients during a median follow-up period of 19 months (range, 1–33 months). The sensitivity to detect new metastases was 29% for protein S-100β, 22% for MIA, 2% for LDH, 17% for AP, and 24% for RT-PCR. The diagnostic accuracy was best for MIA (86%) and S-100β (84%), whereas AP (79%), LDH (77%), and RT-PCR (72%) demonstrated lower values. Elevated values of S-100β and MIA during follow-up examinations were associated with decreased survival rates in the further course of the disease, but pathologic findings of the other tumor markers showed no prognostic impact. CONCLUSIONS To the authors' knowledge, the current study is the first comparison of the diagnostic accuracy of currently available tumor markers in the follow-up of high-risk melanoma patients. Protein S-100β and MIA demonstrated a higher sensitivity, specificity, and diagnostic accuracy in the diagnosis of newly occurring metastasis compared with to the tumor markers AP, LDH, and RT-PCR diagnostics. Therefore, the tumor markers S-100β and MIA may be useful in the follow-up of disease-free Stage II and III melanoma patients. Cancer 2003;97:1737–45. © 2003 American Cancer Society. DOI 10.1002/cncr.11250

Purpose: To prospectively examine and evaluate the results of follow-up procedures in a large cohort of cutaneous melanoma patients.Patients and Methods: This was a prospective study in 2,008 consecutive patients with stage I to IV cutaneous melanoma from 1996 to 1998 on the yield of stage-appropriate follow-up examinations according to the German guidelines. Documentation of patient and follow-up data comprised patient demography, primary tumor specifics, and any clinical and technical examinations performed. The detection of metastasis was classified as early or late, and the means of their detection and the resulting overall survival probabilities were examined.Results: A total of 3,800 clinical examinations and 12,398 imaging techniques were documented. Sixty-two second primary melanomas in 46 patients and 233 disease recurrences in 112 patients were detected during this time. In stage I to III disease, physical examination was responsible for the discovery of 50% of all recurrences. In the primary tumor stages, 21% of all recurrences were discovered by lymph node sonography, with the majority being classified as early detection. Forty-eight percent of the recurrences were classified as early detection, and these patients had a significant benefit of overall survival probability.Conclusion: The results of our study suggest that an elaborated follow-up schedule in cutaneous melanoma is suitable for the early detection of second primary melanomas and early recurrences. The intensity of clinical and technical examinations can be reduced during follow-up of patients in the primary tumor stages and may be intensified in locoregional disease. Recommendations for an effective follow-up strategy are outlined.

Background Several authors have recommended adjuvant radiotherapy following resection of regional lymph node metastases in cutaneous malignant melanoma. There is, however, little evidence from controlled trials that patients benefit from this treatment. Objectives To evaluate the usefulness of adjuvant radiotherapy following resection of lymph node metastases in cutaneous malignant melanoma. Methods We performed a retrospective study comparing 58 patients who underwent radiotherapy following resection of regional lymph node metastases with 58 controls from another centre who exclusively underwent regional lymphadenectomy. Patients and their controls were matched with respect to the number of tumour-bearing lymph nodes (1 vs. > 1) and to gender, although the proportion of thick tumours was greater in the irradiation group. Results The overall survival curves were almost identical in the two groups. There were nine disease recurrences in the study group and 12 in the control group (not significant). Regional recurrences in the irradiated patients were usually accompanied by metastases at other sites. Conclusions The present study does not support the recommendation of adjuvant radiotherapy following resection of regional lymph node metastases in patients with malignant melanoma.

In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2. This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon α (IFN-α) only to that of therapy with DTIC and IFN-α with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy. 290 patients were randomized to receive either DTIC (850 mg/m2every 28 days) plus IFN-α2a/b (3 MIU/m2, twice on day 1, once daily from days 2 to 5; 5 MIU/m23 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m2for 3 hours i.v. on day 3; 9.0 MIU/m2i.v. day 3/4; 4.5 MIU/m2s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms (P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-α as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-α and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-α only (5.6%). In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-α. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced melanoma. © 2001 Cancer Research Campaign http://www.bjcancer.com

This chapter of the 'Flavor in the era of LHC' workshop report discusses flavor-related issues in the production and decays of heavy states at the LHC at high momentum transfer Q, both from the experimental and the theoretical perspective. We review top quark physics, and discuss the flavor aspects of several extensions of the standard model, such as supersymmetry, little Higgs models or models with extra dimensions. This includes discovery aspects, as well as the measurement of several properties of these heavy states. We also present publicly available computational tools related to this topic. © Springer-Verlag / Società Italiana di Fisica 2008., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

A number of recent reports suggest serum protein S100 as a prognostic parameter in patients with metastatic melanoma. In the present study, serum protein S100 was investigated as a tumour marker for screening for melanoma metastasis in patients attending regular follow-up examinations. During the period from September 1997 to December 1998, serum protein S100 levels were measured by an immunoluminometric assay in 411 consecutive high risk melanoma patients (666 samples) and in 120 control subjects. Melanoma patients with resected primary tumours with a tumour thickness of 1.5 mm or more with resected metastasis were included in the study. Overall, 41 of the 411 patients developed metastasis during the period of observation. According to the distribution of protein S100 levels, the following different cut-off values were examined: 0.08 microg/l (95 percentile of the control group) and 0.13 microg/l (95 percentile of the group of melanoma patients without metastasis). The test efficiency for protein S100 as a diagnostic test for the detection of metastasis was highest for the cut-off value of 0.13 microg/l. In eight of the 41 patients (19.5%), elevation of protein S100 was the first sign of recurrence. Of the 41 patients with metastatic disease, 13 had elevated protein S100, giving a sensitivity of 0.32. The specificity for the detection of metastasis was 0.96. In eight of the 14 patients (57%) who developed distant metastasis, elevated S100 values were the first sign of tumour progression. In conclusion, determination of serum protein S100 levels enables earlier detection of distant metastasis in patients at high risk for metastasis. The impact on survival time needs to be investigated in follow-up studies.

Histopathologic parameters of the primary tumor, such as Breslow's tumor thickness and Clark's level of invasion are the current basis for prognostic classifications of primary cutaneous melanoma. Once patients develop regional node metastasis, histopathologic features of the primary melanoma no longer contribute significantly to survival prediction. In this tumor stage, the extent of lymph node involvement is the main prognostic factor. This study addresses the question whether application of a highly sensitive molecular biology assay for detection of submicroscopic melanoma cells in sentinel lymph nodes may be suitable to improve melanoma staging. One hundred and sixteen patients with primary cutaneous melanoma with a total of 214 sentinel lymph nodes were enrolled. Sentinel lymph nodes were analyzed by histopathology including immunohistochemistry and by reverse transcription–polymerase chain reaction for tyrosinase. Patients were examined for tumor recurrences during a follow-up period of 19 mo (median). Disease-free survival probabilities were calculated and independent prognostic factors were determined by multivariate analysis. Using histopathology, micrometastatic nodal involvement was detected in 15 patients (13%). Of the 101 patients with histopathologically negative sentinel lymph nodes, 36 were reclassified by positive tyrosinase reverse transcription–polymerase chain reaction and 65 patients were still negative by reverse transcription–polymerase chain reaction. Recur-rences were observed in 23 (20%) of 116 patients. These tumor recurrences were demonstrated in 10 patients (67%) with histopathologically positive sentinel lymph nodes, in nine patients (25%) with submicroscopic tumor cells detected by reverse tran-scription–polymerase chain reaction, and in four patients (6%) negative by both methods. The differences in recurrence rates were statistically significant (p = 0.01). In a multivariate analysis, histopathologic and reverse transcription–polymerase chain reaction status of the sentinel lymph node were demonstrated to be the only significant prognostic factors for predicting disease-free survival. Tyrosinase reverse transcription–polymerase chain reaction for the detection of minimal residual melanoma in sentinel lymph nodes is a powerful tool to determine patients who are at increased risk for subsequent metastasis. Moreover, a group of patients with high tumor thickness was identified by negative reverse transcription–polymerase chain reaction to be at low risk for recurrent disease. These data may have an impact on future tumor classifications of primary cutaneous melanoma.

The prognostic value of the type of anaesthesia used for the excision of malignant tumours has been a subject of controversy. Cell-mediated as well as humoral immune responses can be compromised after general anaesthesia, and recurrences may therefore occur more frequently. On the other hand, excision of primary tumours under local anaesthesia might also influence the prognosis unfavourably. The aim of the present study was to determine the prognostic impact of general and local anaesthesia for the primary excision of cutaneous melanoma. Follow-up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society were analysed. Cox proportional hazards analysis was performed to evaluate the independent significance of the prognostic factors, and survival probabilities were calculated for matched pairs using Kaplan-Meier estimates. Statistical analysis revealed an independent significant effect on survival for tumour thickness, ulceration, level of invasion, anatomical site and gender. General anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P

The extent and consequences of professional delay in diagnosis were analysed in 83 patients with palmoplantar and subungual melanomas treated from January 1986 to March 1997 in our department. Seventeen (52%) out of 33 subungual melanomas and 10 (20%) out of 50 palmoplantar melanomas were clinically misdiagnosed by physicians. Three palmoplantar melanomas (6%) were initially misinterpreted by pathologists. In 23 of the 27 cases (85%) the clinical misdiagnosis was made by non-dermatologists. Misdiagnosis caused a median delay of 12 months in the diagnosis of palmoplantar melanomas and 18 months in the diagnosis of subungual melanomas. Delay in diagnosis was associated with increased tumour thickness, more advanced stage at time of melanoma diagnosis and a lower estimated 5-year survival rate (15.4% versus 68.9% for palmoplantar; 68.5% versus 90.9% for subungual). Acral melanomas are frequently misdiagnosed due to their less common locations and because plantar and subungual melanomas often do not fit the 'changing mole' pattern. To Improve the patient's prognosis it is necessary to increase the physicians' skill in the diagnosis of acral melanomas. Histological examination should always be performed in acral lesions that do not heal.

The most recent LHC data have provided a considerable improvement in the precision with which various Higgs production and decay channels have been measured. Using all available public results from ATLAS, CMS and the Tevatron, we derive for each final state the combined confidence level contours for the signal strengths in the (gluon fusion + ttH associated production) versus (vector boson fusion + VH associated production) space. These "combined signal strength ellipses" can be used in a simple, generic way to constrain a very wide class of New Physics models in which the couplings of the Higgs boson deviate from the Standard Model prediction. Here, we use them to constrain the reduced couplings of the Higgs boson to up-quarks, down-quarks/leptons and vector boson pairs. We also consider New Physics contributions to the loop-induced gluon-gluon and photon-photon couplings of the Higgs, as well as invisible/unseen decays. Finally, we apply our fits to some simple models with an extended Higgs sector, in particular to Two-Higgs-Doublet models of Type I and Type II, the Inert Doublet model, and the Georgi-Machacek triplet Higgs model., 31 pages, 15 figures; v2: fixed important factor of 2 missing in Eq. (1) (results unchanged), extended discussion in the next-to-last paragraph of Section 3, some references added; v3: appendices and references added, matches version accepted by PRD

During the past decade more than 90% of all melanoma patients in the German-speaking countries have been diagnosed with a primary tumour alone. Therefore, surgical intervention has been the most important element in the management of these patients. The present investigation was performed to analyse the different surgical procedures used in the treatment of primary melanoma during the years 1983-1993. The primary treatment of 15,054 patients with malignant melanoma and without recognizable metastasis has been examined. During the time period under investigation the percentage of cases treated with two-step surgical management increased from 30% to 60%. Primary excision was performed in local anaesthesia in 40% of all patients in 1983, whereas in 1993 surgical intervention under local anaesthesia had increased up to 80%. Over the same time, the average safety margin decreased from 33 mm to 21 mm for the final excision of primary melanomas, and this decrease was paralleled by marked decrease in the average thickness of the tumours excised from 2.1 to 1.5 mm. Elective node dissection was performed in 5% of all patients in 1983, whereas 9% of patients underwent elective node dissection in 1993. The different centres participating were found to differ noticeably in the therapeutic procedures applied for similar indications. In conclusion, the management of primary malignant melanoma has changed considerably during the years 1983-1993 in the German speaking area in favour of a two-step surgical procedure, local anaesthesia for the excision of the primary tumour and smaller safety margins. It seems that earlier diagnosis of the tumour and also ideas about treatment design may be responsible for these changes.

This article is published with open access at Springerlink.com.-- et al., We define benchmark models for SUSY searches at the LHC, including the CMSSM, NUHM, mGMSB, mAMSB, MM-AMSB and p19MSSM, as well as models with R-parity violation and the NMSSM. Within the parameter spaces of these models, we propose benchmark subspaces, including planes, lines and points along them. The planes may be useful for presenting results of the experimental searches in different SUSY scenarios, while the specific benchmark points may serve for more detailed detector performance tests and comparisons. We also describe algorithms for defining suitable benchmark points along the proposed lines in the parameter spaces, and we define a few benchmark points motivated by recent fits to existing experimental data., The work of J.E. and K.A.O. was supported partly by the London Centre for Terauniverse Studies (LCTS), using funding from the European Research Council via the Advanced Investigator Grant 267352. U.E. acknowledges support from the French ANR LFV-CPV-LHC. J.F.G. is supported by U.S. DOE grant No. DE-FG03-91ER40674. The work of S.H. was supported in part by CICYT (grant FPA 2010–22163-C02-01) and by the Spanish MICINN’s Consolider-Ingenio 2010 Program under grant MultiDark CSD2009-00064. The work of K.A.O. is supported in part by DOE grant DE-FG02-94ER-40823 at the University of Minnesota.

We investigate various classes of Gauge Mediated Supersymmetry Breaking models and show that the Next-to-Minimal Supersymmetric Standard Model can solve the mu-problem in a phenomenologically acceptable way. These models include scenarios with singlet tadpole terms, which are phenomenologically viable, e.g., in the presence of a small Yukawa coupling, Comment: 24 pages, 6 figures, typos corrected, reference added

We investigate an action that includes simultaneously original and dual gravitational fields (in the first order formalism), where the dual fields are completely determined in terms of the original fields through axial gauge conditions and partial (non-covariant) duality constraints. We introduce two kinds of matter, one that couples to the original metric, and dual matter that couples to the dual metric. The linear response of both metrics to the corresponding stress energy tensors coincides with Einstein's equations. In the presence of nonvanishing standard and dual cosmological constants a stable solution with a time independent dual scale factor exists that could possibly solve the cosmological constant problem, provided our world is identified with the dual sector of the model., Comment: Parts of the Introduction rewritten; accepted for publication in CQG

Various contributions to the cosmological constant are discussed and confronted with its recent measurement. We briefly review different scenarious -- and their difficulties -- for a solution of the cosmological constant problem., Comment: Lecture given at the XIV Workshop "Beyond the Standard Model", Bad Honnef, 11-14 March 2002

62 patients with a histologically confirmed diagnosis of cutaneous malignant melanoma were interviewed from 1996 to 1998. Lesions were found mostly on patients backs (30.6%) and they were noted most frequently because of a change in colour (darker) (50%) and increase in size (43.5%). The median time between first noticing the melanoma and visiting a physician was one month, but for 28% of the patients it was more than three months. The median time between a medical examination and surgical removal was shorter than one month, but for 22% of the patients it was more than three months. Patients with bleeding lesions sought medical help later (14 months). Misdiagnosis led to a six months delay in treatment and if no action was taken there was a 13 months delay.

Conflicting results were obtained by various research groups using the tyrosinase reverse transcription polymerase chain reaction (RT-PCR) for detecting melanoma cells circulating in peripheral blood. Whereas 100% positivity was initially reported for stage IV patients, more recent investigations reported positive detection rates between 30% and 50% in patients with disseminated melanoma. While the high detection rate initially reported in metastatic melanoma may be explained by contamination problems, methodological differences in different steps of the technical procedure of RT-PCR may account for the differences reported in more recent examinations. Major differences may result from the kind of blood preparation, the RNA isolation method, the kind of RT enzyme used, and the gene targeted by PCR primers. In our experience, blood purification by a Ficoll gradient increased melanoma cell detection rates compared to RNA extraction from total blood or after erythrocyte lysis. Amplification of MelanA in addition to tyrosinase resulted in a 30% enhanced sensitivity of melanoma cell detection compared to amplification to tyrosinase alone, whereas gp100/pMel17 and MUC18 gene products were already detected in blood from nonmelanoma patients. These findings are in agreement with those of other groups. Currently, an increase in the sensitivity for detection of circulating tumour cells to more than 50% of patients with disseminated melanoma seems to be unlikely. It is interesting that between 15% and 30% positive results and sometimes more have already been obtained from patients with primary melanoma. So far, there is no data for judging the prognostic significance of the detection of circulating tumour cells in patients without clinically recognisable metastases. Our limited experience shows that staging examinations in these patients reveal no proof of macrometastasis. Therefore, it is presently unclear whether these positive findings are associated with long-term prognosis or if they merely reflect false positive findings in this highly sensitive RT-PCR technique.

Conflicting results were obtained by various research groups using the tyrosinase reverse transcription polymerase chain reaction (RT-PCR) for detecting melanoma cells circulating in peripheral blood. Whereas 100% positivity was initially reported for stage IV patients, more recent investigations reported positive detection rates between 30% and 50% in patients with disseminated melanoma. While the high detection rate initially reported in metastatic melanoma may be explained by contamination problems, methodological differences in different steps of the technical procedure of RT-PCR may account for the differences reported in more recent examinations. Major differences may result from the kind of blood preparation, the RNA isolation method, the kind of RT enzyme used, and the gene targeted by PCR primers. In our experience, blood purification by a Ficoll gradient increased melanoma cell detection rates compared to RNA extraction from total blood or after erythrocyte lysis. Amplification of MelanA in addition to tyrosinase resulted in a 30% enhanced sensitivity of melanoma cell detection compared to amplification to tyrosinase alone, whereas gp100/pMel17 and MUC18 gene products were already detected in blood from nonmelanoma patients. These findings are in agreement with those of other groups. Currently, an increase in the sensitivity for detection of circulating tumour cells to more than 50% of patients with disseminated melanoma seems to be unlikely. It is interesting that between 15% and 30% positive results and sometimes more have already been obtained from patients with primary melanoma. So far, there is no data for judging the prognostic significance of the detection of circulating tumour cells in patients without clinically recognisable metastases. Our limited experience shows that staging examinations in these patients reveal no proof of macrometastasis. Therefore, it is presently unclear whether these positive findings are associated with long-term prognosis or if they merely reflect false positive findings in this highly sensitive RT-PCR technique.

The prognostic value of the type of anaesthesia used for the excision of malignant tumours has been a subject of controversy. Cell-mediated as well as humoral immune responses can be compromised after general anaesthesia, and recurrences may therefore occur more frequently. On the other hand, excision of primary tumours under local anaesthesia might also influence the prognosis unfavourably. The aim of the present study was to determine the prognostic impact of general and local anaesthesia for the primary excision of cutaneous melanoma. Follow-up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society were analysed. Cox proportional hazards analysis was performed to evaluate the independent significance of the prognostic factors, and survival probabilities were calculated for matched pairs using Kaplan-Meier estimates. Statistical analysis revealed an independent significant effect on survival for tumour thickness, ulceration, level of invasion, anatomical site and gender. General anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P0.0001). This study revealed a slight but significantly increased risk of death for patients treated with general anaesthesia for the primary excision of melanoma. Therefore local anaesthesia should be preferred for the treatment of primary melanoma.

Bei primaren malignen Melanomen wird heute die Prognoseschatzung aufgrund der Parameter des Primartumors vorgenommen. Der wichtigste Faktor ist die Bestimmung der vertikalen Tumordicke am histologischen Praparat nach Breslow (Breslow, 1970). Als zweiter wesentlicher prognostischer Faktor gilt der Invasionslevel nach Clark, bei dem das Eindringen des Tumors anhand des anatomischen Aufbaus der Haut bestimmt wird (Clark et al. 1969). Diese Parameter erlauben statistische Voraussagen, das eine Tumorprogression und ein Versterben an dem Tumor mit einer bestimmten Wahrscheinlichkeit erfolgen wird. Sie erlauben aber keine Aussagen daruber, inwieweit der Einzelne betroffen sein wird oder nicht. Deshalb impliziert diese Art der Prognoseschatzung, das aufwendige diagnostische Masnahmen in der Tumornachsorge ebenso wie adjuvante Therapien bei einem Teil der Patienten durchgefuhrt wird, bei denen eine Mikrometastasierung und damit die Chance zur spateren Manifestation von Tumoren gar nicht vorliegt.

Factors associated with the detection of cutaneous melanomas and reasons for delay in diagnosis were investigated in 429 patients with histologically proven melanoma operated on between January 1993 and June 1996. Patients were interviewed using a standardized questionnaire. In 25% of patients, treatment was delayed for more than 1 year from the time they first noticed a suspicious pigmented lesion. Melanoma was detected by the patients themselves in 67% of women and 45% of men. The three predominant clinical symptoms of melanoma were change in colour (darker), increase in size and increase in elevation of a pigmented lesion. The role of sun exposure and of naevi as risk factors for melanoma, as well as the potential benefit of early treatment, were known by 87%, 66% and 82% of the patients, respectively. However, melanoma awareness had no impact on the time period between first observation of skin changes and treatment. Among the factors associated with delay in melanoma diagnosis, an initial incorrect diagnosis as a benign lesion by the physician first visited (in 18% of all cases) had the highest significance. Patients detecting their lesions themselves were treated significantly later than patients in whom others had remarked on changes in a naevus. Furthermore, melanomas of the head and neck were treated later than melanomas at other body sites. Further efforts to educate both the public and the medical profession are essential to ensure earlier treatment for cutaneous melanomas.

We study the upper limits on the mass of the lightest and second lightest CP even Higgs bosons in the (M+1)SSM, the MSSM extended by a gauge singlet. The dominant two loop contributions to the effective potential are included, which reduce the Higgs masses by 10 GeV. Since the coupling R of the lightest Higgs scalar to gauge bosons can be small, we study in detail the relations between the masses and couplings of both lightest scalars. We present upper bounds on the mass of a 'strongly' coupled Higgs (R > 1/2) as a function of lower experimental limits on the mass of a 'weakly' coupled Higgs (R < 1/2). With the help of these results, the whole parameter space of the model can be covered by Higgs boson searches., Changed notation and added explanations; to appear in European Journal of Physics C

The presence of regional lymph node metastases is one of the most significant prognostic factors for predicting survival in patients with clinical stage I or II cutaneous melanoma. For accurate staging of the primary tumor a sensitive technique is required to detect occult nodal micrometastases. This prospective diagnostic study was designed to evaluate the incidence of nodal micrometastases using nested reverse transcription-polymerase chain reaction (RT-PCR) for tyrosinase in comparison to immunohistochemical examination. Furthermore, the incidence of melanoma micrometastases detected by RT-PCR was analysed in correlation to major prognostic factors. A total of 466 regional lymph nodes from 79 patients with primary cutaneous melanoma (tumor thickness > 0.75 mm) were investigated. In 49 lymph nodes from 31 patients immunohistochemistry demonstrated melanoma metastases. Using tyrosinase RT-PCR, nodal micrometastases were detected in 136 lymph nodes from 52 patients including all lymph nodes positive by immunohistochemical examination. Out of the 417 lymph nodes negative by immunohistochemistry, 87 nodes (21%) were identified to express tyrosinase by the RT-PCR technique. Among the 48 patients negative by immunohistochemical assessment, 21 (44%) had nodal micrometastases (n = 40) using RT-PCR. All 68 lymph nodes from 46 non-melanoma patients serving as negative controls for tyrosinase RT-PCR were negative. The detection of melanocytic nodal micrometastases by tyrosinase RT-PCR is a highly specific method with a sensitivity significantly higher than that achieved by immunohistochemistry (p < 0.0001). Patients with nodal micrometastases identified exclusively by RT-PCR had significantly higher tumor thickness as compared to patients with negative results by RT-PCR (p < 0.01). Int. J. Cancer (Pred. Oncol.) 79:318–323, 1998. © 1998 Wiley-Liss, Inc.

In der Mehrzahl der metastasierenden kutanen Melanome erfolgt die Tumorprogression uber das kutane Lymphsystem in die regionaren Lymphknotenstationen. Insofern stellt der Nachweis einer Tumorinfiltration von Lymphknoten einen signifikanten prognostischen Faktor fur den weiteren Krankheitsverlauf [4,5] und fur das anschliesende therapeutische Vorgehen dar. Die konventionelle histologische Untersuchung von Lymphknotengewebe mittels Hamatoxylin-Eosin(HE)-Farbung ist insbesondere bei oligozellularen Mikrometastasen nicht immer sensitiv genug, um diese histomorphologisch nachzuweisen, selbst unter Einbeziehung immunhistochemischer Verfahren. Durch die Entwicklung moderner molekularbiologischer Techniken, wie der Polymerasekettenreaktion (PCR), ist es moglich eine molekulare Tumordetektion von Melanomzellen mit einer sehr hohen Sensitivitat und Spezifitat durchzufuhren, indem Tyrosinase, ein gewebespezifisches Schlusselenzym der Melaninbiosynthese, identifiziert wird [1,3,6]. Das Ziel dieser diagnostischen Studie ist es, die diagnostische Sensitivitat der Reversen Transkription-Polymerasekettenreaktion (RT-PCR) des Tyrosinase Gens im Vergleich zu konventionellen histopathologischen und immunhistochemischen Techniken am Lymphknotengewebe von Melanompatienten zu untersuchen.

Seasonal patterns in the diagnosis of cutaneous malignant melanoma (CMM) described so far were associated with a higher rate of diagnoses in summer than in winter [1–8]. UV light is assumed to induce the malignant transformation and/or melanoma growth and thus, melanomas might occur more often after recent periods of sun exposure. Another possibility might be that skin lesions are more visible in summer when people wear lighter clothing and have more large amounts of uncovered body surfaces [2,4,5,9].

Postoperative follow-up is generally recommended for patients with malignant skin tumors. It is particularly important both for psychooncological reasons and as a means of ensuring quality control. Preferably, it should be clinical and should be adapted to the degree of risk wherever possible. Its most important technical tool is sonographic examination of the regional lymph nodes.

In the past decades there has been an alarming rise in incidence and mortality rates of melanoma worldwide [1, 18, 19] In Germany there exists several regional melanoma registries (e.g. Hamburg, Saarland), however no national population-based registry.

During the past decade more than 90% of all melanoma patients in the German-speaking countries have been diagnosed with a primary tumour alone. Therefore, surgical intervention has been the most important element in the management of these patients. The present investigation was performed to analyse the different surgical procedures used in the treatment of primary melanoma during the years 1983-1993. The primary treatment of 15,054 patients with malignant melanoma and without recognizable metastasis has been examined. During the time period under investigation the percentage of cases treated with two-step surgical management increased from 30% to 60%. Primary excision was performed in local anaesthesia in 40% of all patients in 1983, whereas in 1993 surgical intervention under local anaesthesia had increased up to 80%. Over the same time, the average safety margin decreased from 33 mm to 21 mm for the final excision of primary melanomas, and this decrease was paralleled by marked decrease in the average thickness of the tumours excised from 2.1 to 1.5 mm. Elective node dissection was performed in 5% of all patients in 1983, whereas 9% of patients underwent elective node dissection in 1993. The different centres participating were found to differ noticeably in the therapeutic procedures applied for similar indications. In conclusion, the management of primary malignant melanoma has changed considerably during the years 1983-1993 in the German speaking area in favour of a two-step surgical procedure, local anaesthesia for the excision of the primary tumour and smaller safety margins. It seems that earlier diagnosis of the tumour and also ideas about treatment design may be responsible for these changes.

The Central Malignant Melanoma Registry of the German Dermatological Society was founded in 1983 and has meanwhile developed into a major continuously updated multicentre project. Up to June 1994, 19,250 reports of cutaneous melanoma had been received, from 41 departments of dermatology in the former Federal Republic of Germany, from 14 departments in the former German Democratic Republic, from 2 departments in Austria, and from 1 department in Switzerland. Analysis of the data revealed some epidemiological trends over time during the years 1983 to 1993. (1) During the last 10 years the percentage of male patients has steadily increased, from an average of 38% in the year 1983 to 46% in 1993. (2) Early diagnosis of malignant melanoma improved during the period of time investigated. The percentage of diagnoses of primary tumour alone increased between 1983 and 1993. The mean tumour thickness (Breslow) decreased in the West Germany from 1.8 mm to 1.3 mm and in East Germany from 2.5 mm to 1.7 mm. The proportion of nodular melanoma decreased correspondingly from 29% to 14% in the former Federal Republic of Germany and from 40.6% to 22.6% in the former Germany Democratic Republic. During the years 1990 and 1993, 64% of melanoma patients with the primary tumour alone were operated on in two consecutive sessions in the former Federal Republic of Germany and 34.2% of those in the former Germany Democratic Republic. During this period 73.7% of all melanoma patients were operated on under local anaesthesia. In recent years surgical operations were more often performed in two consecutive sessions, mostly under local anaesthesia and with decreasing safety margins, in keeping with the decrease in tumour thickness. The present analysis shows that the Central Malignant Melanoma Registry is an important instrument for investigating trends in clinical epidemiology and treatment of malignant melanoma in the German-speaking countries.

We discuss the Higgs sector of the supersymmetric standard model extended by a gauge singlet for the range of parameters, which is compatible with universal soft supersymmetry breaking terms at the GUT scale. We present results for the masses, couplings and decay properties of the lightest Higgs bosons, in particular with regard to Higgs boson searches at LEP. The prospects differ significantly from the ones within the MSSM., Comment: 12 pages (Plain Tex), 7 figs

Triviality and vacuum stability bounds on the Higgs and top quark masses in a rather general class of supersymmetric extensions of the Standard Model are compared with the corresponding bounds without supersymmetry. Due to generic differences of those bounds we find that experimental knowledge of the Higgs and top masses may provide a ``pointer'' into one of these directions. Depending on the values of the masses, however, both scenarios or none could also be allowed., 12 pages, HD-THEP-92-48

We calculate the masses of the Higgs scalars and the lightest chargino for a large number of parameters of the supersymmetric standard model extended by a singlet. This allows us to estimate in which range we have to expect these masses naturally, and which region has to be covered experimentally in order to rule out a large fraction of the parameter space of low energy supersymmetry.

Background Mistletoe preparations Iscucin ® Populi (IP) and Viscum Mali (VM, both WALA GmbH) are licensed in Germany as supportive cancer medication within the concept of Anthroposophical Medicine. Safety and immunological effects in humans of these preparations were for the first time investigated in this study. Methods A 3-armed randomized study in healthy volunteers was performed. The probands injected in increasing doses either IP (strength F, G and H, each for 4 weeks) or VM (strength D3, D2 and 2% each for 4 weeks) or placebo (isotonic solution) subcutaneously twice weekly for a total of 12 weeks. Clinical and safety controls were performed weekly. Immunological outcome parameters (differential blood count, lymphocyte differentiation, interleukin (IL)-6) were analysed every 4 weeks. Results A total of 71 probands were included (IP=30, VM=21, placebo=20), 69 finished the study regularly and were analysed. Application of IP strength G and H caused strong local reactions at the site of injection. In parallel they resulted in distinct eosinophilia ( p p Discussion and conclusion Eosinophilia as an effect of mistletoe-lectin (ML) containing mistletoe preparations is well known and was pronounced due to the high content of ML in IP strength G and H. Most of the probands did not tolerate the full dose of IP strength G and H due to local reactions. Repeated injections induced, however, a certain tolerance (smaller local reactions, less eosinophilia despite inreasing dosages), which was accompanied by induction of mistletoe lectin antibodies in all subjects receiving IP (data not shown). Therefore, IP strength G and H should in general be used only after pretreatment with lower dosages. For the first time there was an increase of T-helper cells during application of mistletoe preparations in a placebo-controlled study. This could be beneficial for the treatment of immunosuppressed cancer patients. Eosinophils play a role in host response against cancer and eosinophilia correlates with a better prognosis in a variety of cancer types. Whether eosinophilia during treatment with IP has a clinical benefit for cancer patients has to be further investigated. Both mistletoe preparations have been shown to be safe. VM induces only mild local reactions and is used as mild counter stimulant in patients with painful osteoarthritis.