Same Site Recurrence is More Frequent After Endovenous Laser Ablation Compared with High Ligation and Stripping of the Great Saphenous Vein: 5 year Results of a Randomized Clinical Trial (RELACS Study).

OBJECTIVE: To compare the long-term clinical efficacy of endovenous laser ablation (EVLA) with high ligation and stripping (HLS) as standard treatment for great saphenous vein (GSV) incompetence. DESIGN: Investigator initiated two centre randomized controlled trial with 5 year follow up. MATERIALS AND METHODS: Interventions were performed on ambulatory and hospitalized patients at two vein centres, a university dermatology department (EVLA) and a specialized vein clinic (HLS). Four hundred patients suffering from GSV incompetence were assigned to EVLA or HLS of the GSV. One hundred and eighty five and 161 patients (=limbs), respectively, were treated per protocol. Main outcome measures were clinically recurrent varicose veins after surgery (REVAS classification, primary study objective), Duplex detected saphenofemoral recurrence, clinical venous severity scoring (Homburg Varicose Vein Severity Score), quality of life (Chronic Venous Insufficiency Questionnaire 2), side effects, and patient satisfaction 5 years after treatment. RESULTS: Two hundred and eighty one legs (81% of the study population) were evaluated with a median follow up of 60.4 (EVLA) and 60.7 months (HLS). Overall, REVAS was similarly observed in both groups: 45% (EVLA) and 54% (HLS), p = .152. Patients of the EVLA group showed significantly more clinical recurrences in the operated region (REVAS: same site): 18% vs. 5%, p = .002. In contrast, more different site recurrences were observed in the HLS group: 50% vs. 31%, p = .002. Duplex detected saphenofemoral refluxes occurred more frequently after EVLA: 28% vs. 5%, p < .001. Both treatments improved disease severity and quality of life without any difference. CONCLUSIONS: EVLA and HLS are comparably effective concerning overall REVAS, improvement of disease severity, and quality of life. In terms of same site clinical recurrence and saphenofemoral refluxes, HLS is superior to EVLA 5 years after treatment. CLINICAL TRIAL REGISTRATION: ISRCTN18322872.

Graft-versus-host disease or toxic epidermal necrolysis: diagnostic dilemma after liver transplantation.

Graft-versus-host disease (GvHD) and toxic epidermal necrolysis (TEN) are rare and severe complications after liver transplantation. While mild acute GvHD is quite different from TEN and easy to distinguish, severe acute GvHD and TEN can be hard to differentiate because of similar clinical symptoms. We herein report a case with rapid progression of critical illness, after liver transplantation, caused by GvHD or TEN, although between those, diagnosis was not possible during the clinical course. Although, based on the timing/progression of the symptoms and the chimerism of >40%, the case seemed much more clinically consistent with GVHD, the combination of clinical symptoms together with skin rashes and the histologic appearance of skin lesions indicated diagnosis of a Stevens-Johnson syndrome/TEN overlap. The true diagnostic dilemma in such cases is discussed in detail, as these cases emphasize the need for more advanced diagnostic techniques.

Sorafenib and pegylated interferon-α2b in advanced metastatic melanoma: a multicenter phase II DeCOG trial.

BACKGROUND: The combination of sorafenib, a multikinase inhibitor, and pegylated interferon-α2b (Peg-IFN-α2b) could potentially lead to an improved antitumoral response. Previously, combinations of interferon and sorafenib have been used in renal cell cancer. PATIENTS AND METHODS: Patients with stage IV metastatic melanoma and no previous systemic therapies apart from adjuvant immunotherapy received Peg-IFN-α2b 3 µg/kg once per week, and sorafenib 400-mg b.i.d. for a minimum of 8 weeks. The primary study end point was disease control rate (DCR). RESULTS: Between February 2008 and February 2009, 55 patients were enrolled with a median age of 64 years (20-85). At 8 weeks, 2 patients (3.6%) had a partial response (PR) and 14 patients a stable disease (25.5%), for a DCR of 29.1% in the intention-to-treat (ITT) population. The median progression-free survival in the ITT population was 2.47 months (95% confidence interval 1.22-3.72 months). The toxicity of sorafenib and Peg-IFN-α2b combination was characterized by mainly hematological side-effects, including one treatment-related bleeding complication with a fatal outcome. Other grade 3/4 toxic effects were fatigue and flu-like symptoms. CONCLUSION: The combination of sorafenib and Peg-IFN-α2b showed modest clinical activity and some serious side-effects including fatal bleeding complications.

MGMT gene promoter methylation correlates with tolerance of temozolomide treatment in melanoma but not with clinical outcome.

BACKGROUND: Despite limited clinical efficacy, treatment with dacarbazine or temozolomide (TMZ) remains the standard therapy for metastatic melanoma. In glioblastoma, promoter methylation of the counteracting DNA repair enzyme O(6)-methylguanine-DNA-methyltransferase (MGMT) correlates with survival of patients exposed to TMZ in combination with radiotherapy. For melanoma, data are limited and controversial. METHODS: Biopsy samples from 122 patients with metastatic melanoma being treated with TMZ in two multicenter studies of the Dermatologic Cooperative Oncology Group were investigated for MGMT promoter methylation. We used the COBRA (combined bisulphite restriction analysis) technique to determine aberrant methylation of CpG islands in small amounts of genomic DNA isolated from paraffin-embedded tissue sections. To detect aberrant methylation, bisulphite-treated DNA was amplified by PCR, enzyme restricted, and visualised by gel electrophoresis. RESULTS: Correlation with clinical data from 117 evaluable patients in a best-response evaluation indicated no statistically significant association between MGMT promoter methylation status and response. A methylated MGMT promoter was observed in 34.8% of responders and 23.4% of non-responders (P=0.29). In addition, no survival advantage for patients with a methylated MGMT promoter was detectable (P=0.79). Interestingly, we found a significant correlation between MGMT methylation and tolerance of therapy. Patients with a methylated MGMT promoter had more severe adverse events, requiring more TMZ dose reductions or discontinuations (P=0.007; OR 2.7 (95% CI: 1.32-5.7)). Analysis of MGMT promoter methylation comparing primaries and different metastases over the clinical course revealed no statistical difference (P=0.49). CONCLUSIONS: In advanced melanoma MGMT promoter, methylation correlates with tolerance of therapy, but not with clinical outcome.

Chemotherapeutics, chemoresistance and the management of melanoma.

Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide. Survival mainly depends on primary tumor thickness, ulceration and sentinel node status at the time of diagnosis. Adjuvant therapies with interferons are able to prolong the recurrence-free survival, but the effects on overall survival are limited. Once, melanoma has metastasized to distant sites, the prognosis is fatal with median survival times between 7 and 9 months. Albeit removal of localized distant metastases is currently the most effective approach in metastatic melanoma in particular cases, chemo- and chemoimmunotherapy has to be regarded as standard treatment in the majority of patients. However, all available cytotoxic drugs and combinations applied so far have only a small impact on overall survival, if any. A fundamental cause of the limited efficacy of chemotherapy in advanced melanoma has to be seen in chemoresistance mechanisms. In melanoma, the intrinsic and mainly anti-apoptotic resistance, due to the physiological role of the UV exposed melanocytes, is prevailing. Further resistance mechanisms discussed in melanoma are DNA repair, multidrug transporter and the existence of cancer stem cells. Promising therapeutic options accrue from the growing insights into signaling pathways of melanoma that cause chemo- and apoptosis-resistance. The development of drugs targeting those mechanisms and their administration in combination with chemotherapy is currently one of the fascinating novel treatment approaches in melanoma.

[Systemic treatment of melanoma. Current clinical trials]. / Systemische Therapie des Melanoms. Aktuelle klinische Studien.

Malignant melanoma is one of the most common cancers accounting for 4-5% of all human malignancies and steadily increasing in incidence. The medical management of melanoma patients in Germany can be regarded as largely standardized based upon interdisciplinary guide lines. The results of adjuvant and especially palliative treatment of melanoma are unsatisfactory. Thus there is an urgent need for controlled clinical trials in order to optimize standard treatment approaches and to evaluate new drugs. The treatment of patients affected with high risk or metastatic melanoma within those clinical trials should be standard of care. This overview delineates the most important clinical trials currently conducted or planned in the adjuvant and palliative setting of melanoma treatment.

[Experimental treatment of malignant melanoma and its rationale]. / Experimentelle Tumortherapie beim malignen Melanom und ihre Rationale.

To treat malignant melanoma successfully currently means to recognize the tumor at an early stage and to remove it immediately. Aside from individual cases, available treatment modalities are not able to increase survival, especially in the palliative situation. Thus innovative experimental approaches are urgently needed to strongly improve the palliative and adjuvant treatment of melanoma. Anti-tumor effects are expected from targeted therapies, which are directed against defined molecules decisive for tumor pathogenesis. Crucial points of attack are signaling pathways, angiogenesis and apoptosis resistance. New diagnostic and therapeutic developments have enhanced the efficacy of chemotherapies. Increasing insights into tumor immunology provide new treatment approaches of vaccination, cell transfer and especially of blocking immune tolerance mechanisms. It will be challenging for the future to identify and characterize more precisely those patients who might most benefit from a certain treatment approach.

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3.

Sezary syndrome (SS) is a rare, aggressive CD4+ cutaneous T-cell lymphoma (CTCL); molecular traits differentiating SS from nonleukemic mycosis fungoides (MF) and from inflammatory skin diseases (ID) are not sufficiently characterized. Peripheral blood mononuclear cells (PBMC) of 10 SS patients and 10 healthy donors (HD) were screened by Affymetrix U133Plus2.0 chips for differential gene expression. Ten candidate genes were confirmed by qRT-PCR to be significantly overexpressed in CD4+ T cells of SS versus HD/ID. For easier clinical use, these genes were re-analyzed in PBMC; qRT-PCR confirmed five novel (DNM3, IGFL2, CDO1, NEDD4L, KLHDC5) and two known genes (PLS3, TNFSF11) to be significantly overexpressed in SS. Multiple logistic regression analysis revealed that CDO1 and DNM3 had the highest discriminative power in combination. Upon comparison of PBMC and skin samples of SS versus MF, CDO1 and DNM3 were found upregulated only in SS. Using anti-CDO1 antisera, differential expression of CDO1 protein was confirmed in SS CD4+ T cells. Interestingly, DNM3 and CDO1 are known to be regulated by SS-associated transcription factors TWIST1 and c-myb, respectively. Furthermore, CDO1 catalyzes taurine synthesis and taurine inhibits apoptosis and promotes chemoprotection. In summary, CDO1 and DNM3 may improve the diagnosis of SS and open novel clues to its pathogenesis.

[Therapy of malignant melanoma. First-, second- and pathogenesis-oriented third-line therapies]. / Therapie des metastasierten Melanoms. First-, Second- und pathogeneseorientierte Third-line-Therapien.

The incidence of malignant melanoma is steadily increasing worldwide. The most crucial requirement to cure the disease is early detection of thin primary tumors. At the stage of distant metastases, the treatment options are predominantly palliative. Resection of localized metastases is currently the most effective approach. Dacarbazine is considered as standard chemotherapy for inoperable metastatic disease showing remission rates of 5-20% without any noteworthy effect on overall survival. Quite recently, a large spectrum of innovative treatment approaches have been developed from an increasing insight into tumor biology. Along with improved vaccination strategies, targeted therapies have attracted the most attention in the treatment of advanced melanoma. Those anti-proliferative, anti-angiogenic and proapoptotic agents are directed against pathogenetically important pathways of the tumor cell. First clinical experiences are encouraging, but results from controlled trials have to be awaited.

[Differential diagnosis of verrucous skin changes. When wild warts grow rapidly...]. / Differenzialdiagnose und Therapie von verrukösen Hautveränderungen. Wenn die wilden Warzen wuchern. . .

This article gives and overview of the various types of verrucous skin changes (viral warts, seborrheic warts).

[Modern aspects of varicose vein surgery]. / Moderne Aspekte der Phlebochirurgie.

In Germany almost every third adult suffers from varicose veins requiring treatment. Conventional varicose vein surgery by high ligation and stripping is widely accepted as standard therapy for saphenous vein insufficiency, although associated with a high frequency of recurrent varicosities. Innovative endovascular procedures laying claim to be minimally invasive have been implemented over the last five years: endovenous radiofrequency obliteration, endovenous laser treatment and ultrasound-guided sclerotherapy with foam. The early treatment outcomes are promising in regard to recurrent varicose veins, cosmetic results and convalescence. Evidence-based prospective trials with large numbers of participants comparing the interventional procedures with high ligation and stripping are still missing. This report delineates current developments in varicose vein surgery and provides information on principles, effectiveness and side effect profiles of endovascular therapy procedures.

DNA mismatch repair enzyme hMSH2 in malignant melanoma: increased immunoreactivity as compared to acquired melanocytic nevi and strong mRNA expression in melanoma cell lines.

Mutations in the mismatch DNA repair gene human MutS homologen 2 (hMSH2) are causative for microsatellite instability and carcinogenesis in various human tumours, including hereditary nonpolyposis colorectal cancer. Because microsatellite instability has been detected in malignant melanoma, we have investigated hMSH2 in melanocytic tumours. We found strong nuclear immunoreactivity for hMSH2 that was elevated in malignant melanoma and melanoma metastases as compared to acquired nevi. These findings suggest that increased genomic instability in malignant melanoma is associated with elevated protein levels of this DNA repair enzyme. hMSH2 is not exclusively regulated by proliferative activity in melanocytes, because there was no correlation between staining patterns of hMSH2 and the proliferation marker Ki-67. In contrast, immunoreactivity scores for hMSH2 and p53 were both upregulated in malignant melanocytic tumours. These findings support the concept that hMSH2 gene expression may be regulated in melanocytes by the p53 protein, as has been reported previously in other tissues. Using the reverse transcription-polymerase chain reaction, we detected strong hMSH2 mRNA expression in each of 8 melanoma cell lines analysed (highest amounts in SK-MEL-25 cells, lowest amounts in MML-I cells). In conclusion, our findings indicate that hMSH-2 may be of importance for genetic stability, tumorigenesis and progression of malignant melanoma.

Immunohistochemical analysis of DNA mismatch repair enzyme hMSH-2 in normal human skin and basal cell carcinomas.

We have analysed the expression and distribution of the DNA mismatch repair enzyme hMSH-2 in normal skin and basal cell carcinomas. hMSH-2 protein was investigated immunohistochemically (normal human skin: n = 10; basal cell carcinomas: n = 16) on frozen sections using a highly sensitive streptavidin-peroxidase technique and a specific mouse monoclonal antibody (clone FE11). In normal human skin, we found nuclear immunoreactivity for hMSH-2 in epidermal keratinocytes of the basal and first 1-3 suprabasal cell layers. All basal cell carcinomas analysed revealed strong nuclear imunoreactivity that was pronounced in peripheral tumour cells and cells of the palisade. Expression of hMSH-2 protein was consistently and strongly upregulated in tumour cells of the carcinomas as compared to adjacent unaffected epidermis or epidermis of normal human skin. Twelve of the sixteen carcinomas analysed revealed no visual correlation in comparing the labelling patterns for hMSH-2 with the labelling pattern for the proliferation marker Ki-67. Our findings indicate that (a) hMSH-2 is expressed in human epidermal keratinocytes, predominantly in lower cell layers of the viable epidermis; (b) expression of hMSH-2 protein is strongly upregulated in basal cell carcinomas as compared to unaffected epidermis; (c) the level of hMSH-2 proteins in the carcinomas is not exclusively regulated by the proliferative activity of these tumour cells; (d) inactivating mutations of the hMSH-2 gene may in the carcinomas not be involved in the carcinogenesis or microsatellite instability secondary to replication errors; (e) expression of hMSH-2 may be of importance for the genetic stability of basal cell carcinomas in vivo.

Reliability of reverse transcription-polymerase chain reaction (RT-PCR)-based assays for the detection of circulating tumour cells: a quality-assurance initiative of the EORTC Melanoma Cooperative Group.

Reverse transcription-polymerase chain reaction (RT-PCR)-based assays detecting occult neoplastic cells are increasingly being used for the study of tumour dissemination and minimal residual disease. However, different methods are employed by various research groups and the results are heterogenous. We prospectively assessed the results from nine laboratories performing tyrosinase RT-PCR assays for the detection of melanoma cells on a series of blind samples. After complete analysis, the results were compared for sensitivity and specificity. All laboratories reported correct results for cDNA standards. Five laboratories attained acceptable specificity and a sensitivity detecting 10 cells in 10 ml of whole blood. Four laboratories had unacceptable specificity and/or sensitivity. This blind study highlights the difficulty of RT-PCR data interpretation and the need for quality assurance between laboratories. Measures to increase the reliability of RT-PCR assays are proposed, which have to be prospectively evaluated in future studies.

Detection of circulating melanoma cells by specific amplification of tyrosinase complementary DNA is not a reliable tumor marker in melanoma patients: a clinical two-center study.

PURPOSE: Recently, the reverse-transcription polymerase chain reaction (RT-PCR) of tyrosinase messenger RNA (mRNA) was reported to be a useful tool for the detection of circulating tumor cells in the peripheral blood of melanoma patients. Our aim was to evaluate critically the diagnostic value of this marker by investigating a significant number of patients in different stages of the disease in a two-center study. PATIENTS AND METHODS: Different techniques of blood collection, RNA isolation, and RT-PCR were compared, and the detectability of tyrosinase mRNA was tested using nine different melanoma cell lines. The sensitivity of the method was confirmed by blood spiking experiments and the specificity by restriction enzyme analysis. Subsequently, a total of 153 blood samples from 137 individuals (30 healthy subjects, five basal cell carcinoma, and 102 melanoma patients) were investigated. RESULTS: The detection level of melanoma cells differed between the cell lines tested. However, we could reproducibly detect single melanoma cells by spiking whole blood samples from healthy volunteers. One of 43 patients with primary melanoma (2.3%), zero of 15 patients with regional metastasis (0%), and 12 of 44 patients with advanced disease (27.3%) were found to be RT-PCR positive. All blood samples obtained from controls and patients with basal cell carcinoma were tyrosinose mRNA negative. CONCLUSION: Our data support the recent doubts that the detection of circulating tumor cells in melanoma patients using the tyrosinase mRNA RT-PCR is not sensitive enough to be used either as a melanoma progression marker in early stages of the disease or to monitor therapy in advanced stages of the disease.