A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.

BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.

Impaired NLRP3 inflammasome expression and function in atopic dermatitis due to Th2 milieu.

BACKGROUND: Atopic dermatitis (AD) and psoriasis patients are frequently colonized with Staphylococcus aureus (S. aureus) that produce the staphylococcal exotoxin α-toxin. However, only patients with AD suffer from bacterial superinfections with this pathogen, which implicates immunological differences in AD vs psoriasis in combating these bacteria. S. aureus recognition is partially mediated by intracellular nucleotide-binding oligomerization domain receptors (NLRs), which link α-toxin to caspase-1 activation through the formation of the NLRP3 inflammasome and to IL-1ß secretion. OBJECTIVE: To investigate (i) NLRP3 expression in the context of different T-helper cytokine milieus and (ii) its function in response to sublytic α-toxin stimulation in patients with AD and psoriasis compared with healthy controls. METHODS: NLRP3 expression and function were investigated in lesional AD and psoriasis skin as well as in primary keratinocytes (HPKs) and monocytes upon stimulation with Th1, Th2, Th17 and Th22 cytokines or staphylococcal α-toxin, respectively, at the mRNA and protein (ELISA, immunohistochemistry and immunofluorescence) level. RESULTS: NLRP3 and caspase-1 expressions were reduced in lesional AD skin compared to psoriatic and healthy skin. IL-4, IL-5 and IL-13 downregulated NLRP3 and ASC, whereas interferon-γ upregulated NLRP3 in HPKs. In monocytes, caspase-1 expression was reduced by Th2 cytokines and enhanced by a Th1 milieu. Caspase-1-dependent IL-1ß secretion was impaired in monocytes from patients with AD compared to patients with psoriasis and healthy controls by α-toxin stimulation following priming with lipoteichoic acid. CONCLUSION: Impaired NLRP3 expression and function may partially explain how skin colonization and infection with S. aureus can contribute to chronic skin inflammation in AD.

Treatment of advanced cutaneous squamous cell carcinomas with epidermal growth factor receptor inhibitors.

In advanced cutaneous squamous cell carcinoma (cSCC), efficient medical treatment options are limited in case surgery and radiotherapy failed, particularly since most patients are of higher age and suffer from comorbidities. In many tumor entities, the epidermal growth factor receptor (EGFR) has been established as an important therapeutic target, and blockade of EGFR signaling by monoclonal antibodies or small molecules achieves a therapeutic benefit. EGFR expression is also often dysregulated in cSCC. We report here two patients with advanced cSCC treated with the EGFR inhibitor cetuximab and summarize the current published experience with the use of EGFR inhibitors in cSCC.

[Remission of an iatrogenic Kaposi sarcoma in a patient with myasthenia gravis after switching immunosuppressive therapy to the mTOR inhibitor everolimus]. / Remission eines iatrogenen Kaposi-Sarkoms bei Myasthenia gravis nach Umstellung der Immunsuppression auf den mTOR-Inhibitor Everolimus.

Iatrogenic Kaposi sarcomas (KS) in organ transplant recipients are often treated by switching immunosuppressive therapy to an mTOR inhibitor, such as sirolimus or everolimus, as these have immunosuppressive as well as anti-tumor effects. We report on an 80-year-old male patient who developed a disseminated cutaneous KS during therapy with prednisone and azathioprine for myasthenia gravis. After discontinuation of azathioprine therapy and despite continuing therapy with cortisone, the KS progressed and autoantibody levels against the nicotinic acetylcholine receptor increased. During the administration of everolimus, a long-term near-complete remission of KS and a decrease in autoantibodies took place. This case study illustrates that even in non-organ transplant patients with iatrogenic KS, switching to immunosuppressive therapy using an mTOR inhibitor can be beneficial.

Sentinel node dissection delays recurrence and prolongs melanoma-related survival: an analysis of 673 patients from a single center with long-term follow-up.

BACKGROUND: The status of the sentinel lymph node is an important predictor for survival in melanoma patients, but it is still unclear if early removal of micrometastases by sentinel lymph node dissection (SLND) alters survival. A large series of melanoma patients from a single center with long-term follow-up was analyzed with regard to a possible effect of SLND on the prognosis. MATERIALS AND METHODS: A total of 673 consecutive melanoma patients were assessed treated in our center either without SLND (377 patients, pre-SLN group, between January 1995 and March 2000) or with SLND (296 patients, SLN group, between April 2000 and March 2003). The median follow-up was 64.0 months in the pre-SLN and 72.5 months in the SLN group. RESULTS: The pre-SLN group and SLN group did not differ significantly with regard to characteristics of the primary melanoma thickness and ulceration, sex, and age. Kaplan-Meier analyses showed a significantly better recurrence-free survival (P < .001), distant metastases free survival (P = .006), and overall survival (P = .049) for patients of the SLN group; the 5-year melanoma-specific survival rates were 80.3% in pre-SLN patients and 84.8% in SLN patients. Initial metastases in the in-transit region and distant locations were of similar frequency in the pre-SLN and SLN groups (P = .191 and P = .959, respectively), but initial regional lymph node metastases were significantly more frequent in the pre-SLN group (P < .001). CONCLUSIONS: Our data point toward a subgroup of melanoma patients who might have a prognostic benefit from SLN.

Does basal cell carcinoma belong to the spectrum of sorafenib-induced epithelial skin cancers?

The multikinase inhibitor sorafenib is therapeutically used in various malignancies. Multiple cutaneous side effects are well described but recent reports indicated a possible association of epithelial skin cancer growth during sorafenib therapy. To our knowledge, few cases of actinic keratoses and variants of squamous cell carcinomas associated with sorafenib have been published. We report 2 patients who developed a basal cell carcinoma (BCC) while treated with sorafenib. Interestingly BCC is a tumor which has not been described yet in association with sorafenib therapy. The tumors were excised completely. After termination of sorafenib treatment, no new BCCs or other epithelial skin cancers occurred. There is accumulating evidence in the literature that sorafenib and possibly other targeted agents are associated with an increased occurrence of epithelial skin cancers. These observations are summarized here and complemented by the new observation that also BCCs might be associated with sorafenib therapy. The pathogenetic mechanisms are unclear so far but induction of the mitogen-activated protein kinase pathway in wild-type RAF cells by RAF inhibitors might play a role. Patients should be informed of this possible side effect and undergo regular dermatological controls before and during sorafenib therapy.

C-kit-positive multipolar cells in human penile erectile tissue: expression of connexin 43 and relation to trabecular smooth muscle cells.

The aim of this study was to evaluate the hypothesis that interstitial cells might play a role in controlling and synchronizing via gap junctions the electrical activity of smooth muscle cells. The expression and distribution of interstitial cells in human penile erectile tissue was evaluated to determine whether or not cavernous interstitial cells express the gap junction protein connexin 43. Specimens of human corpus cavernosum were excised from full preparations of human penises. Cryostat sections (10 microm to 15 microm) of formaldehyde-fixated tissue segments were incubated using a double-labelling technique with antibodies directed against smooth muscle alpha-actin, c-kit, and connexin 43. Then, sections were exposed to secondary antibodies. Visualization was commenced by means of laser fluorescence microscopy. Double-staining techniques revealed immunosignals specific for c-kit (transmembrane receptor protein) and connexin 43 (gap junction protein) in multipolar cells located adjacent to smooth muscle cells. The number of c-kit-positive cells was significantly lower within the smooth musculature than within bundles of connective tissue surrounding smooth muscle cells of corpus cavernosum or cavernous arteries. Our findings demonstrate the distribution of c-kit- and connexin 43-positive interstitial cells in the connective tissue and smooth musculature of the corpus cavernosum. Additional studies are needed in order to evaluate further the ultrastructure of human penile erectile tissue and enable the identification of gap junctions mediating direct cell-to-cell communication.

[Intravascular lymphoma: two case reports demonstrating the heterogeneity of the disease]. / Intravaskuläre B-Zell-Lymphome: Ein heterogenes Krankheitsbild, dargestellt an 2 Patienten.

Intravascular lymphoma (IVL) is a rare subtype of extranodal large-B-cell lymphoma, histologically characterized by accumulation of clonal lymphocytes in small vessels of different organs. Overall survival is usually poor. The clinical manifestations are highly variable, depending on the involved organs. Cutaneous and neurological involvement is frequent; the cutaneous symptoms are heterogeneous with erythema, erythematous papules and plaques, generalized telangiectases and lesions resembling panniculitis or Kaposi sarcoma. IVL may also be limited to the skin; this entity is included the current classifications. We present here two patients with two different variants of IVL. One showed only skin involvement with panniculitis-like induration and responded well to therapy with Rituximab-CHOP (Rituximab plus Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone). The other patient had distinctive cutaneous and neurological symptoms which did not respond to therapy. By means of these two patients, we present the heterogeneity of IVL and discuss current aspects of diagnosis and treatment.

Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas.

Recent data suggested an increased frequency of KIT aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. However, studies investigating the status of the KIT gene in larger, well-characterised groups of patients with mucosal melanomas are lacking. We analysed 44 archival specimens of 39 well-characterised patients with mucosal melanomas of different locations. c-KIT protein expression was determined by immunhistochemistry, KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 9, 11, 13, 17 and 18. c-KIT protein expression could be shown in 40 out of 44 (91%) tumours in at least 10% of tumour cells. DNA sequence analysis of the KIT was successfully performed in 37 patients. In 6 out of 37 patients (16%) KIT mutations were found, five in exon 11 and one in exon 18. The presence of mutations in exon 11 correlated with a significant stronger immunohistochemical expression of c-KIT protein (P=0.015). Among the six patients with mutations, in two patients the primary tumour was located in the head/neck region, in three patients in the genitourinary tract and in one patient in the anal/rectal area. In conclusion, KIT mutations can be found in a subset of patients with mucosal melanomas irrespective of the location of the primary tumour. Our data encourage therapeutic attempts with tyrosine kinase inhibitors blocking c-KIT in these patients.

Prognostic significance of histopathological parameters in sentinel nodes of melanoma patients.

AIMS: The presence of micrometastases in the sentinel lymph node (SLN) is an important prognostic parameter for melanoma patients. The aim was to determine the prognostic relevance of histopathological characteristics of micrometastases in the SLN, which has not been adequately addressed thus far. METHODS AND RESULTS: In 169 melanoma patients with positive SLN, histopathological features of the SLN were correlated with overall survival (OS) and relapse-free survival (RFS). Tumour burden, expansion of melanoma cells in the periphery (infiltration of capsule) and towards the centre of the SLN [tumour penetrative depth (TPN)] were of prognostic significance for OS and RFS on univariate analysis. Multivariate analysis revealed three independent significant parameters which predict a poor prognosis: presence of infiltration of the SLN capsule, TPN > or = 2 mm and size of the largest tumour deposit > or = 30 cells. CONCLUSIONS: Histopathological analysis of SLN allows the identification of patients with a poor prognosis depending on the location of melanoma cells and tumour burden.