Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a prognosis limiting complication of allogeneic stem cell transplantation. The molecular mechanisms underlying cGVHD are incompletely understood, and targeted therapies are not yet established for clinical use. Here we examined the role of the hedgehog pathway in sclerodermatous cGVHD. Hedgehog signaling was activated in human and murine cGVHD with increased expression of sonic hedgehog and accumulation of the transcription factors Gli-1 and Gli-2. Treatment with LDE223, a highly selective small-molecule antagonist of the hedgehog coreceptor Smoothened (Smo), abrogated the activation of hedgehog signaling and protected against experimental cGVHD. Preventive therapy with LDE223 almost completely impeded the development of clinical and histologic features of sclerodermatous cGVHD. Treatment with LDE223 was also effective, when initiated after the onset of clinical manifestations of cGVHD. Hedgehog signaling stimulated the release of collagen from cultured fibroblasts but did not affect leukocyte influx in murine cGVHD, suggesting direct, leukocyte-independent stimulatory effects on fibroblasts as the pathomechanism of hedgehog signaling in cGVHD. Considering the high morbidity of cGVHD, the current lack of efficient molecular therapies for clinical use, and the availability of well-tolerated inhibitors of Smo, targeting hedgehog signaling might be a novel strategy for clinical trials in cGVHD.

Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic bone marrow transplantation, and has a major effect on the long-term prognosis. The molecular mechanisms underlying cGvHD have been only partially revealed, and molecular targeted therapies have not yet been established for clinical use. We examined the effects of the combined inhibition of the Abelson kinase (c-Abl) and platelet-derived growth factor receptors (PDGFR) in experimental sclerodermatous cGvHD. Treatment using imatinib or nilotinib abolished the aberrant activation of c-Abl and PDGFR and protected against experimental cGvHD. Preventive therapy using imatinib or nilotinib inhibited the development of sclerodermatous cGvHD. Clinical features such as weight loss, alopecia, and skin ulcers, and histologic features with dermal thickening and accumulation of collagen were significantly reduced in mice that received imatinib or nilotinib therapy, but not in mice that received prednisone therapy. Of note, imatinib and nilotinib were also effective for treatment of experimental cGvHD that had already been clinically manifested. In summary, the combined inhibition of c-Abl and PDGFR is effective for prevention and treatment of experimental sclerodermatous cGvHD. Considering the high morbidity associated with cGvHD, the lack of efficient molecular therapies for clinical use, and first positive signals from uncontrolled studies of imatinib, combined inhibition of c-Abl and PDGFR might be a promising future strategy for treatment of sclerodermatous cGvHD.

Palliative treatment of skin metastases in dermato-oncology.

Patients with metastatic melanoma, but also other solid tumors (e.g., lung or breast cancer), may develop cutaneous metastases in advanced stages. The goal of treatment is to alleviate symptoms such as pain, fetor, secretions, or bleeding. Current treatment modalities are based on a multimodal treatment approach. Beside surgery, treatment options such as electrochemotherapy, isolated limb perfusion, radiotherapy, and local administration of cytokines or chemotherapy agents are available. In case of concomitant visceral metastases, this local treatment approach may not affect overall survival, but the palliation of these tumor-associated symptoms very often improves the quality of life for the patient.

Cutaneous side effects of combined therapy with sorafenib and pegylated interferon alpha-2b in metastatic melanoma (phase II DeCOG trial).

BACKGROUND AND OBJECTIVES: During a clinical study with combined therapy of sorafenib and pegylated interferon alpha-2b (SoraPeg study) of the German Dermatologic Oncology Group (ADO/DeCOG), multiple and severe cutaneous side effects were observed. This study sought to analyze these cutaneous side effects, particularly because future studies with combinations of interferon alpha and targeted therapies are planned. PATIENTS AND METHODS: In a multicenter phase-II-DeCOG study (NCT00623402) in 10 dermato-oncology centers, 55 patients with metastatic melanoma received a combination of sorafenib (2 x 400 mg/day orally) and pegylated interferon alpha-2b (3 µg/kg body weight 1 x/week subcutaneously). All cutaneous side effects were documented. RESULTS: Forty-one patients (74.5 %) developed cutaneous side effects, particularly exanthems (51.2 %), hand-foot syndrome (36.5 %), alopecia (36.5 %) and pruritus (24.4 %). Due to the cutaneous side effects, dose reductions were required in 10 patients, interruption of therapy in 10 cases and permanent discontinuation of therapy and in one patient with extensive follicular-cystic lesions. Exanthems were seen more frequently in women (76.2 %) than in men (23.8 %). The occurrence of cutaneous side effects was not correlated with clinical outcome or prognosis. CONCLUSIONS: The combination of sorafenib/pegylated interferon alpha-2b caused more cutaneous side effects than have been reported for single agents. Despite intensive dermatologic management of the cutaneous side effects 24 % of patients required a dose modification.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BACKGROUND: Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database. METHODS: Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed. RESULTS: Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN. CONCLUSIONS: These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Prognostic significance of an 11-gene RNA assay in archival tissue of cutaneous melanoma stage I-III patients.

PURPOSE: The purpose of this study was to validate the results of an 11-gene expression profiling (GEP) assay which aims to improve the precision of individual prognosis beyond conventional American Joint Committee on Cancer staging for patients with cutaneous melanoma. METHODS: The reverse transcriptase polymerase chain reaction test of 11 prospectively selected genes was performed on 291 formalin-fixed, paraffin-embedded primary tumours of patients with stage I-III cutaneous melanoma. The expression levels of eight prognostic and three reference genes were used in a predefined algorithm to calculate a numerical score (-0.84 to 3.53) and then assign each patient to a preselected risk group (low versus high score) for melanoma-specific survival (MSS). RESULTS: One hundred twenty-seven patients were allocated to the low-score group, with a corresponding five-year disease-free survival (DFS) and MSS of 95% and 99%, respectively. 164 patients were allocated to the high-score group, with a corresponding five-year DFS and MSS of 78% and 88%. Continuous regression analysis demonstrated decreasing MSS probabilities with increasing scores. In a multivariate cox regression, only the 11-GEP, tumour thickness and age were statistically associated with MSS (p = 0.0068, 0.002 and 0.0159). CONCLUSIONS: The 11-GEP has been validated as an independent predictor of outcome for melanoma patients. More specifically, using an 11-GEP score cut-off of ≤0, the assay can identify patient cohorts with 10-year survival probabilities well above 90%. This information may be used in the decision-making for a potential adjuvant therapy.

Clinicopathologic prognostic markers of survival: an analysis of 259 patients with malignant melanoma >or=1 mm.

The histopathologic status of the sentinel node (SN) and the ulceration of the primary tumor are important indicators of the clinical outcome of melanoma patients. The purpose of this study was to investigate potential correlations between prognostic factors and the sentinel lymph node status as well as their influence on disease-free survival (DFS), distant metastases-free survival (DMFS), and overall survival (OS). The medical records of 259 melanoma patients who underwent sentinel lymph node dissection between 2000 and 2006 were analyzed. DFS, DMFS, and OS were assessed. A uni- and a multivariate analysis to determine prognostic factors were performed. Histologic type, Clark's level, and Breslow's tumor thickness were the only parameters that showed a significant correlation with a positive SN. The univariate analysis revealed SN positivity (DFS and DMFS: p < 0.001; OS: p = 0.039) and ulceration (DFS: p < 0.001; DMFS: p = 0.001; OS: p = 0.003) to be significant prognostic markers. However, ulceration was the only independent prognostic factor for OS that was upheld by the multivariate analysis (p = 0.006; HR 3.89; CI 1.48-10.27). In stage I/II melanoma patients, ulceration of the primary tumor was the strongest prognostic factor for RFS, DMFS, and OS and superior to the pathology status of the SN.

Distinct Clinicopathological and Prognostic Features of Thin Nodular Primary Melanomas: An International Study from 17 Centers.

BACKGROUND: Nodular melanoma (NM) is more likely to be fatal compared with other melanoma subtypes, an effect attributed to its greater Breslow thickness. METHODS: Clinicopathological features of NM and superficial spreading melanoma (SSM) diagnosed in 17 centers in Europe (n = 15), the United States, and Australia between 2006 and 2015, were analyzed by multivariable logistic regression analysis, with emphasis on thin (T1 ≤ 1.0 mm) melanomas. Cox analysis assessed melanoma-specific survival. All statistical tests were two sided. RESULTS: In all, 20 132 melanomas (NM: 5062, SSM: 15 070) were included. Compared with T1 SSM, T1 NM was less likely to have regression (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.29 to 0.72) or nevus remnants histologically (OR = 0.60, 95% CI = 0.42 to 0.85), and more likely to have mitoses (OR = 1.97, 95% CI = 1.33 to 2.93) and regional metastasis (OR = 1.77, 95% CI = 1.02 to 3.05). T1 NM had a higher mitotic rate than T1 SSM (adjusted geometric mean = 2.2, 95% CI = 1.9 to 2.5 vs 1.6, 95% CI = 1.5 to 1.7 per mm2, P < .001). Cox multivariable analysis showed a higher risk for melanoma-specific death for NM compared with SSM for T1 (HR = 2.10, 95% CI = 1.24 to 3.56) and T2 melanomas (HR = 1.30, 95% CI = 1.01 to 1.68), and after accounting for center heterogeneity, the difference was statistically significant only for T1 (HR = 2.20, 95% CI = 1.28 to 3.78). The NM subtype did not confer increased risk within each stratum (among localized tumors or cases with regional metastasis). CONCLUSIONS: T1 NM (compared with T1 SSM) was associated with a constellation of aggressive characteristics that may confer a worse prognosis. Our results indicate NM is a high-risk melanoma subtype that should be considered for inclusion in future prognostic classifications of melanoma.

Impact of the site of anastomosis after oncologic esophagectomy on quality of life--a prospective, longitudinal outcome study.

BACKGROUND: For patients undergoing oncologic surgery, the quality of life (QoL) is generally accepted as an important outcome parameter in addition to long-term survival, mortality, and complication rates. Our study focused on outcome in terms of QoL in patients with esophageal cancer, comparing the sites of anastomosis (cervical versus thoracic anastomosis). METHODS: In a prospective longitudinal single-center study from 1998 to 2005, 105 patients underwent surgery for esophageal cancer. To assess QoL the EORTC-QLQ-C-30 and a tumor-specific module were administered before surgery, at discharge, and three, six, 12, and 24 months after surgery. Clinical data were collected prospectively and follow-up was performed every six months. RESULTS: The histological type was squamous cell carcinoma in 51.4% of the cases, adenocarcinoma in 41.9%, and some other type in 6.7%. There was no significant difference between cervical and thoracic anastomosis with regard to morbidity, mortality, and survival rates (30% five-year survival rate), whereas tumor stage was a significant (p < 0.001) prognostic factor. Most QoL scores dropped significantly below baseline in the early postoperative period. Even though they recovered slowly during the follow-up period, they never reached preoperative levels again. There was no statistically significant difference in any of the QoL scales between patients with a cervical or a thoracic anastomosis. CONCLUSIONS: Esophageal resections are associated with significant deterioration of QoL, which persists during the follow-up period. The surgical technique and position of the esophagogastrostomy did not affect QoL deterioration.

Multiple skin metastases of malignant melanoma with unusual clinical and histopathologic features in an immunosuppressed patient.

Immunosuppressive regimens may have significant impact on the number of pigmented lesions and the clinical appearance of nevi. Whether immunosuppression can also influence the clinical and histopathologic appearance of malignant melanocytic lesions is still a matter of debate. A patient was immunosuppressed because of heart and bone marrow transplantation. A clinically inconspicuous mole was removed from the left flank and was considered to be a papillomatous nevus. After 1 year, the patient developed multiple pigmented lesions over the entire body, which presented clinically as benign papillomatous nevi and histologically as atypical Spitz nevi. Three months later melanoma metastases were removed from the patient's left axilla, which finally resulted in the death of the patient. Thus, in retrospect, the eruptive pigmented lesions have to be considered as cutaneous melanoma metastases. The atypical clinical and histopathologic appearance of the melanocytic lesions as well as the course of disease may have been influenced by the immunosuppression.

Metastasizing epithelioid hemangioendothelioma of the nose in childhood.

Epithelioid hemangioendothelioma (EHE) arising in the skin is extremely rare, and the majority of documented cases have developed in soft tissues or parenchymatous organs. We report on a 9-year-old boy who presented with a painful erythematous plaque on the nose. Histopathological findings showed a dermal tumor composed of epithelioid cells with moderate cellular atypia and characteristic intracytoplasmic vacuoles. Immunohistochemical stainings confirmed the vascular nature of the tumor. On the basis of these findings, the diagnosis of an EHE was made. Then, two cervical lymph nodes were excised and adjuvant therapy with interferon alpha 2b was initiated. Eighteen months after diagnosis, there is no evidence of local tumor recurrence or metastases. To our knowledge, this is the first report of a metastasizing cutaneous EHE on the nose in childhood. As our case shows, this rare tumor entity has to be considered as a differential diagnosis in neoplasms of the skin, even in childhood.

Metastatic melanoma: scientific rationale for sorafenib treatment and clinical results.

In advanced metastatic melanoma (AJCC stage IV), the prognosis is still poor, and views differ on the appropriate systemic treatment for these patients. Therefore, new approaches in therapeutic regimens are mandatory. Sorafenib is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. These kinases include Raf kinases and the vascular endothelial growth factor (VEGF) receptor. Sorafenib has been evaluated as a single therapy agent as well as in combination with various chemotherapeutical drugs in a number of clinical trials. The vast majority of clinical data exists for patients with advanced renal cell cancer for which sorafenib has been approved by the FDA and EMEA. Very recently, sorafenib was approved for advanced hepatocellular cancers due to its overall survival improvement. Since B-raf gene mutations have been found in 69% of melanoma cell lines, sorafenib was brought into various phase I/II and phase III trials in metastatic melanoma. However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. However, these data need to be confirmed in prospective randomized phase III trials. Till then, sorafenib remains an interesting but still experimental new agent for melanoma.

Long-term survival analysis in metastatic melanoma: serum S100B is an independent prognostic marker and superior to LDH.

BACKGROUND: The prognosis of metastatic melanoma is poor. The purpose of this study was to perform a long-term survival analysis on patients with advanced melanoma to determine clinical and laboratory prognostic factors for treatment outcome and long-term survival. The prognostic importance of S100B serum levels on overall survival compared to lactate dehydrogenase (LDH) was evaluated. PATIENTS AND METHODS: The medical records of 105 AJCC (American Joint Committee on Cancer) stage IV melanoma patients from 1994 to 2001 were analyzed retrospectively. Median time to progression and overall survival were assessed. Univariate and multivariate analysis were performed to determine prognostic factors. RESULTS: 86 (81.9%) of the 105 patients died during the observation period. In univariate analysis, pre-therapeutic LDH and S100B levels in serum samples (p = 0.01 and p = 0.002, respectively), tumor stage (AJCC IVa-IVc, p = 0.005), and response to the firstline therapy (p < 0.001) were found to be significant prognostic markers. However, in the multivariate analysis, pre-therapeutic S100B serum levels (p = 0.005, odds ratio (OR): 2.22, confidence interval (CI): 1.22-4.1) as well as presence of brain metastases (p = 0.009, OR: 5.08, CI: 1.51-17.05) were the only independent prognostic factors for overall survival. CONCLUSION: In metastatic melanoma, S100B is a strong prognostic factor for overall and long-term survival, and superior to LDH.

Multiple erythema migrans--manifestation of systemic cutaneous borreliosis.

Erythema migrans is the clinical hallmark lesion of a stage I infection with Borrelia burgdorferi. Multifocal lesions are rarely observed in Europe and thus may be missed, in particular when the typical clinical appearance of the pronounced advancing margin is missing. We present three patients with such a clinical appearance which caused differential diagnostic problems. Multiple erythema migrans represent an early stage of systemic infection. Thus early diagnosis and rapid initiation of therapy are warranted.

Clinically defined subgroups of mycosis fungoides display differing histopathological features at initial biopsy.

Most patients with mycosis fungoides (MF) remain in early disease stages but some progress to tumor stage. The individual course of the disease cannot be predicted. We wanted to assess the clinical and histological characteristics of the first available biopsy. An end-of-spectrum approach with two groups was used, comparing MF remaining long-term stable in T1a ('MF stable') and MF with later tumor development or present T3 stage ('MF tumor'). The clinical and histomorphological features of the initial skin biopsy were compared. Patients in the 'MF tumor' group presented initially with higher disease stages. The first biopsies of 'MF tumor' patients showed significantly higher infiltrate density and depth, more large cells and a higher proliferative index. In summary, long-term stable MF seems to differ in clinical and histopathological parameters from MF with T3 evolution/presence already at the time point of the initial biopsy. Our findings might indicate a predetermined biologic behavior.