Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF ...inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules.
In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment.
Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent.
Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.
Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor ...family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
•DNp73 induces EMT, invasion, and metastasis•DNp73 interferes with p73-mediated EPLIN expression•EPLIN regulates AKT/STAT3 activities via IGF1R•DNp73 promotes EMT via the EPLIN-IGF1R-AKT/STAT3 axis
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.
Purpose
Low-dose (LD) interferon (IFN) alfa (LDI) has demonstrated a consistent disease-free survival benefit for patients with clinically lymph node–negative melanoma in clinical trials. However, ...the optimal duration of treatment is still under discussion, and no previous trial has evaluated this question specifically. A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma.
Patients and Methods
Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospective randomized, multicenter trial in Germany and Austria. Patients had to be clinically lymph node–negative, and sentinel node biopsy (SLNB) was performed in a majority of cases. They were randomly assigned to receive 3 MU IFNα2a three times a week subcutaneously for either 18 months (arm A) or 60 months (arm B).
Results
Of 850 randomly assigned patients, 840 were eligible for evaluation after a median follow-up of 4.3 years. Tumor thickness and other relevant prognostic factors were well balanced between both groups. SLNB was performed in 635 patients (75.6%), with a positivity rate of 18.0% in arm A and 17.5% in arm B. Neither relapse-free survival (arm A, 75.6% v arm B, 72.6%; P = .72; hazard ratio, 1.05; 95% CI, 0.80 to 1.39) nor distant-metastasis–free survival (81.9% v 79.7%; P = .56; HR, 1.10; 95% CI, 0.80 to 1.52) or overall survival (85.9% v 84.9%; P = .86; HR, 1.03; 95% CI, 0.71 to 1.50) showed significant differences.
Conclusion
A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma.
Purpose: To determine the prognostic significance of a multimarker assay incorporating expression levels of three molecular markers
in primary cutaneous melanoma.
Experimental Design: We assessed ...expression levels of NCOA3, SPP1, and RGS1 using immunohistochemical analysis in a tissue microarray cohort of
395 patients. For each marker, we identified optimal cut-points for expression intensity to predict disease-specific survival
(DSS) and, as a secondary endpoint, sentinel lymph node (SLN) status. The cumulative overexpression of all three markers was
embodied in a multimarker index, and its prognostic effect on DSS and SLN status was assessed using Cox regression, Kaplan-Meier
analysis, and logistic regression. The prognostic effect of this multimarker assay on DSS was assessed in an independent cohort
of 141 patients, in which marker expression levels were scored using immunohistochemical analysis of stained tissue sections.
Results: Increasing multimarker index scores were significantly predictive of reduced DSS and increased SLN metastasis in the 395-patient
cohort. Multivariate logistic regression analysis revealed multimarker expression scores as an independent predictor of SLN
status ( P = 0.001). Multivariate Cox regression analysis showed the independent effect of the multimarker index on DSS ( P < 0.001). The multimarker index was the most significant factor predicting DSS when compared with other clinical and histologic
factors, including SLN status ( P = 0.002). Multimarker expression scores were also the most significantly predictive of DSS in the independent cohort ( P = 0.01).
Conclusions: These results describe a multimarker assay with independent prognostic effect on the prediction of survival associated with
melanoma in two distinct cohorts. (Clin Cancer Res 2009;15(22):6987–92)
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.
We previously demonstrated that the aspartate protease cathepsin D is activated by ceramide derived from acid sphingomyelinase. Increased expression of cathepsin D in the skin has been reported in ...wound healing, psoriasis and skin tumors. We explored specific functions of cathepsin D during epidermal differentiation. Protein expression and enzymatic activity of cathepsin D increased in differentiated keratinocytes in both stratified organotypic cultures and in mouse skin during epidermal barrier repair. Treatment of cultured keratinocytes with exogenous cathepsin D increased the activity of transglutaminase 1, known to cross-link the cornified envelope proteins involucrin and loricrin during epidermal differentiation. Inhibition of cathepsin D by pepstatin A suppressed the activity of transglutaminase 1. Cathepsin D-deficient mice revealed reduced transglutaminase 1 activity and reduced protein levels of the cornified envelope proteins involucrin and loricrin. Also, amount and distribution of cornified envelope proteins involucrin, loricrin, filaggrin, and of the keratins K1 and K5 were significantly altered in cathepsin D-deficient mice. Stratum corneum morphology in cathepsin D-deficient mice was impaired, with increased numbers of corneocyte layers and faint staining of the cornified envelope only, which is similar to the human skin disease lamellar ichthyosis. Our findings suggest a functional link between cathepsin D activation, transglutaminase 1 activity and protein expression of cornified envelope proteins during epidermal differentiation.
Divided, or so-called kissing nevi of the penis, which are separated during embryogenesis, are very rare, with only seven studies reported to date. We present a case of a 30-year-old patient with a ...divided nevus located at the penis that rapidly changed in size and color within 4 months. These clinical features and the histopathologic appearance of both parts led to the diagnosis of malignant melanoma. Melanoma of the penis is very rare, and the prognosis is poor. This could be the first case of a “kissing melanoma” of the penis reported in published studies.
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.
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.
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).
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).
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.
•The 11-gene expression profiling (GEP) score enables more precise prognosis than the American Joint Committee on Cancer classification.•Patients with low risk for relapse and death can be detected in stage II and III.•The 11-GEP assay serves to select high-risk patients for adjuvant therapy.•This assay appears to be of significant translational relevance.
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