Joanna Mangana

Sorafenib in melanoma.

Introduction: Sorafenib is an orally available multi-kinase inhibitor that inhibits tumor proliferation by targeting multiple kinases including the vascular endothelial growth factor receptors VEGFR1, VEGFR2, VEGFR3 and the platelet-derived growth factor receptor PDGFR, and it targets tumor progression by inhibiting FLT3, C-Kit and BRAF. Since BRAF mutations are frequent in melanoma, sorafenib was investigated in various Phase I, II and III clinical trials. The drug is well tolerated with mild to moderate adverse effects, which are mostly limited to cutaneous toxicity, diarrhea and fatigue. Areas covered: Systematic literature review of the randomized trials using PubMed was performed. Original articles were reviewed and citations from those were also considered. Additionally, clinical trial databases were examined to identify and summarize ongoing trials of sorafenib in melanoma patients. Expert opinion: Sorafenib as a monotherapy or in combination with chemotherapy is of limited use. Combining it with dacarbazine doubled the response rate and the progression-free survival in metastatic melanoma patients. Unfortunately, these results have never been evaluated in large randomized Phase III clinical trials. According to the trials conducted so far a subpopulation of patients experience substantial benefit, therefore it is essential to identify biomarkers to select the subgroups of patients that are more likely to respond to sorafenib. Furthermore, other less frequent subtypes such as mucosal or ocular melanoma still constitute promising targets; academic institutions are currently launching investigator-initiated trials in these indications.

Prevalence of Merkel Cell Polyomavirus among Swiss Merkel Cell Carcinoma Patients

Background: Merkel cell carcinoma (MCC) is a malignant neuroendocrine neoplasm which shares structural and immunohistochemical features with neuroectodermally derived cells. One hypothesis claims that it arises from Merkel cells, highly innervated neuroendocrine cells involved in mechanoreception in the skin. The incidence rate of this cancer increases with age and sun exposure as well as after immunosuppression. Recently, the clonal integration of a newly identified polyomavirus called Merkel cell polyomavirus (MCPyV) was reported in up to 80% of MCC tissue. Here we report the incidence rate of MCPyV in MCC patients in Switzerland. Methods: We performed polymerase chain reaction in a collection of 32 samples obtained from pathology institutes around Switzerland. We used three different published primer sets. As control groups we used 7 squamous cell carcinoma samples and 11 normal skin samples. Conclusions: We detected viral DNA in 20 out of 30 cases of MCC and in 0 out of 19 control samples. The presence of viral DNA in 66.6% of our MCC tissue specimens confirms the high prevalence of MCPyV in MCC patients described in American, German, French and Hungarian patient collections.

Melanoma after laser therapy of pigmented lesions – circumstances and outcome

The use of laser therapy in the treatment of pigmented lesions is a controversial issue as it can delay melanoma diagnosis and may negatively impact mortality. Few cases of melanoma after laser therapy have been reported. It is still unknown whether melanoma can be induced by lasers. We discuss the outcomes of twelve patients presenting with melanoma subsequent to previous treatment with laser. In four patients, a skin biopsy was performed before laser treatment. Histology was re-evaluated by a panel of experienced dermatopathologists and analyzed in the context of clinical and photo-optical data. There was evidence for pathological misdiagnosis in two cases. The other two cases initially presented with non-suspicious features before laser treatment and were clearly diagnosed as melanoma thereafter, opening the possibility of melanoma induction by laser treatment. Most patients were female and presented with facial lesions. Three patients have already died of melanoma and two are in stage IV, showing progressive disease with distant metastases. Laser therapy is a common treatment for pigmented lesions, increasing the risk of delayed melanoma diagnosis. This prevents appropriate and timely therapy, and may therefore lead to a fatal outcome. A careful examination of all pigmented lesions using surface microscopy and representative biopsies in combination with a close follow-up is recommended.

Skin problems associated with pegylated liposomal doxorubicin-more than palmoplantar erythrodysesthesia syndrome

Liposomal pegylated doxorubicin is an encapsulation form of doxorubicin, with an improved pharmacokinetic profile and the ability to selectively accumulate into tumor tissue. As a result, the tolerated dose of the drug can be increased, followed by a reduced incidence of neutropenia and cardiotoxicity in comparison to doxorubucin treatment. However, a common adverse dose-schedule limiting effect of the treatment is palmoplantar erythrodysesthesia syndrome. In this retrospective study we included six patients hospitalised in the University Hospital of Zurich during the last 2 years, in connection with side effects caused by pegylated liposomal doxorubicin. These patients received this chemotherapeutic agent for treatment of various malignancies such as breast cancer, ovarian cancer, mycosis fungoides and cutaneous B-cell lymphoma. Three of six patients in this study developed classical palmoplantar erythrodysesthesia, one developed palmoplantar erythrodysesthesia associated with extensive bullous disease, one developed eruption of lymphocyte recovery syndrome and one developed intertrigo like dermatitis with stomatitis. Pegylated liposomal doxorubicin induces various skin reactions including palmoplantar erythrodysesthesia syndrome. However, the exact clinical presentation might depend on pre-existing skin diseases.

Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78–13.2) compared to 8.26 months (95% CI 6.02–19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn’t reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

Does the distribution pattern of brain metastases during BRAF inhibitor therapy reflect phenotype switching

Brain metastases (brain mets) are frequent in metastatic melanoma patients. The aim of this study was to investigate the morphology and progression pattern of brain mets in melanoma patients treated with BRAF inhibitors (BRAFi) compared with patients who did not receive targeted therapy (BRAFi group and control group). The number and size of brain mets were compared between a baseline and a comparative MRI at progression. The number of brain mets was grouped into seven number classes (N=1–4, N=5–10, N=11–20, N=21–30, N=31–40, N=41–50, and N>50) and its difference was reported as the change of class that occurred. The mean size of the newly developed lesions was determined by representative measurements and the evolution of three persisting target lesions was assessed on the basis of modified RECIST criteria. Of 96 patients studied, 42 were in the BRAFi group and 54 were in the control group. Patients under BRAFi treatment had a significantly greater increase in the number of brain mets, where the median change of class for the BRAFi compared with the control group was 2 versus 0 (P<0.01). The mean size of the new lesions was smaller in the BRAFi group. Pre-existing target lesions did not show any prominent or different patterns of how they evolved in either group. Brain mets in patients treated with BRAFi showed a progression pattern characterized by a high propensity to disseminate, which might reflect an in-vivo manifestation of phenotype switching in response to targeted therapy, with a predominance of the invasive/migratory tumor cell phenotype. Drivers of invasiveness may present promising targets for therapeutic interventions.

Multicenter, real-life experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland

Metastatic melanoma is a highly aggressive disease. Recent progress in immunotherapy (IT) and targeted therapy (TT) has led to significant improvements in response and survival rates in metastatic melanoma patients. The current project aims to determine the benefit of the introduction of these new therapies in advanced melanoma across several regions of Switzerland. This is a retrospective multicenter analysis of 395 advanced melanoma patients treated with standard chemotherapy, checkpoint inhibitors, and kinase inhibitors from January 2008 until December 2014. The 1-year survival was 69% (n=121) in patients treated with checkpoint inhibitors (IT), 50% in patients treated with TTs (n=113), 85% in the IT+TT group (n=66), and 38% in patients treated with standard chemotherapy (n=95). The median overall survival (mOS) from first systemic treatment in the entire study cohort was 16.9 months. mOS of patients treated either with checkpoint or kinase inhibitors (n=300, 14.6 months) between 2008 and 2014 was significantly improved (P<0.0001) compared with patients treated with standard chemotherapy in 2008–2009 (n=95, 7.4 months). mOS of 61 patients with brain metastases at stage IV was 8.1 versus 12.5 months for patients without at stage IV (n=334), therefore being significantly different (P=0.00065). Furthermore, a significant reduction in hospitalization duration compared with chemotherapy was noted. Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in real life and the results are consistent with published prospective trial data.

Efficacy and safety of oral alitretinoin in severe oral lichen planus – results of a prospective pilot study

Patients with severe oral lichen planus refractory to standard topical treatment currently have limited options of therapy suitable for long‐term use. Oral alitretinoin (9‐cis retinoic acid) was never systematically investigated in clinical trials, although case reports suggest its possible efficacy.

A Longitudinal Analysis of IDO and PDL1 Expression during Immune- or Targeted Therapy in Advanced Melanoma

A deepened understanding of the cellular and molecular processes in the tumor microenvironment is necessary for the development of precision immunotherapy (IT). We simultaneously investigated CD3, PDL1, and IDO by immunohistochemistry in paired biopsies from various organs of 43 metastatic melanoma patients treated with IT and targeted therapy (TT). Intraindividual biopsies taken after a period of weeks to months demonstrate discordant results in 30% of the cases. Overlap of IDO and PDL1 increased after therapy. IT only marginally impacted PDL1 expression over time in contrast to TT. Standardized repeated assessments of multiple immune markers in repeated biopsies will generate detailed insights in melanomas immune evolution and adaption during therapies and might be used to support treatment decisions.