Purpose: Raf/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation. We focus on associated cutaneous toxicity and we attempt to understand the underlying pathophysiology and design treatment strategies.Experimental Design: Dermatologic conditions of 22 patients with unresectable melanoma stage III/ IV in a phase II trial were evaluated. Thirteen patients received AZD6244 initially, and nine patients were treated with AZD6244 following tumor progression with temozolomide. Biopsies were compared with matched controls in normal skin. Immunohistochemistry was performed. Half-side treatment of acute skin toxicity compared therapeutic options.Results: Nineteen of 22 (86%) AZD6244-treated patients presented with cutaneous eruptions. Seventeen patients (77%) developed acute papulopustular rash. Chronic skin changes included xerosis, paronychia, and fissured fingertips, resembling cutaneous toxicity of epidermal growth factor receptor inhibition. In addition, we observed reduced pigmentation of hair and skin. Histology of acute skin lesions revealed a significant increase of apoptotic keratinocytes (P = 0.0008), focal neutrophilic infiltrates, destruction of the adnexal structures by neutrophils, and reduced cytokeratins. A significant proliferation shift from basal to suprabasal keratinocytes was shown in acute and chronic lesions. The number and viability of melanocytes was not affected. Corticosteroids plus antibacterial topical therapy ameliorate acute skin toxicity.Conclusions: AZD6244-associated skin reactions partly overlap with those observed upon epidermal growth factor receptor inhibition. Additionally, pigmentation of skin and hair is affected. The interruption of the MEK signaling pathway results in an acute keratinocyte stress response with disturbed epidermal homeostasis, inflammation, and tissue damage. Chronic adaptation controls inflammatory tissue damage but leads to cutaneous malfunctions that explain chronic skin toxicity. Clin Cancer Res; 16(3); 1058-64. ©2010 AACR.Mutations and amplifications of oncogenes are frequent genetic alterations in cancer that result in the constitutive activation of pathways promoting proliferation and survival (1). For example, kinases involved in the RAS-RAFmitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling pathway are thus activated in most melanomas (2, 3). Critically, this particular malignancy is increasing in incidence worldwide and the current lifetime risk is estimated to be 1:70 for European populations (4).Advanced melanoma palliative therapy using cytostatic drugs, either alone or in combinatory settings, has yielded disappointing results (5). For patients with distant metastases, treatment with dacarbazine remains the standard chemotherapy despite a response rate of under 10% (6). Patients with advanced melanoma are therefore often treated in controlled clinical trial...

Ipilimumab, an immune checkpoint inhibitor, is approved for treatment metastastic melanoma and is a promising agent against other malignancies. There is some preliminary evidence from case reports that ipilimumab treatment may be associated with pulmonary side effects. However, data from prospective studies on ipilimumab-related pulmonary toxicity are still scarce. Serial spirometries and measurements of CO-diffusion capacity (DLCO) in patients with metastatic melanoma before and during treatment with ipilimumab were performed. A reduction from baseline of forced vital capacity (FVC) of ≥ 10%, or ≥ 15% of DLCO was defined as clinically meaningful and indicative for pulmonary toxicity. Of 71 patients included in this study, a clinically meaningful lung function decline was registered in 6/65 (9%), 5/44 (11%), and 9/38 (24%) patients after 3, 6, and 9 weeks of treatment initiation, respectively. Even after adjusting for age, concomitant melanoma treatment, progressive pulmonary metastases, and baseline pulmonary function values, mean ± SD DLCO decreased significantly during follow-up (-4.3% ± 13.6% from baseline, p = 0.033). Only 7% of patients reported respiratory symptoms. Clinically manifest ipilimumab-related pneumonitis was diagnosed only in one patient (1.4%). DLCO decline maybe an early indicator of subclinical pulmonary drug toxicity. Therefore, routine pulmonary function testing including DLCO measurement during treatment might help for risk stratification to screen for ipilimumab-related pneumonitis.

In patients with Trichophyton rubrum infections, refractory to itraconazole treatment, altered drug absorption or drug interactions has to be considered. Careful monitoring and adjustment of itraconazole is of vital importance.

PURPOSE: This study aims to compare the use of 18F-FDG-PET/CT, CT, brain MRI, and tumormarker S-100B in chemotherapy response assessment of stage IV melanoma patients. METHODS: In 25 patients with stage IV melanoma, FDG-PET/CT and S-100B after 2-3 months (three cycles) of chemotherapy was compared with baseline PET/CT and baseline S-100B. Retrospectively, the response was correlated with the outcome. In patients with clinical suspicion for brain metastases, MRI or CCT was performed. RESULTS: There was agreement between FDG-PET/CT and CT regarding response to chemotherapy in all patients. There was a clear trend to a longer OS of PET/CT responders (n = 10) compared with PET/CT non-responders (n = 15; p = 0.072) with remarkably better 1-year OS of 80% compared to 40% (p = 0.048). There was a significant longer PFS of PET/CT responders compared with PET/CT non-responders (p = 0.002). S-100B was normal at baseline in eight of 22 patients where it was available. Chemotherapy response assessment with S-100B failed to show correlation with OS or PFS. Eleven patients developed brain metastases during treatment, first detected by PET/CT in two and by MRI or CCT in nine of 11 patients. Appearance of brain metastases was associated with a poor survival. CONCLUSIONS: 18F-FDG-PET/CT and CT alone are equally suitable for chemotherapy response assessment in melanoma patients and clearly superior to S-100B. PET/CT responders have better early survival, but this is shortlived due to late therapy failure-often with brain recurrence. Additional brain MRI for therapy response assessment in such high-risk patients is mandatory to detect brain metastases missed by PET/CT. Chemotherapy Response Assessment in MethodsIn 25 patients with stage IV melanoma FDG-PET/CT and S-100B after 2-3 months (3 cycles) of chemotherapy was compared with baseline PET/CT and baseline S-100B.Retrospectively, the response was correlated with the outcome. In patients with clinical suspicion for brain metastases MRI or CCT was performed. ResultsThere was agreement between FDG-PET/CT and CT regarding response to chemotherapy in all patients. There was a clear trend to a longer OS of PET/CTresponders (n=10) compared with PET/CT non-responders (n=15) (p=.072) with remarkably better 1-year OS of 80% compared to 40% (p=.048). There was a significant longer PFS of PET/CT-responders compared with PET/CT nonresponders (p=.002). S-100B was normal at baseline in 8 of 22 patients where it was available. Chemotherapy response assessment with S -100B failed to show correlation with OS or PFS. 11 patients developed brain metastases during treatment, first detected by PET/CT in 2 and by MRI or CCT in 9 of 11 patients.Appearance of brain metastases was associated with a poor survival.

Our findings revealed a differentiated and complex picture about relationship changes over time, which also might aid in the development of support programs for couples dealing with advanced cancer, focusing on the aspects of caring, closeness/distance regulation, and communication patterns.