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  • 1
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Melanoma Research Vol. 26, No. 3 ( 2016-06), p. 304-307
    In: Melanoma Research, Ovid Technologies (Wolters Kluwer Health), Vol. 26, No. 3 ( 2016-06), p. 304-307
    Abstract: Cutaneous toxicities under therapy with selective BRAF inhibitors such as vemurafenib or encorafenib (LGX818) are frequent, including plantar hyperkeratosis, squamous cell carcinoma, and second primary melanoma. Pyogenic granuloma is a benign, rapidly growing, eruptive hemangioma that often bleeds and ulcerates. Common causes are mechanical trauma and cast immobilization, as well as multiple drugs such as retinoids and antineoplastic agents. However, the development of pyogenic granuloma under treatment with encorafenib (LGX818) has not yet been reported. These three cases might be further examples for paradoxical activation of the mitogen-activated protein kinase pathway. We report three male patients with metastatic BRAFV600E-mutated melanoma who developed pyogenic granulomas 16, 10, and 12 weeks after treatment initiation with the selective BRAF inhibitors vemurafenib or encorafenib (LGX818). Except for one patient receiving retinoids, the clinical history for other frequent causes of pyogenic granuloma was negative. Pyogenic granulomas are not listed in the drugs investigator brochure but seem to be associated with selective BRAF inhibitors and might be a cutaneous phenomenon of paradoxical mitogen-activated protein kinase pathway activation. This correlation has to be confirmed by further observations.
    Type of Medium: Online Resource
    ISSN: 0960-8931
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1095779-0
    detail.hit.zdb_id: 2030780-9
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  • 2
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Melanoma Research Vol. 27, No. 4 ( 2017-08), p. 396-398
    In: Melanoma Research, Ovid Technologies (Wolters Kluwer Health), Vol. 27, No. 4 ( 2017-08), p. 396-398
    Abstract: Treatment of melanoma remains a challenge in advanced disease. Recently, the molecular differentiation in BRAF-mutated, NRAS-mutated and c-kit-mutated melanomas led to new treatment strategies. Different trials show that imatinib or nilotinib lead to meaningful responses in c-kit-mutated melanoma patients. There are little published data on sequential inhibition using these two drugs in melanoma. We describe the sequential use of imatinib after nilotinib in a c-kit-mutated melanoma patient, who progressed on interferon, Allovectin, dacarbazine, nilotinib and ipilimumab, and was finally treated with the c-kit inhibitor imatinib. From July 2011 to September 2011, the patient received ipilimumab (four doses with 3 mg/kg). Clinical assessment after immunotherapy showed disease progression. Therefore, a treatment change to imatinib 800 mg daily was made from February 2012 to May 2013. Under this treatment, the patient showed a partial response as per the RECIST criteria. The present lesions continued responding (computed tomography scans: May 2012–March 2013). Unfortunately, in October 2012, new brain metastases developed. Nevertheless, the use of c-kit inhibitors in c-kit-mutated melanoma patients seems to be a promising treatment option. Furthermore, a delayed response to ipilimumab after 6 months could also have led to or supported the partial response in this case. However, when two biologically similar compounds are administered in a melanoma patient and the tumour mass shows progressive disease upon administration of the first agent, an additional progression with no effect may be expected when the second one is used. This case shows, in contrast, that the use of imatinib after progression upon nilotinib can be beneficial.
    Type of Medium: Online Resource
    ISSN: 0960-8931
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1095779-0
    detail.hit.zdb_id: 2030780-9
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  • 3
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 9071-9071
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 9071-9071
    Abstract: 9071 Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer cross-resistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi. Duration of disease control (DDC) was measured in time from the initiation of the treatment to discontinuation due to disease progression or toxicity. Results: A total of 16 patients (7 females, 9 males, age 30-73 years) with BRAF mutated mM were evaluated. The median DDC (mDDC) was similar in both groups. When patients were treated first with a BRAFi (n=7), the mDDC for BRAFi was 7.6 and for MEKi 1.7 months, respectively. In contrast, when the treatment sequence was inversed (n=9), the mDDC for MEKi was 3.9 and for BRAFi 4.7 months. We observed some benefit (partial response, stable disease) using chemotherapy after BRAFi/MEKi progression. Conclusions: This analysis indicates that the sequential MEK-RAF inhibition of the MAPK pathway is acceptable in BRAF mutant mM patients. The sum of the DDC of both groups (9.3 and 8.6 months) is comparable to the promising BRAFi/MEKi combination therapy (median PFS 9.4 months). Besides the sequenced administration analyzed here, an intermittent administration should be further studied.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Elsevier BV ; 2013
    In:  European Journal of Cancer Supplements Vol. 11, No. 2 ( 2013-09), p. 92-96
    In: European Journal of Cancer Supplements, Elsevier BV, Vol. 11, No. 2 ( 2013-09), p. 92-96
    Type of Medium: Online Resource
    ISSN: 1359-6349
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 2135697-X
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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 16 ( 2016-08-15), p. 4023-4029
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 16 ( 2016-08-15), p. 4023-4029
    Abstract: Purpose: Immunotherapy has experienced impressive progress in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes, and vitiligo are reported. Although frequent, they have not been characterized further yet. In this analysis, we aimed to systematically assess and characterize the adverse cutaneous reactions observed in patients with melanoma treated with anti-PD-1 antibodies. Experimental Design: Patients with melanoma were treated with anti-PD-1 antibodies within clinical trials and an early-access program. Adverse cutaneous eruptions that emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison with maculopapular drug rash, cutaneous GVHD, and the severe drug eruption toxic epidermal necrolysis (TEN). Results: Between February 2013 and September 2015, 68 patients with stage IV melanoma were treated at the University Hospital Zurich (Zurich, Switzerland); 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes (MPR) without signs of epidermal involvement to severe MPRs, including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as TEN-like reactions. Conclusions: As predicted by the PD-1 knockout mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases of a TEN-like pattern, suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions. Clin Cancer Res; 22(16); 4023–9. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
    Online Resource
    Online Resource
    Elsevier BV ; 1990
    In:  Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology Vol. 1039, No. 3 ( 1990-7), p. 367-373
    In: Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, Elsevier BV, Vol. 1039, No. 3 ( 1990-7), p. 367-373
    Type of Medium: Online Resource
    ISSN: 0167-4838
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1990
    detail.hit.zdb_id: 2209539-1
    SSG: 12
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