[Immune checkpoint inhibition in Merkel cell carcinoma]. / Immuncheckpointinhibition beim Merkel-Zell-Karzinom.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer in which Merkel cell polyomavirus infection and chronic exposure to ultraviolet radiation are key risk factors. Immune checkpoint inhibition has revolutionized the treatment of locally advanced, inoperable and metastatic MCC. AIM: To outline the modern management of MCC based on advances in our understanding of MCC tumour biology and the development of immune checkpoint inhibitors, namely inhibitors of programmed cell death protein (PD)-1- and PD­1 ligand 1 (PD-L1). METHODS: A review of the scientific literature listed in PubMed. RESULTS: First line therapy with the PD-L1 blocking antibody avelumab is associated with a response rate of 62%. In the second line setting, for example after chemotherapy, the response rate only reaches 33%. However, in patients who responded in the second line setting, 69% remained relapse free after 2 years. Treatment responses occurred on average after 6.1 weeks of therapy. First line treatment with pembrolizumab (anti-PD­1 antibody) is associated with a 2-year survival rate of 69% and the median survival rate has not been reached. Whilst the various chemotherapy regimens are associated with similar response rates, these are typically short lived. DISCUSSION: Checkpoint inhibition offers an effective treatment option for patients with MCC. Avelumab is currently licensed as a treatment for metastatic disease. Chemotherapy remains an option to reduce tumor load, or in the context of resistance and/or contraindications to immune checkpoint therapy. Adjuvant and neoadjuvant use of checkpoint inhibition in MCC may represent a future treatment strategy pending the results of on-going clinical trials.

[Cutaneous angiosarcoma : Radiochemotherapy with liposomal pegylated doxorubicin]. / Kutanes Angiosarkom : Radiochemotherapie mit liposomal verkapseltem pegyliertem Doxorubicin.

BACKGROUND: Whilst cutaneous angiosarcoma is rare tumour which primarily affects elderly patients, its management presents a significant therapeutic challenge. Indeed, complete surgical excision is often not possible due to the location and the diffuse and extensive nature of the tumour. Therefore, current treatment strategies often include chemo- and/or radiotherapy. METHODS: We report our experience of combined chemo- and radiotherapy in the clinical course of 6 patients with cutaneous angiosarcoma who were treated between 2007 and 2018. RESULTS: All patients presented non-resectable tumours and were treated with radiotherapy in combination with the administration of liposomal, pegylated doxrubicin (25 mg/m2 every 2 weeks). The mean duration of progression-free survival was 8 months (5-14 months), corresponding to an overall survival of 13 months (13-34 months). A partial response was seen in 4 patients and 1 patient developed progressive disease. One patient abandoned therapy after one administration. Two patients developed severe adverse events which led to termination of therapy after 1.5 months and 7 months, i.e. after 4 and 15 cycles respectively. DISCUSSION: Combined radio- and chemotherapy with liposomal, pegylated doxorubicin is a useful therapeutic option in the management of cutaneous angiosarcoma. Given the short-lived response rate, new treatment options are urgently required.

Are Sonographically Measured Vascular Haemodynamic Parameters Reproducible Using Magnetic Resonance Imaging?

OBJECTIVE/BACKGROUND: Hemodynamic measurements of blood flow in the common femoral vein and artery can be performed readily using duplex sonography. The ratio of venous to arterial volume flow in these vessels, the venous arterial flow index (VAFI), is increased in patients with varicose veins and/or chronic venous disease. The objective was to determine the reproducibility of sonographically measured hemodynamic flow parameters using phase contrast magnetic resonance imaging (MRI). METHODS: Based on hemodynamic volume flow measurements from the common femoral vein and artery the VAFI was calculated in seven patients with varicose veins (C2, Ep, As, Pr) and 32 healthy controls using standard duplex sonography and MRI. RESULTS: Based on duplex sonography, the average VAFI (VAFI_d) was 1.05 ± 0.17. The same ratio, using MRI (VAFI_mri) was 1.05 ± 0.19. There was a significant correlation between the VAFI_d and the VAFI_MRI (p = .0021). In patients with venous disease, the average VAFI_d and VAFI_mri were 1.36 ± 0.21 and 1.36 ± 0.20, respectively. In contrast, in the healthy cohort the VAFI_d was 1.00 ± 0.12 and the VAFI_mri measured 1.01 ± 0.15. As expected, there was a significant difference between the VAFI measured in those with venous disease when compared with that of healthy controls (p < .0001). CONCLUSION: There is a significant correlation between the VAFI measured using sonography and MRI. The study confirmed the elevation of VAFI in patients with chronic venous disease.

Immunohistological pointers to a possible role for excessive cathelicidin (LL-37) expression by apocrine sweat glands in the pathogenesis of hidradenitis suppurativa/acne inversa.

BACKGROUND: The cause of follicular occlusion, a key early event in the pathogenesis of hidradenitis suppurativa (HS), also known as acne inversa, remains unknown. OBJECTIVES: To identify changes, if any, in the antimicrobial peptide (AMP) and cytokine expression profile of HS affected human skin. METHODS: Quantitative immunohistomorphometry was used to compare the in situ protein expression of selected AMPs and cytokines in lesional HS skin from 18 patients with that in healthy skin (n = 12). The lesional skin from patients with HS was histologically subclassified based on the predominance of inflammation vs. scarring. RESULTS: Compared with healthy controls, significantly increased immunoreactivity for cathelicidin (LL-37) was noted in the apocrine sweat gland and distal outer root sheath (ORS) of the hair follicle (HF) epithelium in lesional HS skin. Immunoreactivity for LL-37, psoriasin, human ß-defensin 3 (hBD3), α-melanocyte stimulating hormone (α-MSH), macrophage migration inhibitory factor (MIF), tumour necrosis factor (TNF)-α and interleukin (IL)-8 was significantly increased in HS epidermis. LL-37 and TNF-α immunoreactivity was also increased in the dermis of lesional HS skin. In contrast, lysozyme expression was decreased in the epidermis of lesional HS skin, while that of TNF-α and IL-8 was decreased in the proximal ORS of HFs in HS lesions. These differences were most pronounced in HS with predominant inflammation. CONCLUSIONS: Our observations raise the question as to whether excessive secretion of AMPs by the skin, in particular by the apocrine sweat glands, distal HF epithelium, and epidermis, may attract inflammation and thus facilitate or promote HS development.

Melanotropic peptides: more than just 'Barbie drugs' and 'sun-tan jabs'?

While ultraviolet radiation (UVR) is a major cause of skin ageing and carcinogenesis, public pursuit of a novel tanning strategy circumventing the need for UVR is increasingly reported in the media and scientific press. This involves the subcutaneous self-administration of unregulated products labelled as melanotan I and/or II, synthetic analogues of α-melanocyte stimulating hormone (α-MSH), as obtained via the internet, tanning salons and gyms. The Medicines and Healthcare products Regulatory Authority has recently raised awareness of the public health risk of transmission of blood-borne viruses from the needle sharing that may occur, and of the potential impurity of these products. Dermatologists should also be aware that these agents can complicate the clinical presentation of patients with pigmented lesions; their use may be suspected in unexpectedly tanned individuals with rapidly pigmenting naevi. Meanwhile, the regulated α-MSH analogue afamelanotide (Clinuvel Pharmaceuticals Ltd, Melbourne, Australia) is showing promise for its photoprotective potential, and is undergoing phase II and III clinical trials in people with photosensitivity disorders and those prone to nonmelanoma skin cancer. The photoprotective and other biological effects of α-MSH analogues await full determination.

Thyrotropin-releasing hormone and oestrogen differentially regulate prolactin and prolactin receptor expression in female human skin and hair follicles in vitro.

BACKGROUND: Human skin and scalp hair follicles are both a nonclassical target and an extrapituitary source of prolactin (PRL), which is a potent hair growth modulator. However, how the expression of PRL and PRL receptor (PRLR) is regulated in human skin is unknown. OBJECTIVES: To investigate whether two key stimulators of pituitary PRL secretion, thyrotropin-releasing hormone (TRH) and oestrogen, also regulate cutaneous PRL and PRLR expression. METHODS: Female scalp skin and/or microdissected hair follicles were treated for 6 days in serum-free organ culture with oestrogen (100 nmol L(-1)), TRH (1-10 ng mL(-1), 3-30 nm) or vehicle control. Quantitative immunohistomorphometry of skin and hair follicle sections was complemented with quantitative polymerase chain reaction for PRL and PRLR in cultured hair follicles and/or female human outer root sheath (ORS) keratinocytes. RESULTS: Oestrogen treatment significantly upregulated PRL and PRLR immunoreactivity in selected skin and hair follicle compartments, at the gene and protein level (P < 0.05). TRH significantly increased PRL immunoreactivity and transcription in hair follicles (P < 0.05); however, while it also increased PRLR transcription in hair follicles, it downregulated PRLR immunoreactivity in the hair follicle ORS (P < 0.05). CONCLUSIONS: Our pilot study shows that two key endocrine controls of pituitary PRL secretion, oestrogen and TRH, also regulate PRL and PRLR expression in human skin. This provides novel insights into the regulation of extrapituitary PRL and PRLR expression, and invites exploration of oestrogen and TRH as novel therapeutic agents in the management of skin and hair diseases characterized by aberrant PRLR-mediated signalling.

Lifelong scaling and blistering in a family.

Ichthyosis bullosa of Siemens is a genodermatosis, which presents in childhood with mild blistering and hyperkeratosis. The heterogeneous clinical presentation may lead to misdiagnosis, even in the presence of a strong family history. Genetic testing and counselling may help in diagnosis and treatment.