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New targeted therapies for melanoma, Nail diseases, Female androgenetic alopecia
On Friday, the first day of the meeting coincided with the Lunar New Year and the beginning of the Year of the Dog. Asian communities across San Diego celebrated with colourful processions. Dragons and bands took over the city's streets, stadiums and parks, and the festivities were to continue all weekend.
By the ocean, opposite the harbour, the atmosphere was quite different at the San Diego Convention Center for the first day of the AAD Annual Meeting. Our three doctors reporting onsite to share the event with you did not have a minute to spare to admire the Asian parades. They immediately immersed themselves in the day's sessions: here are their key takeaways.
Dr. Nicole JOUAN
Dermatologist, Brest, France
Dr Lee from Seoul presented his study of 28 nail matrix naevi (NMNs) in children and adults. He compared the clinical, dermoscopic and histological aspects with the data published on subungual melanoma (SUM), which is fairly common in Asia. Longitudinal melanonychia in paediatric NMNs is wider than that of adults and nail dystrophy, never observed in adults, is frequent in the wide lesions of children (over 20% of the nail's width). He observed pseudo-Hutchinson's sign in child but not adult NMNs, with a hyponychial longitudinal brush pigmentation pattern under dermoscopy. Also, note that the pigmentation is sharply demarcated from the healthy nail in all NMNs unlike with SUM where the adjacent nail is slightly brown. The speaker evoked the ABCDEF algorithm for subungual melanoma.
Dr Baran spoke about yellow nail syndrome, which is a rare syndrome characterised by thick, dystrophic yellow nails with slow growth, associated with lymphoedema and respiratory impairment. Aetiologically, the long list of suspected inducing drugs includes titanium dioxide in dental implants. No therapeutic revolution: aside from potentially eliminating the cause, treating the bronchi and lymphoedema: alpha tocopherol and fluconazole (since it accelerates nail growth), triamcinolone injected monthly into the nail matrix – spontaneous resolution is also possible, occurring in 10% to 20% of cases.
Dr Rigopoulos from Athens talked about the still-mysterious link between psoriasis and onychomycosis: is there a real connection between the two, or it is just a coincidence? Is the weakening of the nail plate due to psoriasis a gateway for fungal infection? Or else does the speed of nail growth with psoriasis provide protection? A Greek study in 2017 authenticated onychomycosis in 34% of psoriatic nails not treated with immunosuppressive medications (prevalence of infection in the general Greek population: 15-20%). It was caused by Candida Albicans (known for promoting local IL-17 production and therefore psoriasis) in 37% of cases and by T Rubrum in 12% of cases.
A large-scale Italian study of 16,000 patients who were contacted by phone and evaluated for their NAPSI, PASI, DLQI and GUESS (Glasgow ultrasound) scores once again demonstrated the link between nail psoriasis and psoriatic arthritis (Br J Dermatol 2017, Maccini and Tosti).
There are new local antifungal agents for onychomycosis: a new azole, eficonazole, as a 10% solution and tavaborole as a 5% solution. And a reminder about pulsed terbinafine: 250 mg daily for one week, every two or three months until resolution, or 250 or 500 mg daily, one week per month for three months, as effective as prolonged once-daily treatment.
Dr Jellinek showed some impressive intraoperative videos of the excision of glomus tumours of the nail bed; these tumours are diagnosed by the Love's pin test (sharp pain when pressing with a pinhead) or cold-induced pain and do not require, in the author's experience, ultrasound or MRI confirmation. Dermoscopy can be used: unstructured pink glow with visible ramified vessels under the nail bed.
There was also a short talk about new melanonychia visualisation techniques: confocal microscopy and optical coherence tomography, with impressive 3D images, are continuing to be developed. They will make it possible to refine diagnoses and precisely locate areas to biopsy to minimise nail sequelae.
In a series of clinical cases entitled "My Great Nail Case That Taught a Lesson", there were two that caught my attention: onychomatricoma and failed terbinafine treatment for nail dermatophytosis in a patient on rifampicin before the initiation of biotherapy for psoriasis: enzyme induction by rifampicin was unable to achieve effective therapeutic doses of antifungal agents.
Dr. Rémi MAGHIA
Dermatologist, Brest, France
Treatment of androgenetic alopecia (AGA) in women according to Maryanne Makredes Senna, Massachusetts General Hospital.
The speaker recommends topical minoxidil 5% as a foam or solution once a day. Its efficacy is similar to minoxidil 5% twice a day or minoxidil 2% twice a day. Since women prefer fewer applications, once-daily use suits them better. Minoxidil 5% once a day is slightly less likely to induce hypertrichosis and scalp irritation.
LLLLDs: Low Level Laser/Light Devices
These are near-infrared devices with a wavelength of 650 nm. The FDA has approved them for androgenetic alopecia in men and women. Patients can buy them online without a prescription.
The mechanism of action is unknown: there may be photodissociation of inhibitory nitric oxide from cytochrome C oxidase in the mitochondria. This leads to an increase in ATP production and in the cellular activity of the hair follicle stem cells and keratinocytes.
A study in Am J Clin Dermatol 2014 dealt with 120 women with female AGA treated twice a week for 15 minutes in each session. The average increase in hair in the treated area was 20 hairs/cm2, vs 2.8 hairs in the "false device" group. No side effects.
Research in mice has shown that micro-wounds in the skin not containing hair follicles can trigger new follicle growth from epithelial cells, which will have a hair follicle stem cell phenotype. These studies in animals have shown that micro-wounds in the skin increase the expression of growth genes such as VEGF, beta-catenin and Wnt. The Wnt pathway is critical for hair growth.
A randomised study published in Int J Trichology 2013, dealing with 100 subjects with male AGA, compared microneedling plus minoxidil 5% twice daily to minoxidil on its own. For 2 weeks. In the microneedling group, 82% of the patients achieved over 50% improvement vs 4% in the minoxidil only group.
Research in mice recently showed that hair follicle stem cells use glycolytic metabolism and produce significant quantities of lactates compared to other epidermal cells. Still, in mice, deletion of lactate dehydrogenase inhibits lactate production and stem cell activation. Application of a new pharmacological agent, UK 5099, which increases lactate production, induces the hair cycle in mice.
Prostaglandin D2 inhibitors
We know that PDG2 inhibits hair growth and that its concentration is elevated in the bald scalps of men with AGA. However, we do not know if this is valid in female AGA; but the PG pathways seem to be same in the two conditions. PGD2 seems to promote the transition of anagen hair to the catagen phase and shorten the growth phase. These discoveries suggest that PDG2 inhibitors may be relevant targets for hair loss.
Prof. Frédéric CAUX
Dermatologist, Bobigny, France
New targeted therapies for melanoma:
For this first day of the conference, a session led by Dr Debjani Sahni (Boston, USA) was devoted to progress in the area of skin cancer. The first presentation by Dr Rhoda Alani from Boston dealt with targeted therapies for the treatment of melanoma. Until 2010, the treatment of metastatic melanoma was very disappointing, with ineffective molecules such as dacarbazine and interleukin-2 at high doses that did not improve overall patient survival (six to nine months). Between 2011 and 2015, 11 new medications were developed, obtained marketing authorisations, and helped extend overall patient survival to around 30 months. Regarding targeted therapies, they were developed based on the fact that melanoma is the cancer with the most mutations. In 2002, BRAF somatic mutations, mainly at codon 600 (V600E), were identified in 50% of cutaneous melanomas. This led to the development of a BRAF V600E inhibitor, vemurafenib, which has very fast action against metastases (clinical response rate of 90% in the first month). However, this treatment is made complicated by side effects such as squamous cell carcinoma; most importantly, after around six months, there is escape related to various resistance mechanisms and especially NRAS and MEX mutations. To get around these mechanisms, MEK inhibitors have been developed (cobimetinib, trametinib) and used in combination with mutated-BRAF inhibitors (vemurafenib, dabrafenib), resulting in a better therapeutic response and fewer side effects such as squamous cell carcinoma. Other MEK inhibitors are under development including selumetinib, which is currently being tested for ocular melanoma. The combination of a BRAF V600E inhibitor and an MEK inhibitor is no longer reserved for metastatic melanoma; it can now be used for stage III melanoma. In fact, a study published in November 2017 in the New England Journal of Medicine showed, in 870 patients with stage III BRAF-mutated melanoma, that the dabrafenib-trametinib combination improves progression-free survival. Dr Sahni also explained that in the future, the molecular typing of melanomas will probably be more complete, since the profile of somatic mutations (in the BRAF, NRAS, NF1, KIT, PTEN, GNAQ and GNA11 genes) is correlated with the clinical forms of melanoma (superficial, acral, ocular, etc.), and will make it possible to choose therapies tailored to each patient (personalised medicine). She concluded by discussing the future of epigenomics. For example, the modification of histones via histone deacetylases inhibits the expression of certain genes and plays a role in carcinogenesis. Molecules blocking the CoREST complex, which is involved in this histone modification, were recently developed (Nature Commun, 2018; 9:53). They are capable of inhibiting cellular melanoma and squamous cell carcinoma lines and of reducing tumour growth in a melanoma mouse xenograft model.
Dr Susan Swetter (San Francisco, USA) then presented the immunotherapies used in metastatic melanoma, i.e. ipilimumab, nivolumab and pembrolizumab. She reiterated that with these molecules, the therapeutic response is delayed but sustainable with four-year survival rates of around 20% for ipilimumab, 40-50% for nivolumab and pembrolizumab and 60% for the combination of ipilimumab and nivolumab. Other immunotherapies targeting the PD1 immune checkpoint have been tested, including lambrolizumab which has a 40% response rate. These treatments are associated with numerous immunological side effects. For ipilimumab, their frequency is 60%, and they include colitis and endocrinopathy and, dermatologically, pruritus, morbilliform rash, and hypopigmentation resembling vitiligo. For nivolumab and pembrolizumab, the cutaneous side effects are vitiligo, lichenoid dermatitis, oral lichenoid lesions, psoriasiform rash and bullous pemphigoid. These side effects can be of late onset, for example after 18 months for induced bullous pemphigoid, and even after stopping immunotherapy for lichenoid dermatitis. The combination of nivolumab and ipilimumab increases the severity of these toxicities and the risk of side effects becomes close to 100%.
Dr Paul Nghiem (Seattle, USA) gave a presentation on Merkel cell carcinoma. It has been demonstrated that the incidence of this tumour is increasing and that it has a high mortality rate of around 40%. This carcinoma is related to polyomavirus infection in 80% of cases and to multiple UV-induced mutations involving the TP53, RB1 and HRAS genes in 20% of cases. Local forms of Merkel cell carcinoma are treated by excision followed by radiotherapy but the rate of recurrence is high; metastatic forms respond to chemotherapy, but the risk of relapse is also high. Tumour burden is correlated with the level of circulating antibodies directed against the viral T-antigen and this serological test is a way to monitor patients and predict relapses. From a therapeutic standpoint, metastatic forms can benefit from a new treatment, avelumab, which is a biotherapeutic agent for hospital use directed against the PD-L1 immune checkpoint. Pembrolizumab and nivolumab, which have 3-month tumour reduction rates of 70% and 84% respectively, can also be used. Therapeutic trials are in progress with checkpoint inhibitors for Merkel cell carcinoma.