M. Saint-Jean

Severe radiotherapy-induced extracutaneous toxicity under vemurafenib

BACKGROUND Vemurafenib is a BRAF inhibitor indicated for the treatment of metastatic melanoma. We report the two first cases of severe and prolonged radiotherapy-induced visceral toxicity in patients treated concomitantly with vemurafenib: a brain radionecrosis and an anorectitis. It raises the question of both the risks of this association and its benefit in melanoma. OBSERVATIONS The first patient, a female aged 32, treated with vemurafenib for three months, presented a steroid-dependent radionecrosis after brain stereotactic radiosurgery. Symptoms persisted until her death six months later. The second patient, a male aged 64 and treated with vemurafenib for nineteen days, presented a radiation-induced anorectitis complicated by diarrhoea, anorexia and weight loss following the concomitant radiation of a primary rectal tumour. A colostomy was needed after ten months in order to improve local status and general health. CONCLUSIONS In our patients, the radiotherapy-induced toxicity under vemurafenib was unusual in its intensity and duration, suggesting a radiosensitization phenomenon. This hypothesis is reinforced by the publication of six cases of severe radiodermatitis under vemurafenib and by in vitro data. The combination of vemurafenib and radiotherapy should thus lead to discussion of a transient cessation of vemurafenib, given the severity of the adverse events experienced. Meanwhile, further studies are needed to determine the potential benefit of this combined treatment in metastatic melanoma.

Is a Single BRAF Wild-Type Test Sufficient to Exclude Melanoma Patients from Vemurafenib Therapy?

TO THE EDITOR Vemurafenib, a BRAF-targeted therapy, has revolutionized the treatment of metastatic melanoma by showing highly significant clinical objective responses compared with those obtained hitherto with standard treatments in patients presenting a BRAF mutation in their tumor in a phase III clinical trial (Flaherty et al., 2010; Chapman et al., 2011). These mutations are found in B50% of melanoma patients (Davies et al., 2002). Since then, this new drug has been approved in many countries for the treatment of patients with unresectable or metastatic melanoma with a BRAF mutation (BRAF in the United States, BRAF in Europe). Therefore, daily practice requires BRAF mutation testing of patients’ tumors, in order to start BRAF-inhibitor therapy. However, it is not known whether primary tumors and metastatic lesions can be tested equivalently for BRAF mutations, and there is no recommendation on the number of samples to be tested (Gonzalez et al., 2013). Furthermore, little data are available on multiple melanoma sample testing in the same patient. We retrospectively determined the BRAF mutation status of all samples from consecutive inpatients with melanoma available in our unit between January 2011 and June 2012. DNA was extracted from paraffin-embedded tumor blocks after highlighting tumor areas by a pathologist and macrodissection. Detection of the most frequent 35

Development of squamous cell carcinoma into basal cell carcinoma under treatment with Vismodegib.

Basal cell carcinoma (BCC) is the most common cancer in humans. Vismodegib, a Hedgehog pathway inhibitor, has proved its effectiveness in treating non‐resectable advanced BCC.

Onychopathy Induced by Temsirolimus, a Mammalian Target of Rapamycin Inhibitor

Temsirolimus belongs to the mammalian target of rapamycin (mTOR) inhibitors, targeted therapies for which indications are booming in oncology. While their tolerance is usually good, mucocutaneous toxicity is the most common, including stomatitis, rashes, edemas, pruritus, dry skin and nail disorders. The latter are common in clinical practice but have not yet been well characterized. We report 2 cases of patients who developed, after 6–7 months with temsirolimus, a dystrophy of the 20 nails with fragility, distal onycholysis, yellow discoloration, associated in 1 case with painful paronychia. Topical steroids improved the paronychia, without changing the nail dystrophy. To our knowledge, the occurrence of yellow nail discoloration with temsirolimus has never been reported before. We review the cutaneous and mucosal toxicities induced by temsirolimus and everolimus, two mTOR inhibitors used as anticancer agents and by their parent molecule sirolimus.

Evaluation of Quality of Life after a Medical Corrective Make-Up Lesson in Patients with Various Dermatoses

Background: Apparent skin lesions can impair quality of life (QoL). Objective: To assess QoL improvement brought by a medical corrective make-up lesson and its daily use in practice using the Dermatology Life Quality Index (DLQI). Methods: Patients with facial disorders participating during 2 years in our lessons conducted by a trained nurse were included in an open prospective study. Results: 86 patients aged 4–79 years were included. They suffered from acne (25), rosacea (10), scars (14) and various dermatoses (19). 63 patients (73%) sent back the questionnaire. One-month DLQI improvement was significant (p < 0.001) in acne (p = 0.006) as well as rosacea (p = 0.036), with a trend for scars (p = 0.057). QoL significantly improved, independently of a low (p < 0.001) or high (p = 0.006) initial DLQI. Since the lesson, 95% of patients re-made up with 97% of good tolerance. Conclusion: This is the first study examining at-home make-up completion and showing the beneficial effect of a medical corrective make-up lesson on the QoL of patients with various facial dermatoses in France.

Photodynamic therapy with methyl-aminolevulinic acid for paucilesional mycosis fungoides: A prospective open study and review of the literature

BACKGROUND Publications reporting photodynamic therapy (PDT) in mycosis fungoides (MF) are rare, involve small samples, and are difficult to compare because of a lack of technical standardization. OBJECTIVE We sought to assess PDT effectiveness and tolerability in early-stage MF using a strict reproducible procedure. METHODS This was a prospective study conducted in Nantes University Hospital, France, including patients older than 18 years with histologically proven MF (stage IA or IB). Methyl-aminolevulinic acid-PDT sessions were repeated monthly for 6 months. Clinical and histologic responses were assessed 1 month after the last session. Patient satisfaction was assessed by telephone survey. RESULTS Twelve patients (with 29 lesions) were treated with PDT. An objective response in target lesions was obtained in 75% of patients. Response rates were similar between plaques and patches but higher in sun-protected compared with sun-exposed areas (trend without reaching significance). During PDT, new lesions appeared in 5 of 12 patients in untreated areas. Most patients were highly satisfied and preferred PDT to the topical chemotherapy previously used. LIMITATIONS PDT procedure criteria selection was partially arbitrary. CONCLUSIONS In early-stage MF, PDT is effective and appreciated (especially when compared with conventional topical chemotherapy). Unilesional and paucilesional forms and lesions in sun-protected areas are to be preferred.

Bexarotene in cutaneous T-cell lymphoma: third retrospective study of long-term cohort and review of the literature

Background: Bexarotene was approved for cutaneous T-cell lymphoma (CTCL) in 1999. Apart from the two first clinical trials published ten years ago, very few data were published on the long-term use of bexarotene in CTCL patients. Objectives: We performed a retrospective review of CTCL patients treated with bexarotene at a single skin Cancer department between 2002 and 2012. We aimed to determine retrospectively the long-term tolerability and outcome of bexarotene in a cohort of CTCL patients and to compare these results with data from the literature. Results: Thirty-two patients were included (18 men/14 women); 20 patients had a mycosis fungoïdes and 12 a Sézary syndrome. The longest bexarotene treatment duration observed was 65.2 months and 10 patients were treated for more than 24 months. A clinical response was reported in 60% of all patients and in 75% of patients with Sézary syndrome. Most common drug-related adverse events were hypothyroidism (94%), hypertriglyceridemia (78%) and hypercholesterolemia (44%). Most events (84%) were mild to moderate. Conclusions: This study with a very long observation time confirms that bexarotene is well tolerated by CTCL patients during long-term use. It is effective in early and advanced stages of CTCL.

Importance of spironolactone in the treatment of acne in adult women

Editor We present a case series of women older than 20 years of age treated with low-dose spironolactone for acne. Even though this drug has not been granted a marketing authorization in France for treatment of acne, it has been used for treating that condition for many years. Our objective was to evaluate its efficacy and tolerance in the French population. The evaluation of acne severity was defined on the basis of the Acne Lesions Grading Scale before and during treatment (after a minimum period of 2 months). The clinical response on the lesions of the face and of the back was defined by a reduction of at least 50% of the total number of lesions (both retentional and inflammatory). Fourteen female patients were included on the basis of a failure of a previous systemic therapy (with any of the following: zinc, isotretinoin and ⁄ or tetracyclines). The median age was 30 years. Four patients reported a worsening of their lesions during the menstrual cycle, five patients presented with irregular menstrual cycles. One patient suffered from polycystic ovarian syndrome. A hormonal checkup was conducted in seven patients and was mostly normal. About 79% of the patients had not responded to two different treatments attempted and three patients had not been improved by any of the three systemic treatments mentioned. Spironolactone therapy was initiated at a dose set between 75 and 150 mg ⁄ day during an average period of 17 months. In all cases, spironolactone therapy was associated with a topical treatment. A reduction of the total number of lesions by 50% in the face was obtained in six patients (of whom four had had failure with isotretinoin treatment) (Fig. 1a,b). We noted that five patients responded for retentional lesions and six patients responded for inflammatory lesions (Fig. 2). Five patients presented with a clinical response on the acne lesions of the back with a significantly higher effectiveness in the case of an irregular menstrual cycle (P = 0.0278). Spironolactone was very well tolerated with only three patients reporting side-effects (asthenia of low intensity in two patients and epigastric pain in the third patient necessitating stopping of the treatment). In articles published recently, several researchers have reiterated the necessity for an appropriate selection of female patients who could benefit from a hormonal acne treatment and the criteria for inclusion into the hormonal treatment group stipulated that the patients should have undergone repeated courses of isotretinoin treatment without much improvement. Among the 11 publications in literature which studied the effectiveness of spironolactone for the treatment of acne, only five authors had selected, as we

Clinical significance of BRAF mutation status in circulating tumor DNA of metastatic melanoma patients at baseline

Circulating tumor DNA is a promising non‐invasive tool for cancer monitoring. The main objective of our work was to investigate the relationship between mutant BRAF DNA in plasma and clinical response. Thirty‐eight stage IV patients with a V600 mutated BRAF melanoma were included prior to any treatment. DNA was extracted from plasma and mutant DNA was detected using the amplification‐refractory mutation system method. Before the beginning of any treatment, the corresponding BRAF mutation was detected in 29 of the 38 tested plasma samples (76.3% positive per cent agreement). We observed a strong correlation between the presence of circulating mutated DNA and overall survival (OS; P=.02), and with the number of metastatic sites (P=.01). The presence of circulating mutated DNA was also strongly correlated with serum LDH activity (P<.01) and S100 protein concentration (P<.01). Finally, seven patients presented discordant BRAF status in different tumor sites. In all these patients, the test performed on ctDNA was positive, suggesting that ctDNA analysis might be less sensitive to tumor heterogeneity. Altogether, these results suggest that plasmatic mutant BRAF DNA is a prognostic factor of OS, correlated with tumor burden. In addition, it represents an interesting alternative source of DNA to detect BRAF mutations before treatment.

TLR expression in human melanoma cells

UNLABELLED There is increasing evidence that melanoma cells express TLR2, -3, and -4. However, the expression of other TLRs by these cells still remains unknown. We investigated the expression patterns of TLR2, -3, -4, -7, -8 and -9 both on melanoma-invaded lymph nodes and on melanoma cell lines. TLR2, -3, -4, -7 and -9 mRNA expression was determined by quantitative RT-PCR. The TLR protein expression level was measured ex vivo by immunohistochemistry and in vitro by flow cytometry. RESULTS At the mRNA level, melanoma cells in vitro, and possibly ex vivo, expressed TLR2, -3, -4, -7 and -9. TLR2 and -4 protein expressions ex vivo were over 50%, contrasting with an absence of these 2 TLRs in vitro. On the contrary, TLR-3 and -8 proteins had a low expression ex vivo with a high expression in vitro. TLR-7 and -9 proteins were expressed ex vivo and in vitro. Our study demonstrates for the first time that melanoma cells express TLR7 and -8.