[Rieger-Marchac flaps: Complications and patient satisfaction]. / Le lambeau de Rieger-Marchac : complications et satisfaction des patients.

PURPOSE: Like all surgical procedures, dorsal nasal flaps may be followed by both early and late complications. The aim of this study was to evaluate the surgical complications and cosmetic outcome of dorsal nasal flaps over a 7-year period in an academic dermatologic surgery unit. PATIENTS AND METHODS: Data were collected retrospectively for all patients undergoing dorsal nasal flap between 1 January 2006 and 31 December 2013. Early and late complications were recorded. Patients were contacted by phone to assess long-term outcomes. RESULTS: A total of 35 patients were included. Early complications included bleeding (n=2), local infection (n=2) and focal flap necrosis (n=1). Late complications comprised flap thickening (n=7), restriction of the medial canthus (n=2), opening of the labionasal angle (n=1), stitch granuloma (n=1) and telangiectasia on the flap (n=1). Regarding the aesthetic result, seven patients were very satisfied with the flap. Four patients underwent corrective surgery and one patient had laser treatment for telangiectasia on the flap. CONCLUSION: Two thirds of patients were satisfied with the aesthetic results and one third had late complications of the flap. Consequently, patients undergoing Rieger-Marchac procedures must be informed of the potential need for further corrective measures following nasal dorsal flap repair.

A fifth subtype of Kaposi's sarcoma, classic Kaposi's sarcoma in men who have sex with men: a cohort study in Paris.

BACKGROUND: Classic Kaposi's sarcoma (CKS) occurs predominantly among elderly men and is associated with Kaposi's sarcoma-associated herpesvirus (KSHV). In low-endemic countries, KSHV infects predominantly men having sex with men (MSM). OBJECTIVES: To describe a cohort of classic Kaposi sarcoma in a low-endemic area for KSHV, to highlight the features of CKS in MSM and identify prognostic factors. METHODS: Retrospective single-centre study of CKS cases. We compared MSM to heterosexual patients. Then, we divided the patients into two subgroups, those requiring a systemic treatment and the others, and we performed univariate and multivariate analyses to determine aggressiveness of CKS. RESULTS: Between 2006 and 2015, seventy-four patients were included. Mean age at diagnosis was 68.9 years; sex ratio (M/F) was 6.4, and 28% were MSM; MSM patients were younger (P = 0.02), less often originated from endemic areas (P < 0.0001). KS was less severe (P = 0.04), required more often a local treatment than a systemic one (P = 0.03). On multivariate analysis, CD4 T-cell count > 500/mm3 at baseline was associated with a reduced risk of severe evolution. CONCLUSION: First CKS cohort in low-endemic zone. We describe a fifth subtype of KS: KS in MSM. The CD4 T-cell count was found to correlate with prognosis.

[Dermatologic surgery, hemophilia and Von Willebrand disease]. / Risques en dermatologie interventionnelle chez les patients hémophiles ou atteints de la maladie de Willebrand.

BACKGROUND: Von Willebrand disease (VWD) and hemophilia A and B are the most common types of hereditary coagulation-factor deficiencies. The frequency and type of complications of skin surgery in these patients are unknown. The increasing incidence of skin cancer prompted us to reflect upon this issue. While the incidence of skin cancer is increasing, the complications of skin surgery or ablative laser treatment remain unknown in this population. AIM: The aim of this study was to determine the frequency of bleeding complications during and after skin surgery in patients with a hereditary coagulation-factor deficiency (hemophilia or VWD). PATIENTS AND METHODS: We conducted a retrospective study in patients with hemophilia A or B or VWD undergoing skin surgery or ablative laser treatment at the Dermatology Department of the Cochin Hospital in Paris, France. RESULTS: Fourteen procedures were performed in 8 patients. Three episodes of bleeding occurred (n=3/14, 21.4%): one hematoma, one delayed bleed and one immediate bleed. None of these complications required surgical revision or resuscitation. DISCUSSION: The rate of hemorrhagic complications was higher than in the general population. However, these complications can be considered non-serious and the risk-benefit ratio remains favorable. Multidisciplinary management and coordination with the reference hemophilia center are mandatory in this population to establish a coagulation-factor (CF) substitution protocol suited to the disease characteristics and the surgical procedure.

Anaplastic Kaposi's sarcoma: 5 cases of a rare and aggressive type of Kaposi's sarcoma.

BACKGROUND: Anaplastic Kaposi's sarcoma (KS) is a rare form of KS characterized clinically by the development of a tumour mass with unusual local aggressiveness and histologically by a specific architecture and cytological morphology. A very small number of limited series in endemic countries have established characteristics common to these anaplastic forms of KS. We present five patients with an anaplastic form in a context of KS ongoing for several years in a non-endemic country. MATERIALS AND METHODS: We collected 5 cases of anaplastic KS followed in our department over a period of 20years. We describe the main developmental, clinical, virological and histological features. RESULTS: The cases involved 4 men and 1 woman whose mean age at diagnosis of anaplastic KD was 70years, with an average time of 25years between initial diagnosis of KD and anaplastic transformation. Our patients were all treated with chemotherapy and/or radiotherapy (RT) prior to diagnosis of anaplastic transformation. All patients had a tumour mass of the lower limbs developing in classically indolent KS with associated chronic lymphoedema. Progression was very aggressive locally with deep invasion of the soft tissues as well as osteoarticular involvement, without visceral dissemination. At present, three patients are dead, one patient is showing partial response, and one patient is in locoregional progression. Diagnosis of the disease was based on histopathological findings. The tumour cells were undifferentiated, pseudo-cohesive, and chiefly organized in sheets. The mitotic count was high (27 mitoses per 10 fields at high magnification). Necrosis was constant. DISCUSSION: To our knowledge, this is the first series describing anaplastic Kaposi's sarcoma in a non-endemic country. The severity of the prognosis, despite the absence of visceral dissemination, is related to the local aggressiveness of anaplastic KS and to its resistance to radiotherapy and chemotherapy, with amputation being required in certain cases.

Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study.

Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response. Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.

Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers.

We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining 14, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI: 11-29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma. CONCLUSION: Our findings have direct implications regarding the identification and management of HLRCC patients.

Neutrophilic eccrine hidradenitis in two patients treated with BRAF inhibitors: a new cutaneous adverse event.

Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis, first described in patients undergoing chemotherapy for a malignant haemopathy. It has polymorphous clinical features and the association of both clinical and histological features is necessary to make a diagnosis. We report the first two cases of NEH in patients treated with a BRAF inhibitor (BRAFi), either dabrafenib or vemurafenib, for a stage IV metastatic melanoma. Disseminated erythematous plaques associated with fever and polyarthralgia occurred early after the initiation of treatment and were badly tolerated. Histological analyses confirmed the diagnosis of NEH. Symptoms disappeared a few days after the cessation of treatment and introduction of topical steroids. The replacement of one BRAFi with another is a therapeutic alternative as it is not necessarily associated with a relapse of NEH. NEH can be added to the spectrum of neutrophilic dermatoses induced by BRAFis. It occurs earlier (3-4 days) than previously described drug-induced NEH (9-12 days) and may be an earlier stage of eccrine squamous syringometaplasia, which has already been reported in the context of BRAFi-treated patients.

[Dermatoses and herpes superinfection: A retrospective study of 34 cases]. / Dermatoses et surinfection herpétique : étude rétrospective de 34 cas.

BACKGROUND: Although varicelliform Kaposi eruption is a well-known complication of dermatoses, it has not been widely investigated. AIM: To investigate features of dermatoses and herpes superinfection in patients hospitalized in a dermatology department. PATIENTS AND METHODS: We performed a single-centre, retrospective study between 2008 and 2014 that included cases of Kaposi varicelliform eruptions defined by positive PCR of an unconventional site of herpetic recurrence in a setting of active dermatitis. A record was compiled of each case giving details of the history, clinical and laboratory findings, therapeutic data and outcome. RESULTS: Thirty-four cases of Kaposi varicelliform eruptions in 30 subjects were studied. Mean age at diagnosis was 63.3±24.2 years. The underlying dermatoses were as follows: 7 pemphigus, 6 bullous pemphigoid, 3 cicatricial pemphigoid, 3 atopic dermatitis, 1 Darier disease, and 14 other dermatoses. Patients presented with skin (94.1 %) or mucous membrane lesions (62 %), mostly erosive (79 %), vesicular (27 %) or bullous (41 %), often painful (56 %) or pruritic (29 %). At diagnosis, 41.2 % were undergoing systemic immunotherapy and 24 % were on topical corticosteroids. PCR was positive for HSV1 in 20 cases and for HSV2 in 4 cases, and indeterminate in 10 cases. Lymphocytopenia was seen in 59 % of cases. The majority of patients received treatment. Nine patients experienced at least one relapse. CONCLUSION: Our study confirms the over-representation not only of the expected dermatoses (pemphigus and atopic dermatitis), but also of others such as pemphigoid and acute dermatoses; these results should be investigated in a more systematic prospective study.

First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.

BACKGROUND: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma. METHODS: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg. RESULTS: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%). CONCLUSIONS: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.

BACKGROUND: Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. PATIENTS AND METHODS: In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. RESULTS: Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). CONCLUSIONS: The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell polyomavirus (MCPyV) is the main aetiological agent of Merkel cell carcinoma (MCC). Serum antibodies against the major MCPyV capsid protein (VP1) are detected in the general population, whereas antibodies against MCPyV oncoproteins (T antigens) have been reported specifically in patients with MCC. OBJECTIVES: The primary aim was to assess whether detection of serum antibodies against MCPyV proteins at baseline was associated with disease outcome in patients with MCC. The secondary aim was to establish whether evolution of these antibodies during follow-up was associated with the course of the disease. METHODS: Serum T-antigen and VP1 antibodies were assessed by enzyme-linked immunosorbent assay using recombinant proteins in a cohort of 143 patients with MCC, including 84 patients with serum samples available at baseline. RESULTS: Low titres of VP1 antibodies at baseline (< 10 000) were significantly and independently associated with increased risk of recurrence [hazard ratio (HR) 2·71, 95% confidence interval (CI) 1·13-6·53, P = 0·026] and death (HR 3·74, 95% CI 1·53-9·18, P = 0·004), whereas T-antigen antibodies were not found to be associated with outcome. VP1 antibodies did not differ between patients in remission and those with recurrence or progression during follow-up. However, T-antigen antibodies were more frequently detected in patients with recurrence or progression at 12 months (P = 0·020) and 24 months (P = 0·016) after diagnosis. CONCLUSIONS: VP1 antibodies constitute a prognostic marker at baseline, whereas T-antigen antibodies constitute a marker of disease recurrence or progression if detected > 12 months after diagnosis.

[Angiomatoid fibrous histiocytoma in children: 6 cases]. / Histiocytome fibreux angiomatoïde de l'enfant : 6 cas.

BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a soft-tissue tumour of uncertain differentiation most often arising in the extremities of children and young adults. AFH is a little-known neoplasm and its rarity may result in it being misdiagnosed as either a reactive lesion or a benign or higher-grade tumour. We report 6 cases of AFH in children and we review the clinicopathological and molecular features of this neoplasm published in the literature. PATIENTS AND METHODS: The children (aged 4 to 16 years) presented a single nodule involving the forearm (4/6), the trunk or the buttock, and all 5 nodules appeared spontaneously. Microscopic examination revealed well-circumscribed nodular lesions comprising a fibrous pseudo-capsule, haemorrhagic non-endothelial-lined pseudocystic spaces, and sheets of spindle and ovoid cells with dense surrounding lymphoplasmacytic infiltrate. Tumours were positive for desmin, CD68, CD99 and smooth-muscle actin markers. A fusion gene (EWSR1-ATF1) was found in the 3 cases in which molecular investigation was performed. DISCUSSION: In our series, a diagnosis of AFH had in no event been evoked after clinical examination and radiological investigation. The diagnosis was based in all cases on recognition of characteristic features during histological examination and it was confirmed in 3 cases by the recognition of fusion genes. Complete excision with wide margins allowed complete cure in all cases, supporting a good prognosis of AFH, although long-term follow-up is still mandatory to rule out relapse or metastases, which although rare, are responsible for fatal cases. To avoid unnecessary surgery in patients with AFH, an ultrasound core-needle biopsy should be performed as a first step in order to provide precise diagnosis enabling complete excision to be performed, with the margins being decided in multidisciplinary meetings involving teams specialised in soft-tissue tumours.

[Recommendations for genetic testing and management of individuals genetically at-risk of cutaneous melanoma]. / Recommandations pour le diagnostic de prédisposition génétique au mélanome cutané et pour la prise en charge des personnes à risque.

Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly.

Vitamin D deficiency is associated with greater tumor size and poorer outcome in Merkel cell carcinoma patients.

BACKGROUND: Merkel cell polyomavirus has been recognized to be associated with Merkel cell carcinoma (MCC), but the evolution of this cancer probably depends on various factors. Vitamin D deficiency, defined by serum 25-hydroxyvitamin D levels <50 nmol/L, seems to influence cancer behavior and progression, but has never been assessed in MCC patients. OBJECTIVES: First, to evaluate whether vitamin D deficiency was associated with tumor characteristics and prognosis in a cohort of MCC patients. Second, to assess expression of the vitamin D receptor (VDR) in MCC tumors. METHODS: Clinical findings, Merkel cell polyomavirus markers and vitamin D status were assessed in a cohort of French MCC patients. The study was limited to the 89 patients for whom the serum sample had been collected within 3 years after the diagnosis of MCC. Correlation between vitamin D deficiency and MCC characteristics and outcome were determined in regression analyses. VDR expression in MCC tumours was assessed by immunohistochemistry. RESULTS: Vitamin D deficiency was noted in 65.1% of the patients and was independently associated with greater tumor size at diagnosis (P = 0.006) and with metastasis recurrence (HR, 2.89; 95% CI, 1.03 to 8.13; P = 0.043), but not with death from MCC, although there was a trend (HR, 5.28; 95% CI, 0.75 to 36.96; P = 0.093). VDR was found to be strongly expressed in all 28 MCC tumor specimens investigated. CONCLUSION: The association between vitamin D deficiency and MCC characteristics and outcome, together with detection of the VDR in MCC cells, suggest that vitamin D could influence the biology of MCC.

Skin necrosis due to fluindione treatment: a rare but serious complication.

In the setting of protein C deficiency, skin necrosis, which occurs most often at the initial phase of oral anticoagulants therapy, is a rare side effect. Six cases have previously been reported in the literature. In this case report, we present a protein C deficient 42-year-old woman who was being treated for venous thrombosis. Five days after the initiation of oral anticoagulant treatment, she developed extensive skin necrosis on her left calf, followed by a painful leg ulcer. The pathogenesis underlying skin necrosis caused by anticoagulation therapy is still not clear. Despite only a few cases being reported in the literature, it is important to recognise this complication since adequate therapeutic approaches leading to a stable anticoagulation state may prevent it.

Acute kidney injury in patients with severe rash on vemurafenib treatment for metastatic melanomas.

Vemurafenib, a selective BRAF (v-raf murine sarcoma viral oncogene homologue B1) kinase inhibitor, is a new targeted biotherapy that improves survival in patients with metastatic melanomas harbouring the BRAF V600E mutation. However, this drug has significant dermatological adverse effects. We report a new severe cutaneous reaction to this drug associated with acute kidney injury (AKI). Four patients presented a generalized grade 3 (Common Terminology Criteria for Adverse Events) erythematous eruption with hyperkeratosis pilaris, 5-14 days after the introduction of vemurafenib. These symptoms were associated with AKI in all cases and transitory hypereosinophilia in two cases. Vemurafenib treatment was stopped in three patients and the dose was reduced in the fourth, leading to a gradual improvement of skin symptoms and renal function. Positron-emission tomography scans showed a complete response in three cases and a major response in one case. Vemurafenib was reintroduced at a lower dose, without a relapse of the rash, but renal function again deteriorated. Thus, we report a cluster of four cases of AKI associated with similar, severe, grade 3 cutaneous drug reactions related to vemurafenib.

Genital and anorectal mucosal melanoma is associated with cutaneous melanoma in patients and in families.

BACKGROUND: Genital and anorectal mucosal melanomas (GAMMs) are rare compared with cutaneous melanoma (CM). Many epidemiological and genetic studies have been carried out on CM. In contrast, the genetic and environmental risk factors for GAMM have been poorly documented up to now. OBJECTIVES: To compare the distribution of pigmentation and naevus phenotypes, sun exposure and family history of melanoma between patients with GAMM and CM. METHODS: We compared two series of patients, 81 with GAMM and 293 with CM. RESULTS: Patients with GAMM and CM did not show significant differences for phenotypic risk factors. However, patients with GAMM tended to display red hair (11% vs. 5·5%, P = 0·08) and a poor tanning ability (22% vs. 13·3%, P = 0·06) at a higher frequency than patients with CM. A family history of melanoma was significantly more frequent with GAMM than with CM (18% vs. 7·5%, P = 0·005). Apart from the GAMM index case, affected relatives had CM except in one family. The frequency of multiple primary melanomas (MPMs) was similar in the GAMM and CM series (6% vs. 5·3%, P = 0·43). All patients with GAMM and MPM had only one GAMM primary, while the other primary was cutaneous. No CDKN2A germline mutation was detected in patients with GAMM. CONCLUSIONS: This study shows that GAMM and CM may occur in the same patient, and GAMM may develop in a familial setting. The association of both GAMM and CM in patients and families suggests shared genetic factors by these two types of melanoma.

Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

BACKGROUND: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. PATIENTS AND METHODS: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. RESULTS: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6-78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11-0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13-0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand-foot skin reaction were correlated with drug exposure. CONCLUSIONS: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.

Evaluation of a PCR test for detection of treponema pallidum in swabs and blood.

Syphilis diagnosis is based on clinical observation, serological analysis, and dark-field microscopy (DFM) detection of Treponema pallidum subsp. pallidum, the etiological agent of syphilis, in skin ulcers. We performed a nested PCR (nPCR) assay specifically amplifying the tpp47 gene of T. pallidum from swab and blood specimens. We studied a cohort of 294 patients with suspected syphilis and 35 healthy volunteers. Eighty-seven of the 294 patients had primary syphilis, 103 had secondary syphilis, 40 had latent syphilis, and 64 were found not to have syphilis. The T. pallidum nPCR results for swab specimens were highly concordant with syphilis diagnosis, with a sensitivity of 82% and a specificity of 95%. Reasonable agreement was observed between the results obtained with the nPCR and DFM methods (kappa = 0.53). No agreement was found between the nPCR detection of T. pallidum in blood and the diagnosis of syphilis, with sensitivities of 29, 18, 14.7, and 24% and specificities of 96, 92, 93, and 97% for peripheral blood mononuclear cell (PBMC), plasma, serum, and whole-blood fractions, respectively. HIV status did not affect the frequency of T. pallidum detection in any of the specimens tested. Swab specimens from mucosal or skin lesions seemed to be more useful than blood for the efficient detection of the T. pallidum genome and, thus, for the diagnosis of syphilis.