[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
British Journal of Cancer 07/2012; 107(3):455-61. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary cutaneous follicle center lymphoma (PCFCL) is the most common cutaneous B cell lymphoma. It is most often indolent and responds well to rituximab. We present a case of transient rituximab-induced edematous lesions located exclusively on tumor papules in a patient treated for PCFCL. Based on this observation and on a review of the literature, we discuss the mechanism of this edematous reaction which does not seem to be allergic. Indeed, this focal reaction observed solely during the first infusion of rituximab is more likely linked with local cytokine release induced by B cell lysis in the skin. This reaction is neither unusual nor severe and should not lead to an interruption of rituximab.
[Show abstract][Hide abstract] ABSTRACT: Thin melanomas (Breslow thickness < or = 1 mm) are considered highly curable. The aim of this study was to evaluate the correlation between histological tumour regression and sentinel lymph node (SLN) involvement in thin melanomas.
This was a retrospective single-centre study of 34 patients with thin melanomas undergoing SLN biopsy between April 1998 and January 2005.
The study included 14 women and 20 men of mean age 56.3 years. Melanomas were located on the neck (n=3), soles (n=4), trunk (n=13) and extremities (n=14). Pathological examination showed 25 SSM, four acral lentiginous melanomas, three in situ melanomas, one nodular melanoma and one unclassified melanoma with a mean Breslow thickness of 0.57 mm. Histological tumour regression was observed in 26 over 34 cases and ulceration was found in one case. Clark levels were as follows: I (n=3), II (n=20), III (n=9), IV (n=2). Growth phase was available in 15 cases (seven radial and eight vertical). Mitotic rates, available in 24 cases, were: 0 (n=9), 1 (n=11), 2 (n=2), 3 (n=1), 6 (n=1). One patient with histological tumour regression (2.9% of cases and 3.8% of cases with regressing tumours) had a metastatic SLN. One patient negative for SLN had a lung relapse and died of the disease. Mean follow-up was 26.2 months.
The results of the present study and the analysis of the literature show that histological regression of the primary tumour does not seem predictive of higher risk of SLN involvement in thin melanomas. This suggests that screening for SLN is not indicated in thin melanomas, even those with histological regression.
Annales de Dermatologie et de Vénéréologie 04/2010; 137(4):276-80. · 0.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis predisposing to the development of multiple fibrofolliculomas (FFs), pulmonary cysts, spontaneous pneumothorax and renal neoplasms. The association of BHDS with various nonrenal neoplasms has been reported but remains controversial.
To report the clinical features and germline mutations in 22 patients from 10 unrelated families with BHDS investigated during a 5-year prospective study by the Department of Dermatology at the University Hospital of Montpellier, France. Also, to define more clearly the characteristics of pulmonary, thyroid, renal and colorectal manifestations associated with BHDS.
Twenty-two patients with clinical and histological criteria of BHDS confirmed by FLCN (previously BHD) germline mutation were evaluated. Lung cysts and pneumothorax were detected by thoracic computed tomography (CT) scanning. Abdominal magnetic resonance imaging (MRI) or CT scans and/or renal ultrasonography were performed to screen for tumours. Thyroid nodules and goitres were assessed by clinical examination, ultrasound imaging and measurement of serum thyroid-stimulating hormone and thyrocalcitonin.
Eighteen of the 22 individuals affected by BHDS (82%) were diagnosed with five or more FFs. Multiple epidermal cysts, severe facial hyperseborrhoea and oral papules were noted, respectively, in three of 22 (14%), nine of 22 (41%) and nine of 21 patients (43%). Spontaneous pneumothorax was reported in seven affected patients (32%). Cystic lesions were detected in 14 of 20 patients (70%) and mainly displayed a subpleural and basal location. Renal ultrasound, CT scan and/or MRI revealed renal cysts in 10 patients (45%), without renal carcinoma diagnosed thus far. Thyroid nodules and/or cysts were disclosed by ultrasound examination in 13 of 20 cases (65%). No medullary carcinoma or other thyroid carcinomas were detected. Colonoscopy failed to detect colorectal carcinoma.
We report here the largest series to date of French patients with BHDS. We noted a high prevalence of thyroid nodules and renal cysts. However, the lack of a control group does not allow assessment of whether or not such association with BHDS is fortuitous.
British Journal of Dermatology 09/2009; 162(3):527-37. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Basal cell carcinoma of the skin is the most common type of cancer in humans. The majority of these tumors displays aberrant activation of the SONIC HEDGEHOG (SHH)/PATCHED pathway, triggered by mutations in the PATCHED tumor suppressor gene, which encodes a transmembrane receptor of SHH. In this study, we took advantage of the natural genotype (PATCHED(+/-)) of healthy keratinocytes expanded from patients with the nevoid basal cell carcinoma or Gorlin syndrome to mimic heterozygous somatic mutations thought to occur in the PATCHED gene early upon basal cell carcinoma development in the general population. PATCHED(+/-) epidermis developed on a dermal equivalent containing wild-type (WT) PATCHED(+/+) fibroblasts exhibited striking invasiveness and hyperproliferation, as well as marked differentiation impairment. Deciphering the phenotype of PATCHED(+/-) keratinocytes revealed slight increases of the transcriptional activators GLI1 and GLI2-the latter known to provoke basal cell carcinoma-like tumors when overexpressed in transgenic mice. PATCHED(+/-) keratinocytes also showed a substantial increase of the cell cycle regulator cyclin D1. These data show for the first time the physiological impact of constitutive heterozygous PATCHED mutations in primary human keratinocytes and strongly argue for a yet elusive mechanism of haploinsufficiency leading to cancer proneness.
[Show abstract][Hide abstract] ABSTRACT: Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.
British Journal of Cancer 08/2008; 99(2):364-70. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Summary Sarcoidosis or granulomatous reactions have rarely been reported in association with malignant melanoma (MM). We describe seven patients who presented with both granulomatous disease and MM, and discuss the physiopathoiogical and prognostic significance of this association. In three patients, the granulomatosis was diagnosed as true sarcoidosis and in one patient, as tumour-associated granuloma. In three cases, designated here as atypical tumour-associated granulomatoses, the presence of clear-cut pulmonary granulomatous nodules was typical neither for sarcoidosis nor for tumour-associated granuloma and was highly suggestive of melanoma metastases. Mediastinal lymphadenopathy was present in every patient, hi ail seven patients, the question of mediastinal or pulmonary involvement or relapse of the MM was raised, but could be confirmed in only one patient. MM can be associated with granulomatous disease. Knowledge of this association has implications in the management of patients with MM.
British Journal of Dermatology 06/2008; 137(5):787 - 792. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gorlin syndrome, or naevoid basal cell carcinoma syndrome (NBCCS), is an autosomal dominant disorder associated with mutations in the PTCH1 gene, which encodes the receptor of SONIC HEDGEHOG. In addition to developmental abnormalities, patients with NBCCS are prone to basal cell carcinoma (BCC), the most frequent type of nonmelanoma skin cancer in humans.
As ultraviolet (UV) exposure plays a prominent role in the development of sporadic BCC, we aimed to determine whether primary NBCCS skin cells exhibit differential responses to UV exposure compared with wild-type (WT) skin cells.
Primary fibroblast and keratinocyte strains were isolated from nonlesional skin biopsies of 10 patients with characteristic NBCCS traits. After identification of PTCH1 mutations, capacities of NBCCS cells to repair UV-induced DNA lesions and to survive after UV irradiation, as well as p53 responses, were compared with those of WT skin cells.
The c1763insG PTCH1 mutation is described for the first time. DNA repair and cell survival analyses following UV irradiation revealed no obvious differences between responses of NBCCS and WT fibroblasts and keratinocytes. However, p53 accumulation after UV irradiation was abnormally persistent in all NBCCS primary keratinocyte strains compared with WT keratinocytes.
Our observations that NBCCS cells harbour normal DNA repair and survival capacities following UV irradiation better explain that BCC proneness of patients with NBCCS does not solely concern body areas exposed to sunlight and suggest rather that it might be due to cell cycle alterations.
British Journal of Dermatology 06/2008; 159(2):445-52. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nevus spilus is defined as café-au-lait macules with dark maculopapular speckles. Histologically, it has the aspect of lentigo associated with nevocellular nevus. There are 3 types of nevus spilus: small or medium-sized (<20 cm), giant and zosteriform. Malignant transformation of nevus spilus is rare.
We analyzed the cases of 5 patients presenting melanoma within nevus spilus as well as 20 published cases. The evaluation criteria were: for nevus spilus: size, type, topography, age of onset and presence of dysplastic nevi within the nevus spilus; for melanoma: clinical aspect, histological type, thickness, level and age at diagnosis. The presence of other risk factors for melanoma was noted.
The 14 women and 11 men had a mean age of 49 years at melanoma diagnosis. Type of nevus spilus was: small or medium-sized (15 cases), zosteriform (6 cases) and giant (4 cases). Only 3 nevi spili were<4 cm in diameter. Nevus spilus was present since birth (11 cases), childhood (7 cases), after the age of 20 years (3 cases) and was unspecified in 4 cases. Three of our five patients had other risk factors for melanoma. Two patients were presenting 2 melanomas within nevus spilus. The histological type of melanoma was not specified in 8 cases but SSM was the most common type (13 cases). Median Breslow thickness was 1.25 mm (0.27 to 8 mm) for the 19 cases in which it was specified.
The following criteria appeared to be associated with risk of developing melanoma in nevus spilus patients: nevus spilus present since birth, nevus spilus over 4 cm in diameter, and giant or zosteriform nevus spilus. Development of melanoma within nevus spilus is a rare event. Consequently, guidelines for follow-up of nevus spilus cannot be defined. However, follow-up is recommended, and in particular, self-examination.
Annales de Dermatologie et de Vénéréologie 04/2006; 133(4):323-8. · 0.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized by developmental abnormalities and cancer predisposition. The PTCH 1 gene, the human homolog of the Drosophila segment polarity gene patched, has been shown to be involved in the development of nevoid basal cell carcinoma syndrome. PTCH 1 is mapped to chromosome 9q22.3. The aim of the present study was to report on clinical and genetic characteristics in patients followed for nevoid basal cell carcinoma syndrome and to compare them to the data in the literature.
Screening for PTCH 1 mutations was done in 22 patients followed between 1981 and 2003 for clinical suspicion of nevoid basal cell carcinoma syndrome. Clinical and radiological data were reviewed retrospectively from records. Genetic analysis was performed using blood samples after patient informed consent was obtained. When possible, DNA was also analyzed from the parents of patients in whom PTCH 1 mutations were found.
All patients had developed basal cell carcinomas: 45% palmar and plantar pitting, 62% jaw cysts and 66% calcification of falx cerebri. Medulloblastomas and meningiomas were the most common associated tumors. PTCH 1 mutations were identified in 13 patients: 6 familial cases, 3 sporadic cases and for 4 patients, it was not possible to conclude. Nine different new germ-line mutations were identified.
Genetic analysis allows molecular confirmation of diagnosis in about half of all patients. Early diagnosis is essential for detection of clinical and radiological manifestations in young patients and for provision of advice concerning protection of the skin from the sunlight.
Annales de Dermatologie et de Vénéréologie 03/2006; 133(2):117-23. · 0.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Microcystic adnexal carcinoma (MAC) is a rare cutaneous neoplasm, with a high rate of local recurrences.
A series of MAC was analyzed and compared to previously published cases.
Seven cases of MAC were identified in the register of the institution. Medical and pathological records were reviewed.
The primary MAC were located on the face in all patients, and 85% were initially misdiagnosed. The mean follow-up duration was 108 months. The recurrence rate was high: 4 patients developed recurrences. In 3 patients, the course of the disease was severe: one of them developed pathologically proven lung metastasis.
The present study and review of the literature confirm the clinically aggressive evolution of MAC and its rare ability to give rise to metastasis. Long-term clinical follow-ups with imaging investigations are mandatory.
[Show abstract][Hide abstract] ABSTRACT: Some cases of dermatofibrosarcoma protuberans (DFSP) do not protrude above the skin.
To assess the prevalence of these DFSPs and further to describe their presentation and course.
One hundred and forty-three patients were retrospectively collected. They were asked to complete a standardized questionnaire indicating the history and appearance of the DFSP from the first skin changes identified to the time of diagnosis.
Eighty-one DFSPs were described as protuberant ab initio, and 62 as initially nonprotuberant (npDFSP). The latter remained at this stage for a mean period of 7.6 years. Twenty-nine per cent of npDFSPs were 'morphoea-like', 19% were 'atrophoderma-like' and 42% were 'angioma-like'. Age at diagnosis was similar for both initial presentations. npDFSPs were most often misdiagnosed by physicians.
Nearly half the patients first identified their early DFSP-related skin changes as patches. Both this frequency and the long duration at this preprotuberant stage should prompt dermatologists to consider the diagnosis of DFSP earlier, in order to make surgical treatment easier.
British Journal of Dermatology 12/2005; 153(5):932-6. · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This aim of this study was to analyse outcome after surgery for primary anorectal melanoma and to determine factors predictive of survival.
Records of 40 patients treated between 1977 and 2002 were reviewed.
Twelve men and 28 women of mean age 58.1 (range 37-83) years were included in the analysis. Overall and disease-free survival rates were 17 and 14 per cent at 5 years. Median overall survival was 17 months and disease-free survival was 10 months. The 5-year survival rate was 24 per cent for patients with stage I tumours, and zero for those with stage II or stage III disease. There was no significant difference in overall survival after wide local excision (49 and 16 per cent at 2 and 5 years respectively) and abdominoperineal resection (33 per cent at both time points). In patients with stage I and stage II disease, there was a significant association between poor survival and duration of symptoms (more than 3 months), inguinal lymph node involvement, tumour stage and presence of amelanotic melanoma.
Anorectal melanoma is a rare disease with a poor prognosis. Wide local excision is recommended as primary therapy if negative resection margins can be achieved.
British Journal of Surgery 10/2004; 91(9):1183-7. · 5.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Merkel cell carcinoma is an aggressive cutaneous neoplasm with a high propensity for nodal metastases. Regional lymph node involvement develops in 45 to 65 p. 100 of patients. We evaluated in Merkel cell carcinoma the use of sentinel lymph node biopsy which allows the identification of occult nodal metastases.
Eleven patients diagnosed with Merkel cell carcinoma without clinical nodal involvement underwent pre-operative lymphoscintigraphy followed by sentinel lymphadenectomy with histologic analysis. Identification of microscopic nodal metastases led to complete lymph node dissection and adjuvant radiation therapy to the lymph node basin.
The sentinel lymph node was successfully identified in 9 patients. Two patients demonstrated metastatic disease in their sentinel lymph nodes. At subsequent complete node dissection, one of two patients had an additional metastatic lymph node. None of the eleven patients experienced recurrent disease at a follow-up varying from 1 to 42 months. One patient with a negative sentinel lymph node experienced lymphoedema.
Our results are consistent with the 14 published studies which totalled 93 patients with Merkel cell carcinoma and identified 29 patients (30 p. 100) with nodal involvement. Metastatic disease was identified only after immunohistochemical analysis in 20 p. 100 of these patients (n=6). Lymph node involvement appears to be a bad prognostic factor with 29.6 p. 100 of disease recurrence, as opposed to 3 p. 100 in patients with an uninvolved sentinel lymph node. Although the prognostic significance of this technique seems interesting, there is no optimal therapeutic approach to sentinel lymph node involvement.
Annales de Dermatologie et de Vénéréologie 05/2003; 130(4):417-22. · 0.67 Impact Factor