Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆.

BACKGROUND: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy. PATIENTS AND METHODS: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out. RESULTS: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI. CONCLUSION: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Molluscum contagiosum surrounded by a white halo and Sezary syndrome.

BACKGROUND: Molluscum contagiosum (MC) is caused by a DNA virus of the poxvirus group. It is common in children, and is also found in sexually active adults and HIV-seropositive patients. Cellular immunity is essential to controlling MC virus infection. We report the first observation of a patient with stage IV Sezary syndrome, who presented multiple molluscum contagiosum, spread and surrounded by a pale halo. CASE REPORT: A woman aged 70 presented with aggravation of Sezary syndrome diagnosed in 2009 and treated with topical corticosteroids. The examination showed a generalized pruritic exanthem and multiple flesh-coloured papules from 1 to 3 mm, spread over the entire skin surface and surrounded by a white halo. Histological examination of a lesion showed the presence of infected cells with intracytoplasmic inclusions infected in an acanthotic epidermis, surrounded by a melaninopenic hypomelanosis with a normal melanocyte density. There was no inflammatory character. The diagnosis of multiple molluscum contagiosum was given, the application of clobetasol propionate was suspended and treatment with chlorambucil 4 mg/day and prednisone 0.5 mg/kg/day was started. The evolution of the rash and pruritus was rapidly favourable. After 3 months, the rash and pruritus had regressed. There was no molluscum contagiosum or clear halo. CONCLUSION: We report the original observation of a patient with stage IV Sezary syndrome, who presented multiple molluscum contagiosum, spread and surrounded by a pale halo, without inflammation, eczema or disappearance of melanocytes. This halo could be due to the secretion of a protein by molluscum contagiosum inhibiting inflammation around this MC. To our knowledge, this phenomenon reported in a patient with severe atopic dermatitis associated with Sezary syndrome has not previously been described.

[Extranodal NK/T-cell lymphoma, nasal-type, revealed by cutaneous breast involvement]. / Localisation cutanée mammaire révélatrice d'un lymphome T/NK extranodal de type nasal.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTL) is a rare form of non-Hodgkin's lymphoma and carries a poor prognosis. Depending on the primary sites of anatomical involvement, it is subcategorized into nasal or extra-nasal ENKTL. Cutaneous involvement is the second localization reported for these lymphomas. PATIENTS AND METHODS: A woman was admitted for erythematous infiltrative patches on the breasts having an ulcerative course. Cutaneous histopathology showed a dense, diffuse infiltrate of atypical lymphocytes. Immunohistochemistry revealed expression of specific markers for NK-cells and of cytotoxic molecules (TIA-1, granzyme B and perforin), lack of expression of T-cell markers (except positivity of cytoplasmic CD3 and CD2), and the presence of EBV-DNA in lymphoma cells. Positron emission tomography-computed tomography revealed sub- and supra-diaphragmatic multi-organ involvement (kidneys, breasts, stomach, duodenum, lungs, pleural cavity, uterus, bones). No bone marrow infiltration was noted. PCR (polymerase chain reaction) showed high circulating levels of EBV-DNA in peripheral blood. A systemic nasal-type ENKTL was diagnosed. A chemotherapy regimen including high-dose methotrexate, oxaliplatin, gemcitabine, L-asparaginase and dexamethasone was started. Despite good initial therapeutic response, the outcome was rapidly fatal with bone marrow involvement and multi-organ failure. DISCUSSION: Major cutaneous manifestations of ENKTL comprise erythematous infiltrative patches mimicking panniculitis or cellulitis and evolving towards ulceration or necrosis. Subcutaneous nodules may also be noted. Late diagnosis at an advanced stage accounts for the poorer prognosis in extra-nasal ENKTL. In the advanced stages, treatment is based on a chemotherapy regimen including L-asparaginase, possibly followed by autologous or allogeneic hematopoietic stem cell transplantation.

Diagnosis and management of melanoma with regional lymph node metastases: a population-based study in France.

BACKGROUND: Stage III melanoma represents a borderline situation regarding the potential curability of this potentially aggressive cancer and consequently, regional lymph node metastases (RLNM) are a major challenge for melanoma management. OBJECTIVE: To describe the management of melanoma with RLNM as practised in France in 2008 and compare results with previous data from 2004, considering that new French recommendations were published in 2005. METHODS: Retrospective population-based study in five regions of France totalling 8.3 million inhabitants, targeting all incident cases of RLNM diagnosed in 2008. Questionnaires were mailed to physicians to identify cases and collect data, with verification by cancer registries for cases diagnosed concomitantly with the primary tumour using sentinel lymph node biopsies (SLNB). RESULTS: Data were collected for 101 patients in 2008, and compared to 89 cases treated in 2004. Palpation by a dermatologist was the most common circumstance of diagnosis of RLNM in 2008 (36%), followed by SLNB (29%), self-palpation by the patient (16%) and lymph node ultrasonography (6%), without significant modification from 2004. After lymphadenectomy an adjuvant therapy was proposed in 62% of cases, mainly consisting in high-dose interferon (HD-IFN) (80%). Overall, HD-IFN was proposed in 49% of cases, but effectively started in only 40% of cases after being proposed, and prematurely withdrawn in 28%, showing major changes as compared with 2004 (33%, 77% and 67%, respectively, P < 0.05). Adjuvant chemotherapy was not proposed to any patients in 2008, compared to 29% in 2004. Surveillance procedures included medical imaging less often in 2008 (76%) than in 2004 (92%) (P = 0.004), but more often included FDG-PET (23% vs. 12%, P = 0.09). CONCLUSION: Overall, actual practice was in accordance with French recommendations. The main developments from 2004 to 2008 were the disappearance of adjuvant chemotherapies and a more accurate selection of patients for adjuvant interferon.

[Melanoma of the anal margin]. / Mélanome de la marge anale.

BACKGROUND: Primary anal mucosal melanoma is rare and is associated with a poor prognosis. The observation of a case of anal melanoma at a localized stage in a woman led us to analyze recent data from the literature on therapeutic alternatives. PATIENTS AND METHODS: A 49-year-old woman presented with a pigmented swelling of the anal margin that had begun three months earlier. Complete local excision of the tumour was performed with the conservation of the anal sphincters. Histological examination revealed SSM mucosal melanoma. Abdominoperineal resection was finally performed because of tumoural invasion of the lateral margins. Staging assessment was normal. Half-yearly MRI monitoring of the pelvis was proposed and at nine months no relapse was seen. DISCUSSION: The unusual and misleading symptoms often account for the late diagnosis and poor prognosis of anal melanoma. Treatment is not well defined: local excision with conservation of the anal sphincters is recommended as first-line therapy, but the surgical technique is controversial. Abdominoperineal resection is recommended if the surgical margins are invaded, in the case of local recurrence or if the tumour is inaccessible. The place of adjuvant therapies remains to be defined. More recently, the discovery of mutation in c-KIT mucosal melanoma has allowed the use of biotherapy. Our observation underscores the importance of early detection of anal melanoma by all practitioners concerned in view of its aggressiveness and we report the difficulties of therapeutic management in the absence of established guidelines.

[Adverse cutaneous effects and quality of life in patients treated with mTOR inhibitors for renal carcinoma]. / Effets indésirables cutanés et retentissement sur la qualité de vie des inhibiteurs de mTOR au cours du traitement du cancer du rein.

BACKGROUND: Mammalian target of rapamycine (mTOR) inhibitors are being increasingly prescribed as antitumoural drugs, and associated adverse cutaneous effects are frequent but poorly described. The aim of this study was to describe such adverse effects and to assess the quality of life of patients experiencing them. PATIENTS AND METHODS: Over a period of 18 months, 18 patients treated with mTOR inhibitors for renal carcinoma were included and 77 dermatological examinations performed. Wherever a cutaneous adverse event was present, quality of life was evaluated using the Skindex 30 questionnaire. RESULTS: Fifteen of the 18 patients included presented adverse cutaneous events, consisting of buccal ulcers (61.1%), xerosis (55.5%), distal onycholysis (50%), acneiform eruption (38.8%), paronychia (22.2%) and pruritus (22.2%). Buccal ulcerations and perionyxis had an especially marked impact on quality of life, which was greatest in terms of physical score (19%), followed by emotional (9%) and functional (6%) scores. CONCLUSION: Cutaneous adverse effects of mTOR inhibitors are frequent and have a considerable impact on quality of life, particularly as regards physical scores. Dermatological examination appears useful to allow early management of cutaneous adverse effects and improve the quality of life of these patients.

Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study.

BACKGROUND: The treatment of stage I Merkel cell carcinoma (MCC) usually includes wide local excision (WLE) combined with irradiation of the tumor bed (ITB). No randomized study has ever been conducted in MCC. The purpose of this study was to assess the efficacy and safety of prophylactic adjuvant radiotherapy on the regional nodes. PATIENTS AND METHODS: In this randomized open controlled study, patients for a stage I MCC treated by WLE and ITB were randomly assigned to regional adjuvant radiotherapy versus observation. Overall survival (OS) and probability of regional recurrence (PRR) were primary end points. Progression-free survival (PFS) and tolerance of irradiation were secondary end points. RESULTS: Eighty-three patients were included before premature interruption of the trial, due to a drop in the recruitment mainly due to the introduction of the sentinel node dissection in the management of MCC. No significant improvement in OS (P = 0.989) or PFS (P = 0.4) could be demonstrated after regional irradiation, which, however, significantly reduced the PRR (P = 0.007) with 16.7% regional recurrence rate in the observation arm versus 0% in the treatment arm. The treatment was well tolerated. CONCLUSION: The adjuvant regional irradiation significantly decreased the PRR in MCC, but benefit in survival could not be demonstrated.

The role of general practitioners in diagnosis of cutaneous melanoma: a population-based study in France.

BACKGROUND: Little data are available concerning the role of general practitioners (GPs) in the diagnosis of melanoma. OBJECTIVES: To evaluate the actual role of GPs in a population-based study covering five regions of France and 8·2 million inhabitants. MATERIALS AND METHODS: A survey of cancer registries and pathology laboratories, and questionnaires to practitioners were used to identify incident melanomas in 2008, and evaluate characteristics of patients (age, sex, area of residence, social isolation), tumours (Breslow, ulceration, location, histological type), and GPs (training, conditions of practice), and their influence on patterns of diagnosis and Breslow thickness. RESULTS: Among 898 melanomas, 376 (42%) were first diagnosed in a general practice setting (GP group). Breslow thickness was much higher in the GP group than in other melanomas (median: 0·95 vs. 0·61 mm, P < 0·0001). Multivariate analysis identified an older age, lower limb location, nodular subtype and Breslow thickness as factors associated with the GP group. Within this group, 52·5% of melanomas were detected by patients (median Breslow thickness: 1·30 mm) and 47·5% by GPs (median Breslow thickness: 0·80 mm, P = 0·0009), including 8% during a systematic full-body skin examination. Previous GP training on melanoma was associated with active detection by GPs. Male sex and social isolation of patients were associated with thicker melanomas, whereas active detection by GPs was associated with thinner CMs. CONCLUSIONS: GPs play a key role in melanoma diagnosis in France, but still frequently detect thick tumours. Increasing awareness and training of GPs and focusing attention on male and/or socially isolated patients should help to improve early detection of melanoma.

[Evaluation of information about prophylactic treatment and management of hand-foot reactions caused by antiangiogenic therapies]. / Évaluation d'une information pour prévenir et prendre en charge les réactions mains-pieds secondaires aux traitements anti-angiogéniques.

BACKGROUND: Antiangiogenic agents may be associated with severe hand-foot reactions (HFR) requiring dose adjustment by oncologists. Many preventive and curative treatments are described in the literature but their efficacy has not been assessed in clinical trials. The aim of this study was to examine information given to patients about HFR and to evaluate compliance with prophylactic therapy for this complication. PATIENTS AND METHODS: Fifty-one patients receiving antiangiogenic therapy were followed up for a period of 19 months. At each visit, a dermatological examination was performed, compliance with topical treatment was assessed and advice was provided. At the end of the study, patients' perception of the information given was assessed by means of a questionnaire, completed either during consultations or by telephone. RESULTS: Although all patients were given information about HFR, 11 of 39 subjects claimed they had received no such information. There was no difference regarding compliance with topical treatment whether the information was provided by a dermatologist or an oncologist. Eleven patients consulted a podiatrist and nine patients used soft insoles. Twenty-two of 40 patients used topical treatments, with nine using such treatment from the outset. A statistically significant correlation was noted between compliance with preventive topical therapy and onset of HFR (P=0.028), and this finding merits confirmation in a larger-scale study. CONCLUSION: This study highlights the difficulties in implementing a programme to prevent HFR and suggests the value of providing multidisciplinary therapeutic education and of financing preventive and curative care.

[An atypical presentation of primary cutaneous diffuse B-cell lymphoma, leg type]. / Une présentation atypique de lymphome cutané B primitif à grandes cellules de type jambe.

BACKGROUND: Primary cutaneous diffuse B-cell lymphoma, leg type, are rare and aggressive tumours frequently affecting elderly patients. We present a case of a 53-year-old woman with an atypical presentation of primary cutaneous diffuse B-cell lymphoma, leg type. CASE REPORT: Eight years after complete excision of a Jessner-Kanof lymphocytic infiltration on the right shoulder, the patient developed a primary cutaneous diffuse B-cell lymphoma, leg type at the same site. The isolated lesion was treated using local radiotherapy. One year later, the patient presented headache associated with a temporal lesion, and biopsy confirmed a relapse. Cerebral CT scan showed an osteolytic temporal lesion while the other investigations revealed no extracutaneous extension. She was treated with R-CHOP chemotherapy and intrathecal methotrexate due to the osteolytic lesion. DISCUSSION: The particularity of this case consists in the age of this woman, who was younger than the average, the two atypical localizations on the shoulder, then the temple, and osteolysis, which is not the most frequent extension. Furthermore, to our knowledge, transformation of a Jessner-Kanof lesion into local aggressive primary cutaneous diffuse B-cell lymphoma, leg type, has not been yet described.

[Impact of whole body magnetic resonance imaging (MRI) in the management of melanoma patients, in comparison with positron emission tomography/computed tomography (TEP/CT) and CT]. / Apport de l'imagerie en résonance magnétique (IRM) du corps entier dans la prise en charge du mélanome : comparaison avec la tomoscintigraphie par émission de positons couplée à la tomodensitométrie (TEP-TDM) et à la TDM seule.

BACKGROUND: PET/CT has proven extremely useful in the management of melanoma patients, with great sensitivity (Se), but it tends to give false-positive results. Whole-body MRI (wb-MRI) is a new method that has made considerable progress. STUDY AIMS: The aim of this study was to assess the Se and specificity (Sp) of wb-MRI with a diffusion sequence for detecting melanoma metastasis compared to PET/CT. METHODS: This was a prospective study, including patients at any AJCC (American Joint Committee on Cancer) stage of melanoma. PET/CT, wb-MRI and CT, including the brain, were performed on the same day. For each of the three exams, the number of lesions per patient was counted. The treatments proposed by the doctor immediately after PET/CT and then MRI were compared. RESULTS: Forty patients were included and a total of 72 metastases were noted. CT detected 53 of these metastases (Se 80%, Sp 95%), while PET/CT detected 53 metastases, with four false-positive (Se 74%, Sp 89%) and Wb-MRI detected 59, with two false-positive (Se 83%, Sp 96%). The sensitivity of MRI was distinctly superior to PET/CT for both hepatic and pulmonary lesions. The treatment proposed after PET/CT and MRI differed in three cases: one patient was falsely reclassified by MRI (AJCC IV instead of IIB) while two others were falsely reclassified by PET/CT (AJCC IV instead of IB and IIIC). Exclusively whole-body scan influenced the treatment of four patients (10%). CONCLUSION: Wb-MRI with diffusion sequence, which is less costly than PET/CT and is also non-radioactive, could play an important role in the detection of metastases in melanoma patients.

Efficacy of sonic hedgehog inhibitors rechallenge, after initial complete response in recurrent advanced basal cell carcinoma: a retrospective study from the CARADERM database.

BACKGROUND: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib. MATERIALS AND METHODS: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment. RESULTS: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months). CONCLUSION: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms.

Management and outcome of metastatic melanoma during pregnancy.

BACKGROUND: Although metastatic melanoma occurrence during pregnancy challenges the physician in several ways, only a few studies have been published. OBJECTIVES: Our aim was to investigate therapeutic management together with maternal and fetal outcomes in pregnant women with advanced melanoma. METHODS: A French national retrospective study was conducted in 34 departments of Dermatology or Oncology. All patients with American Joint Committee on Cancer (AJCC) stage III/IV melanoma diagnosed during pregnancy were included. Data regarding melanoma history, pregnancy, treatment, delivery, maternal and infant outcomes were collected. RESULTS: Twenty-two women were included: 10 AJCC stage III and 12 stage IV. Abortion was performed in three patients. Therapeutic abstention during pregnancy was observed in three cases, 14 patients underwent surgery, four patients received chemotherapy and one patient was treated with brain radiotherapy alone. The median gestational age was 36 weeks amenorrhoea. Neither neonatal metastases nor deformities were observed. Placenta metastases were found in one case. Among 18 newborns, 17 are currently alive (median follow up, 17 months); one died of sudden infant death. The 2-year maternal survival rates were 56% (stage III) and 17% (stage IV). CONCLUSIONS: Faced with metastatic melanoma, a majority of women chose to continue with pregnancy, giving birth, based on our samples, to healthy, frequently premature infants. Except during the first trimester of pregnancy, conventional melanoma treatment was applied. No serious side effect was reported, except one case of miscarriage after surgery. Mortality rates do not suggest a worsened prognosis due to pregnancy but larger prospective controlled studies are necessary to assess this specific point.

[Leg ulcerations and sunitinib]. / Ulcérations des membres inférieurs sous sunitinib.

BACKGROUND: Sunitinib is an antiangiogenic tyrosine kinase inhibitor indicated in the treatment of metastatic renal cancer and gastrointestinal stromal tumours (GIST). We report a case of leg ulcer apparently triggered by this drug and we discuss the potential implication of the antiangiogenic effect of sunitinib in ulcer genesis. CASE REPORT: A 73-year-old woman with a history of deep venous thrombosis of the lower limbs was treated with sunitinib for renal cancer with hepatic and pulmonary secondaries. While on this treatment, she developed painful ulcers of the right lower limb, despite having never previously presented leg ulceration. On discontinuation of sunitinib, the lesions improved, and resumption of this drug, even at a lower dosage, resulted in relapse of her ulcers. DISCUSSION: Although questions may legitimately be asked about the contribution of the patient's venous condition, withdrawal of sunitinib followed by a positive rechallenge tend to suggest the role of this drug in recurrence of ulcers. Their recurrence despite the decreased dosage of the drug points to a nondose-dependent pathogenic mechanism.

[Sézary syndrome and Leser-Trélat sign: a chance association?]. / Syndrome de Sézary et syndrome de Leser-Trélat: association fortuite?

BACKGROUND: Leser-Trélat sign involves the combined sudden onset of seborrheic keratosis and cancer. However, some doubt surrounds the existence of this syndrome. We report a case of Leser-Trélat sign that led to the discovery of Sézary syndrome. PATIENTS AND METHODS: A 59-year-old woman presented generalized pruritus with secondary appearance of multiple seborrheic keratosis. Leser-Trélat sign was diagnosed and 20 months later, Sézary syndrome was discovered. Extracorporeal photopheresis was initiated, after which there was a marked reduction in the patient's pruritus, erythroderma and numbers of seborrheic keratoses and Sézary cells. DISCUSSION: Leser-Trélat sign is often associated with gastric carcinoma or lymphoproliferative tumours. Rampen and Schwengle [J Am Acad Dermatol 21 (1989) 50-5] have thrown doubt on this entity because of the "subjective" definition, the frequent dissociation between the course of the tumour and that of the seborrheic keratosis, the disparity between the frequency with which rapid onset seborrheic keratosis is seen and the rarity of cases in which this phenomenon reveals a tumour and the absence of association with any specific type of malignancy. The time between diagnosis of Sézary syndrome and cutaneous symptoms of Leser-Trélat sign appears very long in the present case. In the absence of any established physiopathology, it is impossible to prove any direct link between these two syndromes. Leser-Trélat sign remains controversial. Knowledge of its pathogenesis could help determine whether Leser-Trélat sign should or should not be considered a paraneoplastic syndrome.