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.

[Sebotropic drug eruption after ingestion of bee pollen]. / Éruption induite à tropisme sébacé après consommation de pollen d'abeille.

INTRODUCTION: The medical literature contains five cases of exanthema with sebaceous tropism induced by consumption of kava-kava extract filed under the name of sebotropic drug reaction. Herein we report a new case following consumption of bee pollen. PATIENTS AND METHODS: A 37-year-old man consulted for erythemato-papular and fixed plaques of the face, upper trunk and shoulders present for 3 days. Standard blood tests were normal except for neutrophil leukocytosis at 9.8 G/l and eosinophilia at 1.4 G/l. Cutaneous biopsy of a facial plaque revealed folliculocentric lesions with necrosis of sebocytes in the sebaceous gland, associated with an eosinophil-rich infiltrate. The patient had begun consuming bee-pollen granules 3 weeks before the onset of symptoms. The rash regressed within 3 weeks of cessation of pollen consumption. Patch tests (ICDRG battery, propolis 1% Vaseline dilution and bee pollen provided by the patient, both pure and in a 30% dilution in Vaseline) were negative at 48 and 72h. DISCUSSION: The clinical-pathological correlation was consistent with a diagnosis of sebotropic drug reaction induced by the consumption of bee pollen. The diagnosis was based on papular exanthema of the seborrheic zones occurring 2 to 3 weeks after initial intake of the offending substance, with histological evidence of inflammatory necrosis of the sebaceous glands. CONCLUSION: We report what is to our knowledge the first case of sebotropic drug reaction following ingestion of bee pollen.

High-frequency ultrasound quantification of acute radiation dermatitis: pilot study of patients undergoing radiotherapy for breast cancer.

BACKGROUND: Acute radiation dermatitis (ARD) is a frequent complication after breast cancer radiotherapy and is usually assessed by semi-quantitative clinical scores, which may be subject to inter-observer variability. High-frequency ultrasound imaging of the skin can reliably quantify thickness and edema in diseased skin. We aimed to compare the relative increase in dermal thickness of the irradiated zone in breast-cancer patients undergoing radiotherapy, with clinical severity. METHODS: A consecutive series of patients undergoing treatment for breast cancer by lumpectomy and radiotherapy in a 6-month period also underwent clinical and ultrasound evaluation of ARD. RESULTS: We included 34 female patients 17 had grade 1 (group 1), 17 had grade 2 or grade 3 ARD (group 2). The mean relative increase in dermal thickness in irradiated skin (RIDTIS) was greater for group 2 than 1: 0.53 vs 0.29 mm (P=.023). On univariate analysis, ARD was associated with skin phototype, breast volume and RIDTIS, and on multivariable analysis, breast volume and age remained predictive of the disease. CONCLUSION: Patients with more severe dermatitis showed significantly increased dermal thickness. Dermal thickness is a quantitative variable that could help quantify the efficacy of drugs and improve the treatment of this disease in patients undergoing radiotherapy.

High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma.

BACKGROUND: There is an unmet need to identify markers predictive of response to ipilimumab in patients with melanoma because the number of responders to ipilimumab is low and its cost is very high. An increase in absolute lymphocyte count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third infusion has been reported to be associated with better overall survival (OS). OBJECTIVES: Our aim was to determine whether NLR measured before the first infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a consecutive series of 58 patients treated with ipilimumab in four hospitals, including 51 at stage M1c and four at stage M1b. The influences of the NLR and other factors such as lactate dehydrogenase (LDH), performance status, ALC, absolute neutrophil count (ANC) and corticosteroids on survival were studied. We also assessed this association with NLR categorized as a binary variable. The cut-off value for the NLR was determined with time-dependent receiver operating characteristic (ROC) analysis. Univariate and multivariate analyses were performed using Cox regression models. RESULTS: High NLR (≥) 4, high ANC LDH levels (>2), performance status ≥2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 1·21, 95% confidence interval (CI) 1·07-1·36]. NLR ≥4 was an independent prognostic factor (HR = 2·2, 95% CI 1·01-4·78). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 1·28, 95% CI 0·54-3·06). CONCLUSIONS: High NLR (≥4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.

[High-resolution ultrasonography for differential diagnosis between nodular basal carcinoma and sebaceous hyperplasia of the face: A pilot study]. / Échographie cutanée haute résolution dans le diagnostic différentiel entre carcinome basocellulaire nodulaire et hyperplasie sébacée du visage: une étude pilote.

BACKGROUND: Clinical differential diagnosis between incipient nodular basal carcinoma (NBC) and sebaceous hyperplasia (SH) of the face is difficult in some cases. A comparative histological analysis of these two entities led us to the hypothesis that 20MHz high-resolution ultrasonography (HRUS) may enable differentiation between NBC and SH. PATIENTS AND METHODS: Seventy-seven facial tumours requiring histological confirmation to distinguish between NBC and SH were scanned using HRUS before excision. No other imaging technique was used. The ultrasound scans were submitted to two blinded reviewers who were asked to classify the ultrasound pictures of the tumours as either hypoechoic or isoechoic/hyperechoic. Hypoechogenicity was defined as a diagnostic criterion for NBC. RESULTS: Reviewer response reproducibility for 2 images of the same tumour was 90%. Both reviewers agreed regarding the echogenicity classification of an image in 87.4% of cases. The sensitivity of the procedure was 90.9% for detection of NBC and 89.4% for detection of malignant lesions. Specificity was 69.6% for detection of basal cell carcinomas and 78.8% for detection of malignant lesions. DISCUSSION: HRUS is a non-invasive examination technique with excellent sensitivity for the detection of NBC in differential diagnosis with SH. Hypoechogenicity is not specific to NBC. The sensitivity of HRUS in our study suffered as a result of ultrasonography difficulties regarding unexpected differential diagnoses of NBC as well as tumour localisation in seborrhoeic areas.

[Expert consensus on the management of Merkel cell carcinoma]. / Consensus formalisé d'experts pour la prise en charge du carcinome à cellules de Merkel.

INTRODUCTION: Merkel cell carcinoma (MCC) is a rare form of tumour that develops from neuroendocrine skin cells. There is no consensus concerning diagnosis and therapy for this disease. To establish recommendations, the Skin Oncology Group of the French Dermatology Society drew on existing recommendations in the US and Germany. Concordance between the two sets of recommendations was validated by the group, who, in view of the large number of discrepancies, decided to use the formalised expert consensus method. METHODS: Twelve practitioners known for their experience in the management of Merkel cell carcinoma completed a standardised questionnaire. This group consisted of seven dermatologists, three radiotherapists and two plastic surgeons. They answered a total of 82 questions concerning the diagnosis, treatment and follow-up of MCC. A strong consensus was declared where all answers were in the same third of the table; a weak or relative consensus was declared where answers overlapped for adjacent scores, and an absence of consensus was declared in the event of dispersal of values. RESULTS: On completion of this process, the method revealed strong concordance on the following points: value of CK7 and CK20 immunolabelling; lack of value of chest radiography in the initial work-up, but value of lymph node ultrasound; inadequacy of an excision margin of 1cm but lack of any need for a margin greater than 3cm; absence of any value of chemotherapy for inoperable tumours; value of seeking sentinel nodes in tumours measuring less than 2cm outside the head and neck and more than 2cm for head and neck tumours; value of additional radiotherapy at the initial tumour site. Relative agreement was reached concerning the value of thoracic-abdominal-pelvic computed tomography (CT) scans in all cases, together with a head CT scan for cervical-facial tumour sites. CONCLUSION: The creation of a formalised expert consensus helps complete the existing recommendations, particularly on those points where no consensus exists between the American and German recommendations and where no strong evidence is to be found in the literature.

[Guidelines for the diagnosis and treatment of Merkel cell carcinoma]. / Recommandations du groupe de cancérologie cutanée de la Société française de dermatologie pour la prise en charge diagnostique et thérapeutique du carcinome à cellules de Merkel.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma that originates in the skin. Epidemiological factors strongly associated with MCC are: age over 65 years, fair skin, history of extensive sun exposure and chronic immune suppression. The literature is sparse and many questions currently remain unanswered regarding optimal treatment of MCC. OBJECTIVE: To provide clinical practice guidelines for the diagnosis and treatment of MCC. METHODS: Literature data were analysed and the existing German and American practice guidelines were compared. Where German and US guidelines were identical, the recommendations in question were adopted. Regarding discordant points, a formalized consensus process was devised. The guidelines were then written by an editorial group and validated by the cutaneous oncology group of the French Society of Dermatology. RESULTS: The guidelines were drawn up according to three levels of scientific evidence: a: complete agreement between the German and American guidelines; b: results of the formalized consensus process; c: expert opinion of the steering group based on available evidence. Our guidelines present up-to-date recommendations on clinical and pathological procedures for diagnosis, staging, surgical treatment, sentinel lymph node biopsy, radiotherapy and follow-up. CONCLUSION: We created a set of diagnostic and treatment guidelines in order to standardize management of MCC, which may be not optimal throughout France.

[Photosensitivity in lupus erythematosus]. / Photosensibilité du lupus érythémateux.

Photosensitivity is one of the ARA diagnostic criteria of systemic lupus erythematosus. Sun exposure can also induce extracutaneous manifestations of the disease. Photosensitivity may be difficult to prove by history taking in lupus patients, as the delay between sun exposure and the onset of specific skin lesions is rather long. Photo-induction of lupus can occur by ultraviolet A (UVA) radiation in the shadow or behind window glass, so that the relationship between radiation exposure and exacerbation of the disease may not seem obvious to the patient. Phototesting procedures for lupus erythematosus have been described, but they are not used in routine practice. Both UVB and UVA play a role in the pathogenesis of lupus erythematosus: in the epidermis they induce DNA damage, they expose nuclear antigens and photo-induced neo-antigens at the cell surface, they lead to an accumulation of apoptotic material, and they induce several pro-inflammatory cytokines. In the dermis, UV radiation triggers skin infiltration by inflammatory cells by modulation of microvascular flow rates and by upregulation of white blood cell migration from dermal capillaries to the skin. Photodistribution of skin lesions and a delay of their onset of more than 48 hours after sun exposure are clinical hallmarks of cutaneous lupus erythematosus that are usually completed by histological confirmation. Photoprotection is essential in the treatment of lupus patients: it comprises sun avoidance suitable for both UVB and UVA radiation, protective clothing, and topical broad-spectrum filters.

[Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis: role of gadolinium?]. / Dermopathie néphrogénique fibrosante traitée par photochimiothérapie extracorporelle: rôle du gadolinium?

BACKGROUND: Nephrogenic fibrosing dermopathy is a cutaneous and systemic sclerosis affecting patients with renal failure. CASE-REPORT: A 68-year-old man with renal insufficiency and on dialysis developed hardening of the skin and severe joint contractions. He had previously undergone angiography with gadolinium-containing contrast agents. A skin biopsy confirmed nephrogenic fibrosing dermopathy. The patient was treated by oral steroids followed by extracorporeal photopheresis. An improvement was seen after 12 cycles. DISCUSSION: Treatment of nephrogenic systemic fibrosis is not codified and is normally based on the methods used for other forms of systemic sclerosis. Six cases of patients showing improvement under extracorporeal photopheresis have been published. The physiopathology of the disease is unknown. Gadolinium could act as a triggering agent by attracting circulating fibrocytes in the dermis of patients. Medical authorities recommend avoidance of gadolinium in patients with advanced kidney failure unless strictly necessary.

Successful treatment with infliximab and methotrexate of pyostomatitis vegetans associated with Crohn's disease.

A 35-year-old woman with severe fistulizing Crohn's disease presented with pyostomatitis vegetans affecting both the mouth and the vulva. The coalescing pustules transformed within several days into vegetating lesions on areas of inflammation. Microbial assessments revealed no pathogenic agent. Histology showed neutrophilic microabscesses, but no granulomas. Three injections of infliximab and maintenance therapy with methotrexate resulted in rapid and complete regression of both the pyostomatitis vegetans and the Crohn's disease. Infliximab and methotrexate may be a promising treatment for the rare cases of pyostomatitis vegetans associated with Crohn's disease.

Detection of new human papillomavirus sequences in skin lesions of a renal transplant recipient and characterization of one complete genome related to epidermodysplasia verruciformis-associated types.

Human papillomavirus (HPV) DNA, originally isolated from patients suffering from the skin disease epidermodysplasia verruciformis (EV), and a growing number of related sequences have recently been detected in a high percentage of benign and malignant skin lesions of both immunosuppressed and immunocompetent people. HPV L1 DNA fragments (374-389 bp long) from a solar keratosis and a squamous cell carcinoma (SCC) of a renal transplant recipient were amplified, cloned and sequenced. In 54 clones, six different HPV sequences were identified. One of these six corresponded to the known type HPV-8 and two (RTRX3 and RTRX7) have been described previously in cutaneous lesions of immunosuppressed patients. The remaining three sequences were different from all known HPV types: an HPV-9-related sequence (77.4% identity), an RTRX2-related sequence (82.6% identity), and an HPV-22-related sequence (83.7% identity). These three sequences, representing putatively new HPV types, were named RTRX8, RTRX9 and RTRX10, respectively. RTRX7 was found in the majority of clones from both lesions. The complete genome of RTRX7 (7731 bp) was cloned as six overlapping subgenomic fragments, generated by nested PCR with DNA extracts from the SCC. RTRX7 showed a genome organization typical of HPVs associated with EV. The L1 DNA sequence differed by 15% from the corresponding region of its closest known relative, HPV-12; thus, RTRX7 can be regarded as a new HPV type. RTRX7 DNA could not be detected by Southern blot hybridization with the homologous probe, indicating that the DNA concentration was below one copy per 10 cells in the investigated SCC.

Human papillomavirus DNA in non-melanoma skin cancers of a renal transplant recipient: detection of a new sequence related to epidermodysplasia verruciformis associated types.

The detection of human papillomavirus (HPV) types originally isolated from patients with epidermodysplasia verruciformis (EV) in skin tumors of transplant recipients may point to a role of this HPV subgroup in non-melanoma skin cancer in immunosuppressed people. We analyzed 17 formalin-fixed, paraffin-embedded biopsies of benign or malignant skin tumors of a renal transplant patient with unusually widespread cutaneous carcinomas. Using a nested polymerase chain reaction (PCR), HPV-specific DNA was demonstrated in 11 specimens (65%). Analysis of nine PCR amplification products revealed four different sequences related to EV-associated HPVs. Three sequences occurred only in one lesion. In six samples identical sequences were found that differed from all HPV sequences published to date and may therefore represent a novel EV-HPV type, preliminarily labeled RTRX7. RTRX7 was found in benign, premalignant, and malignant skin lesions. Alignments identified HPV12 as the closest relative of RTRX7, both in the DNA (81% homology) and in the amino acid sequence (84% homology).