Early diagnosis of melanoma: a randomized trial assessing the impact of the transmission of photographs taken with a smartphone from the general practitioner to the dermatologist on the time to dermatological consultation.

BACKGROUND: Difficulty obtaining a dermatological consultation is an obstacle to the early diagnosis of melanoma. On the one hand, patients survival depends on the lesion thickness at the time of diagnosis. On the other hand, dermatologists treat many patients with benign lesions. Optimizing patient care pathways is a major concern. The aim of the present study was to assess whether the e-mail transmission of photographs of suspected melanoma lesions between general practitioners (GPs) and dermatologists reduces the time to dermatological consultation for patients whose suspicious skin lesions ultimately require resection. METHODS: We conducted a cluster-randomized controlled study in primary care involving 51 French GPs between April 2017 and August 2019. A total of 250 patients referred to a dermatologist for a suspected melanoma lesion were included GPs were randomized to either the smartphone arm or the usual care arm. In the smartphone arm, the GPs referred patients to the dermatologist by sending 2 photographs of the suspicious lesion using their smartphone. The dermatologist then had to set up an appointment at an appropriate time. In the usual care arm, GPs referred patients to a dermatologist according to their usual practice. The primary outcome was the time to dermatological consultation for patients whose lesion ultimately required resection. RESULTS: 57 GPs volunteered were randomized (27 to the smartphone arm, and 30 to the usual care arm). A total of 125 patients were included in each arm (mean age: 49.8 years; 53% women) and followed 8 months. Twenty-three dermatologists participated in the study. The time to dermatological consultation for patients whose suspicious skin lesion required resection was 56.5 days in the smartphone arm and 63.7 days in the usual care arm (mean adjusted time reduction: -18.5 days, 95% CI [-74.1;23.5], p = .53). CONCLUSIONS: The e-mail transmission of photographs from GPs to dermatologists did not improve the dermatological management of patients whose suspicious skin lesions ultimately required resection. Further research is needed to validate quality criteria that might be useful for tele-expertise in dermatology. TRIAL REGISTRATION: Registered on ClinicalTrials.gov under reference number NCT03137511 (May 2, 2017).

TRASS: a global approach to assess the severity of truncal acne.

INTRODUCTION: Only a small amount of published data regarding truncal acne is available, and no proper tool to assess its severity exists. AIM: The aim of the study was to provide dermatologists with an easy-to-use tool to assess truncal acne (TRASS, truncal acne severity scale) using a global approach. METHODS: A scoring tool that assesses the severity of acne (based on GEA and ECLA scales) on the trunk using a global approach was built, including three sub-scores: family history, clinical signs and quality of life (QoL). In order to test TRASS, the experts used photographs of 47 patients attending their clinics with truncal acne. The regression optimized (ROP) model was applied to assess the diagnosis performance of TRASS and to identify items contributing to the classification of the patients. Internal testing was made to demonstrate the robustness of the model. Correlation analyses between the different items were performed to evaluate the interaction between the different items and their impact on the severity grading of truncal acne. RESULTS: Patients with the most severe acne were identified by TRASS. The error level was 6.6% after internal validation and 10.4% when using the median value or the centile 75th (6.6% and 10.4%). Correlation was significant between systemic treatment and scars (P = 0.0025) and nodules (P = 0.01988) and between location and QoL (P = 0.0095). CONCLUSION: Truncal acne severity scale is the first global, patient-centred approach to evaluate truncal acne by scoring the importance of each factor independently from its clinical severity. TRASS may allow the practitioner to choose and validate the most suitable therapy together with the patient in order to treat his or her truncal acne successfully and to limit treatment failure.

Same-day discharge of Gynecologic Oncology patients following ileostomy closure is feasible and safe.

OBJECTIVE: Gynecologic Oncology patients are traditionally admitted for 2-3 days following ileostomy closure. Our aim was to assess feasibility and safety of same-day discharge (SDD), by comparing 30-day clinical outcomes after SDD and standard admission. METHODS: Retrospective study of patients who underwent ileostomy closure at two academic tertiary centres in Toronto, Canada, between January 2010 and October 2017. RESULTS: In total 117 patients underwent ileostomy closure: 23 had SDD and 94 were admitted for a median of 3 days. There were no significant differences between groups in terms of age, body mass index, comorbidities, primary malignancy, tumor stage, indication for ileostomy, previous radiation therapy, chemotherapy, interval between ileostomy formation and closure, and intraoperative complications. Median operative time was shorter (47 versus 60 min, p = 0.0001) and there was a longer median interval between last chemotherapy cycle to ileostomy closure (145 versus 106 days, p = 0.01) in the SDD group. SDD was not associated with an increased risk of adverse events (13% versus 24.5%, p= 0.24), as assessed by a composite outcome which included small bowel obstruction, anastomotic leak, surgical site infection, clostridium difficile infection, sepsis, and thromboembolic events, when compared to standard admission. Moreover, SDD did not lead to more emergency room visits (17.4% versus 16%, p = 0.87) or readmissions within 30 days of surgery (17.4% versus 8.5%, p= 0.21). CONCLUSIONS: SDD is a safe alternative to routine hospitalization that has the potential to improve healthcare resource utilization, without increasing readmissions or emergency room visits. Careful patient selection is warranted.

Predictive value of FDG-PET imaging for relapse in metastatic melanoma patients treated with immunotherapy.

BACKGROUND: Anti-PD1 immunotherapy has shown a sustainable clinical activity in patients with metastatic melanoma. However, strong predictive factors of the long-term response or risk of relapse remain to be identified. OBJECTIVES: To determine whether FDG-PET imaging could be superior to CT scan in distinguishing residual tumours versus the absence of tumour in patients with a partial response (PR) or stable disease (SD) and whether a complete metabolic response (CMR) was associated with better outcomes. METHODS: Retrospective study conducted in all patients with metastatic melanoma treated with anti-PD1 immunotherapy between October 2014 and October 2017 considered to be in complete remission. The primary outcome was the occurrence of a relapse during the follow-up. CT scan and FDG-PET scan had to be performed within a maximum of 2 months of treatment discontinuation. For CT imaging, the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 were used and included progressive disease (PD), SD, PR and complete response (CR). For FDG-PET imaging, the metabolic responses were classified as progressive metabolic disease, stable metabolic disease, residual FDG avidity (RFA) and CMR. RESULTS: Twenty-six patients were in complete remission after collegial decision. Two patients had a SD on CT scan and a CMR on FDG-PET scan, and none of them relapsed. Ten patients had a PR on CT scan and a CMR on FDG-PET scan, and none of them relapsed. The mean treatment duration to achieve a complete remission was 7 months (3-23). A univariate analysis showed that a RFA assessed on the FDG-PET scan was significantly associated with a relapse (P = 0.00231). CONCLUSIONS: Most patients with a PR on the CT scan and a CMR on the FDG-PET scan should be considered with a CR. Our study showed that FDG-PET imaging could play a crucial role in predicting the long-term outcome and help to decide whether treatment should be discontinued.

Cutibacterium acnes phylotypes diversity loss: a trigger for skin inflammatory process.

BACKGROUND: Acne has long been understood as a multifactorial chronic inflammatory disease of the pilosebaceous follicle, where Cutibacterium acnes (subdivided into six main phylotypes) is a crucial factor. In parallel, the loss of microbial diversity among the skin commensal communities has recently been shown as often accompanied by inflammatory skin disorders. OBJECTIVE: This study investigated the association of C. acnes phylotype diversity loss and the impact on Innate Immune System (IIS) activation. METHODS: The IIS response of skin after incubation with phylotypes IA1, II or III individually and with the combination of IA1 + II + III phylotypes, was studied in an in vitro skin explant system. The inflammatory response was monitored by immunohistochemistry and ELISA assays, targeting a selection of Innate Immune Markers (IIMs) (IL-6, IL-8, IL-10, IL-17, TGF-ß). RESULTS: IIMs were significantly upregulated in skin when being incubated with phylotype IA1 alone compared with the combination IA1 + II + III. In parallel, ELISA assays confirmed these results in supernatants for IL-17, IL-8 and IL-10. CONCLUSION: We identify the loss of C. acnes phylotype diversity as a trigger for IIS activation, leading to cutaneous inflammation. These innovative data underline the possibility to set up new approaches to treat acne. Indeed, maintaining the balance between the different phylotypes of C. acnes may be an interesting target for the development of drugs.

Influence of meteorological data on sun tolerance in patients with erythropoietic protoporphyria in France.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare metabolic disorder, characterized by photosensitivity, caused by errors of the haem biosynthetic pathway. Avoidance of sun exposure is recommended; however, some patients suggested a paradoxical improvement of symptoms when they move to sunny areas. OBJECTIVES: In a national French study, we sought to investigate the influence of sun exposure on EPP symptoms. MATERIALS AND METHODS: We used a national transversal observational study by questionnaire. Patients were selected from the national record of the Centre Français des Porphyries (French Porphyrias referral centre). Sun exposure level by geographic area was assessed using climate data provided by the French national meteorological service (Météo France). RESULTS: Eighty-nine patients were included. We notably observed that 40% of patients declared an improvement in their tolerance of sun exposure after repeated sun exposures. In the more sunny areas, the intensity of the pain was lower (r = -0·26) and the duration of the sun exposure responsible for flares was longer (r = 0·39) than in the areas that were less sunny (P < 0·05). CONCLUSIONS: This study proposes a benefit of natural progressive sun exposure for patients with EPP.

Development of brain metastases in patients with metastatic melanoma while receiving ipilimumab.

UNLABELLED: Ipilimumab is a monoclonal antibody blocking the inhibitory molecule CTLA4 expressed by activated T lympocytes, used for the treatment of metastatic melanoma. Recent studies have shown its potential efficacy on brain metastases. OBJECTIVES: To assess the development of brain metastases under ipilimumab and identify clinical, histological or evolving criteria related to the appearance of these metastases. A retrospective study was conducted in 52 patients treated with 4 cycles of ipilimumab 3 mg/kg every 3 weeks for unresectable stage III or stage IV melanoma between January 2011 and July 2013 in a Department of Dermato-Oncology. As no data has been find in the literature, the results were compared to our other cohort of patients treated with vemurafenib during the same period. Ten patients (21.7 %) developed brain metastases under ipilimumab in a median time of 6.58 months after treatment initiation. The multivariate analysis showed a lower rate of brain metastases in patients with acral lentiginous melanoma and melanoma of unknown primary site. The median survival after diagnosis of brain metastases was of 2.5 months. There was no significant difference with vemurafenib-treated patients in terms of incidence rate of brain metastasis, time of development and survival after diagnosis of cerebral metastases. This was the first study focused on the development of brain metastases under treatment with ipilimumab 3 mg/kg. Although ipilimumab is used for the treatment of brain metastases, it paradoxically did not seem to reduce the risk of developing brain metastases.

Profile of vemurafenib-induced severe skin toxicities.

BACKGROUND: Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. OBJECTIVE: To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. METHODS: Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. RESULTS: Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. CONCLUSION: In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed.

Verneuil's disease, innate immunity and vitamin D: a pilot study.

BACKGROUND: Verneuil's disease is a chronic inflammatory skin disease of the follicles in apocrine glands rich area of the skin (axillary, inguinal, anogenital) and is associated with a deficient skin innate immunity. It is characterized by the occurrence of nodules, abscesses, fistulas, scars. Recently, vitamin D has been shown to stimulate skin innate immunity. OBJECTIVE: The primary objective of the study was to assess whether Verneuil's disease was associated with vitamin D deficiency. The secondary objective was to determine whether vitamin D supplementation could improve inflammatory lesions. METHODS: First, 25(OH) vitamin D3 serum levels in patients with Verneuil's disease followed at Nantes University Hospital were compared to those of healthy donors from the French Blood Bank. Then, a pilot study was conducted in 14 patients supplemented with vitamin D according to their vitamin D level at baseline at months 3 and 6. The endpoints at 6 months were decreased by at least 20% in the number of nodules and in the frequency of flare-ups. RESULTS: Twenty-two patients (100%) had vitamin D deficiency (level <30 ng/mL) of whom 36% were severely deficient (level <10 ng/mL), having correlation with the disease severity (P = 0.03268) vs. 20 controls with vitamin D deficiency (91%) of whom 14% were severely deficient. In 14 patients, the supplementation significantly decreased the number of nodules at 6 months (P = 0.01133), and the endpoints were achieved in 79% of these patients. A correlation between the therapeutic success and the importance of the increase in vitamin D level after supplementation was observed (P = 0.01099). CONCLUSION: Our study shows that Verneuil's disease is associated with a major vitamin D deficiency, correlated with the disease severity. It suggests that vitamin D could significantly improve the inflammatory nodules, probably by stimulating the skin innate immunity. A larger randomized study is needed to confirm these findings.

Topical corticosteroid phobia in atopic dermatitis: a study of its nature, origins and frequency.

BACKGROUND: Topical corticosteroids remain the mainstay of atopic dermatitis therapy. Many atopic dermatitis therapeutic failures appear to be attributable to poor adherence to treatment due to topical corticosteroid phobia. OBJECTIVES: To assess the facets, origins and frequency of fear of topical corticosteroid use among patients with atopic dermatitis. METHODS: A questionnaire comprising 69 items, generated from information gathered during interviews with 21 patients and 15 health professionals, was given to consecutive patients consulting at the outpatient dermatology departments of five regional university hospitals or with 53 dermatologists in private practice. RESULTS: A total of 208 questionnaires were analysed (including 144 from parents and 87 from adult patients, 27 of whom were also parents); 80·7% of the respondents reported having fears about topical corticosteroids and 36% admitted nonadherence to treatment. A correlation was found between topical corticosteroid phobia and the need for reassurance, the belief that topical corticosteroids pass through the skin into the bloodstream, a prior adverse event, inconsistent information about the quantity of cream to apply, a desire to self-treat for the shortest time possible or poor treatment adherence. Topical corticosteroid phobia was not correlated with atopic dermatitis severity. CONCLUSION: Topical corticosteroid phobia is a genuine and complex phenomenon, common among French patients with atopic dermatitis, that has an important impact on treatment compliance.

Is primary melanoma ulceration a factor of good response to adoptive immunotherapy?

BACKGROUND: Primary melanoma ulceration is a factor of poor prognosis at the local and regional stage. The physiopathological mechanisms which explain its prognostic impact are still little known. However, two recent studies suggest that it could be a predictive factor of good response to a non-specific immunotherapy (interferon-alpha) and to an active immunotherapy (vaccine). OBJECTIVE: The aim of this study was to determine whether ulceration could be a factor of good prognosis in the context of an adoptive immunotherapy with tumour infiltrating lymphocytes (TIL) in stage III regional lymph node metastatic melanoma (sixth American Joint Committee on Cancer staging system) and whether it was associated with an improvement in the effectiveness of this treatment compared with the control group. METHODS: We have included all the patients treated in open prospective randomized TIL vs. control protocols in our unit from 1997 to 2009. Clinical data were derived retrospectively from patient files. Statistical analysis was performed using log-rank tests, Cox models and tests for interaction. RESULTS: A total of 144 patients were included. In the group of 80 patients treated with TIL, primary melanoma ulceration remained a pejorative factor for relapse-free and overall survival in univariate and multivariate analysis. The presence of ulceration did not change the effectiveness of TIL treatment in comparison with the control group with regards to relapse-free and overall survival. CONCLUSION: Our study demonstrates that primary melanoma ulceration does not have any impact on the response to TIL adoptive immunotherapy and thus does not confirm its positive prognostic value suggested by two other immunotherapy approaches.

Evolution of clinical and molecular responses to bexarotene treatment in cutaneous T-cell lymphoma.

BACKGROUND: The mechanisms of action of bexarotene are not well understood. METHODS: A retrospective study on patients with cutaneous T-cell lymphoma (CTCL) treated with bexarotene was performed to see if bexarotene could act on the dominant T-cell clones. Thirty-five patients were included. Twenty-three were treated with bexarotene for more than 3 months (300 mg/m(2)). In 7 patients, phototherapy was given with bexarotene. RESULTS: Dominant T-cell clones were observed in 11 patients in peripheral blood and in 19 patients in skin. Our results demonstrate no significant evolution of T-cell clones either in skin or peripheral blood. Furthermore, the detection of T-cell clones in peripheral blood before starting bexarotene was significantly associated with the progression of the disease. UV therapy given with bexarotene significantly improved therapeutic response without any correlation with T-cell clones. CONCLUSION: This is the first study on the evolution of the T-cell clone in blood and skin in CTCL patients during bexarotene therapy.

Relationship between responsiveness of cancer cells to Oncostatin M and/or IL-6 and survival of stage III melanoma patients treated with tumour-infiltrating lymphocytes.

Immunotherapy by adoptive transfer of autologous tumour-infiltrating lymphocytes (TIL) shows promising clinical results for stage III (lymph nodes metastasis) melanoma patients, but some of them remain unresponsive. Here we analysed retrospectively the impact of resistance of melanoma cells to anti-proliferative cytokines on the clinical outcome of 24 TIL-treated metastatic melanoma patients. Patient relapse-free survival correlated significantly with Oncostatin M (OSM) and/or IL-6 sensitivity of melanoma cells, but not with interferon (IFN) gamma or tumour necrosis factor (TNF) alpha sensitivity. However, OSM/IL-6 sensitivity did not correlate with other known prognostic factors. Moreover, OSM and IL-6 were produced by TIL just before their injection to patients. In immunodeficient mice, OSM reduced human melanoma xenograft tumour growth, this effect being directly through inhibition of tumour cell proliferation rather than induction of apoptosis or necrosis. Thus, OSM/IL-6 resistance of melanoma cells appears to be a new escape mechanism to TIL treatment that could be added to the existing prognostic factors for early stage melanoma patients. This mechanism of action could be also relevant in other immunotherapy protocols, and could lead to better prognosis and anti-cancer treatments.

Loss of oncostatin M receptor beta in metastatic melanoma cells.

Oncostatin M (OSM) is an interleukin-6 (IL-6) type cytokine originally described by its capacity to inhibit melanoma proliferation in vitro. Here, the mechanisms involved in resistance to growth inhibition by OSM were analysed for the first time on a large panel of metastatic melanoma cell lines. OSM resistance did not strictly correlate with IL-6, interferon-gamma or tumor necrosis factor-alpha resistance. Rather, it correlated with a specific loss of the OSM receptor-beta (OSMRbeta) subunit, in conjunction with a lower level of histone acetylation in the OSMRbeta promoter region. Treatment of various OSM-resistant melanoma cells with the histone deacetylase inhibitor Trichostatin A increased activity and histone acetylation of the OSMRbeta promoter as well as expression of OSMRbeta mRNA and protein, allowing OSM to activate the signal transducer and activator of transcription 3 (STAT3) and to inhibit proliferation. Other defects associated with OSM resistance were identified at the level of OSMRbeta transcription or protein expression, as well as downstream of or parallel to STAT3 activation. Altogether, our results suggest a role for OSM in the prevention of melanoma progression and that metastatic melanoma cells could escape this growth control by the epigenetic silencing of OSMRbeta.

Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study.

PURPOSE: Antibiotic prophylaxis is given to children at risk for urinary tract infection. However, evidence concerning its effectiveness in grade I to III vesicoureteral reflux is lacking. The objective of this study was to determine whether antibiotic prophylaxis reduces the incidence of urinary tract infection in young children with low grade vesicoureteral reflux. MATERIALS AND METHODS: Children 1 month to 3 years old with grade I to III vesicoureteral reflux were assigned randomly to receive daily cotrimoxazole or no treatment, and followed for 18 months. A urinary tract infection constituted an exit criterion. Infection-free survival rates were calculated using the Kaplan-Meier method and compared using the log rank test. RESULTS: A total of 225 children were enrolled in the study. Distribution of gender, age at inclusion and reflux grade were similar between the 2 groups. There was no significant difference in the occurrence of urinary tract infection between the 2 groups (17% vs 26%, p = 0.2). However, a significant association was found between treatment and patient gender (p = 0.017). Prophylaxis significantly reduced urinary tract infection in boys (p = 0.013), most notably in boys with grade III vesicoureteral reflux (p = 0.042). CONCLUSIONS: These data suggest that antibiotic prophylaxis does not reduce the overall incidence of urinary tract infection in children with low grade vesicoureteral reflux. However, such a strategy may prevent further urinary tract infection in boys with grade III reflux.

An objective method for bed capacity planning in a hospital department - a comparison with target ratio methods.

OBJECTIVES: To propose an objective approach in order to determine the number of beds required for a hospital department by considering how recruitment fluctuates over time. To compare this approach with classical bed capacity planning techniques. METHODS: A simulated data-based evaluation of the impact that the variability in hospital department activity produces upon the performance of methods used for determining the number of beds required. The evaluation criteria included productive efficiency measured by the bed occupancy rate, accessibility measured by the transfer rate of patients due to lack of available beds and a proxy of clinical effectiveness, by the proportion of days during which there is no possibility for unscheduled admission. RESULTS: When the variability of the number of daily patients increases, the Target Occupancy Rate favors productive efficiency at the expense of accessibility and proxy clinical effectiveness. On the contrary, when the variability of the department activity is marginal, the Target Activity Rate penalizes the proxy of clinical effectiveness, and the Target Occupancy Rate underoptimizes productive efficiency. The method we propose led to a superior performance in terms of accessibility and proxy of clinical effectiveness at the expense of productive efficiency. Such a situation is suitable for intensive care units. In the case of other departments, a weighting procedure should be used to improve productive efficiency. CONCLUSIONS: This approach could be considered as the first step of a family of methods for quantitative healthcare planning.