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).

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.

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.

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.

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.

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.

Melanoma gene expression and clinical course.

Evidence for the in vitro lymphocyte response against autologous melanoma has been accumulating over the past 10 years, leading to the identification of numerous melanoma-associated antigens recognised by T cells. These antigens are targets for specific immunotherapy protocols. However, their expression is heterogeneous during tumour progression and may contribute to therapeutic escape mechanisms and disease progression. This study was designed to chart the importance of these escape mechanisms, and to assess the relationship between gene expression and the clinical profile (especially survival data) of patients with melanoma. We studied the expression of certain melanoma genes in tissue biopsies from 202 patients using reverse transcriptase-polymerase chain reaction (RT-PCR). The evaluated genes were Melan-A, tyrosinase, Na-17A, MAGE-1, MAGE-3 and Ny-ESO-1. We then correlated the results to the patients' survival data. 202 samples (cutaneous, nodal and visceral biopsies) were analysed by RT-PCR. No relationship was found between clinical data and gene expression. No relationship was found between survival data and gene expression, when samples of all stages were combined in the analysis. However, interactions between gene expression and disease stage were significant. When stage III samples alone were considered, MAGE-3 expression alone or in association with the expression of the other tumour-specific genes was found to be significantly associated with a higher disease-free survival (respectively, P = 0.0349; 0.007). Our results provided no evidence for a relationship between gene expression and clinical data, or between gene expression and survival data. However, with regard to certain sub-groups, such as stage III samples, tumour gene expression was significantly associated with survival.

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.

[Correction of stiff thoracic idiopathic adult scoliosis. Prediction from the traction radiograph]. / Réduction des scolioses idiopathiques raides de l'adulte.

PURPOSE OF THE STUDY: The aim of this study was to determine the predictive value of the traction radiograph in adults with stiff curve (preoperative Cobb angle>60 degrees and reduction of less than 35% with traction) thoracic scoliosis. We wanted to compare this predictive value with that observed in reducible scoliosis. MATERIAL AND METHODS: A traction radiograph was obtained using a standard protocol with dynamometric control of the force applied. Patients with stiff scoliosis had 47 thoracic curves and 11 thoracolumbar curves (with primary anterior release for ten thoracic curves and eight thoracolumbar curves) and patients with reducible scoliosis had 56 thoracic curves. Cortre-Dubousset instrumentation was used for treatment in all patients. RESULTS: The postoperative Cobb angle for the stiff curves (without anterior release) was strongly correlated with the preoperative angle with traction (r=0.91; p<0.0001). The correlation between the postoperative Cobb angle and the preoperative Cobb angle without traction was less pronounced (r=0.86; p<0.0001). The traction radiographs were less predictive of the Cobb angle correction than the postoperative Cobb angle. The difference was 17.5+/-7 degrees , which corresponds to a supplementary gain in reduction after surgery. For the thoracic curves alone, the differences between the traction Cobb angle and the postoperative Cobb angle was 14.5 degrees for stiff curves and 6.5 degrees for reducible curves. Furthermore, the correlation between the Cobb angle with traction and the postoperative Cobb angle was stronger for stiff curve thoracic scoliosis (r=0.90) than reducible thoracic scoliosis (r=0.78). DISCUSSION AND CONCLUSION: The standard traction radiographs were highly predictive of postoperative reduction of stiff thoracic and thoracolumbar curves treated by segmental instrumentation. The postoperative result can thus be estimated with a margin of error of +/-7 degrees . For the stiff curves, the postoperative Cobb angle was 17.5 degrees on average less than predicted on the traction radiograph (on average 20% supplementary gain in reduction). This angle gain, which was greater for stiff than reducible curves, corresponds to the determining effect of release occurring with stiff curves. Finally, because of the stronger correlation between the traction Cobb angle and the postoperative Cobb angle for stiff curves, the predictive value of the traction radiograph is greater for stiff curves than for reducible curves. In conclusion, one of the contributions of the traction radiograph, which results from the predictability of the postoperative angle with a small margin of error, is to enable adequate prediction of the postoperative outcome for a given patient or a specific sub-group of patients, e.g. with or without anterior release.

A simple method to optimize hospital beds capacity.

OBJECTIVE: The number of acute hospital beds is determined by health authorities using methods based on ratios and/or target bed occupancy rates. These methods fail to consider the variability in hospitalization demands over time. On the other hand, the implementation of sophisticated models requires the decision concerning the number of beds to be made by an expert. Our aim is to develop a new method that is as simple to use as the ratio method while minimizing the roundabout approaches of these methods. METHOD: A score was constructed with three parameters: number of transfers due to lack of space, number of days with no possibility for S unscheduled admissions and number of days with at least a threshold of U unoccupied beds. The optimal number of beds is the number for which both the mean and the standard deviation of the score reach their minimum. We applied this method to two internal medicine departments and one urological surgery department and we compared the solutions proposed by this method with those put forward by the ratio method. RESULTS: The solutions proposed by this method were intermediate to those calculated by the local and national length of Stays ratio methods. Simulating an unusual increase in admission requests had no consequence on the bed number selected, indicating that the method was robust. CONCLUSION: Our tool represents a real alternative to the ratio methods. A software has been developed and is now available for use.

Cyclo-oxygenase-2 over-expression in sporadic colorectal carcinoma without lymph node involvement.

BACKGROUND: Cyclo-oxygenase-2 over-expression has been reported in most advanced human colorectal cancers. AIMS: To assess the prevalence of cyclo-oxygenase-2 over-expression in non-advanced colorectal cancers, to investigate the correlation between cyclo-oxygenase-2 status and tumour clinicopathological features and molecular phenotype, and to determine the impact of cyclo-oxygenase-2 status on long-term clinical outcome. METHODS: Sixty-one patients who had undergone surgery for colorectal cancer without lymph node involvement were evaluated retrospectively. Cyclo-oxygenase-2 expression was determined by immunohistochemistry. The tumour replication error phenotype was assessed by amplification of the two microsatellites, BAT-25 and BAT-26. RESULTS: Thirty-six tumours were classified as cyclo-oxygenase-2 positive and 25 as cyclo-oxygenase-2 negative. No correlation was found between cyclo-oxygenase-2 over-expression and clinicopathological features or molecular phenotype. Cyclo-oxygenase-2 over-expression was an independent predictor of a poor prognosis. Indeed, the relative risk of tumour recurrence or death for patients with cyclo-oxygenase-2-positive tumours was 2.13 times that of patients with cyclo-oxygenase-2-negative tumours (P=0.008; 95% confidence interval, 1.22-3.73). This difference remained significant when post-operative deaths were censored in the multivariate analysis (P=0.014). CONCLUSION: Cyclo-oxygenase-2 over-expression is not associated with tumour phenotype, but is indicative of a poorer clinical outcome in patients with non-advanced colorectal carcinoma.

[Free flap for soft tissue loss of the limbs in trauma victims]. / Les lambeaux libres dans la couverture des pertes de substance des membres: analyse des facteurs prédictifs des résultats sur une série de 67 cas.

PURPOSE OF STUDY: We report a series of 67 free flaps performed between 1995 and 2001 for soft tissue loss of the limbs in trauma victims. We searched for elements predictive of failure in order to better identify indications. MATERIAL AND METHODS: The series was predominantly masculine (52 men, 15 women). Mean age was 38.7 years (range 18-63). Thirty-four free flaps were performed on the upper limb and 33 on the lower limb. Trauma was caused by: direct crush with or without bone injury (n=23), burns (n=10), stripping (n=5), complications of open fractures (n=29). The free flaps were performed on day 0 (day of trauma) (n=7), on day 1 or 2 (n=5), from day 3 to 7 (n=12), and from day 8 to 31 (n=43). RESULTS: There were 19 complications: hematoma (n=2), infection (n=1), vascular problem (n=16), and 7 flaps were lost (10.4%). Logistic regression analysis demonstrated that the type of trauma and vascular complications were determinant factors predictive of failure. Conversely, the limb (upper versus lower), side, gender, age, or time from trauma to flap were not found to influence chances of success. DISCUSSION: Our series demonstrated that free flap repair performed in a trauma context for loss of soft tissues of the limbs is a relatively reliable surgical technique since the rate of success is similar to that reported for pediculated flaps. The usefulness of free flaps in the trauma setting is thus demonstrated, but the most appropriate modality remains to be determined. Many authors point out the importance of early cover to limit the risk of complications (osteitis, delayed bone healing). Others have not found this factor to be determinant. In everyday practice, emergency cover is not always possible and the question is whether a flap can be successful if performed late after the initial trauma. Our study demonstrates that the chances of success of a free flap are equivalent when performed early or late after trauma. CONCLUSION: Free flaps play an important role in achieving cover of tissue loss of the limbs. The type of trauma appeared to be the only factor predictive of failure.