One Health epidemic preparedness: Biosafety quality improvement training in Nigeria.

Background and Aim: One of the key components of the One Health approach to epidemic preparedness is raising awareness and increasing the knowledge of emerging infectious diseases, prevention, and risk reduction. However, related research can involve significant risks to biosafety and biosecurity. For this purpose, we organized a multidisciplinary biosafety hands-on workshop to inform and increase the knowledge of infectious diseases and risk mitigation. This study aimed to describe the process and outcome of a hands-on biosafety training program using a One Health approach across a multidisciplinary and multi-specialty group in Nigeria. Materials and Methods: A face-to-face hands-on training for 48 participants was organized by the West African Center for Emerging Infectious Diseases (WAC-EID) at the Jos University Teaching Hospital, serving as a lead institution for the Nigeria project site. Topics covered included (1) an overview of the WAC-EID research; (2) overview of infection prevention and control; (3) safety in animal handling and restraint, sample collection, and processing; (4) safety in field studies including rodent, bird and bat handling; (5) safety practices in the collection of mosquito and other arthropod vectors; (6) personal protective equipment training (disinfection, donning and doffing); and (7) safety in sample collection, labeling, and transportation. The program was executed using a mixed method of slide presentations, practical hands-on sessions, and video demonstrations. Pre- and post-course evaluation assessments and evaluation measures were used to assess training. Results: A total of 48 trainees participated in this training, with 12 (25%), 16 (33.3%), 14 (29.2%), 6 (12.5%) categorized as ornithology, entomology, mammalogy, and clinical interest groups, respectively. The pass rate for the pre-test was 29.4%, while for the post-test, it was 57.1%, or a 28% improvement. 88.6% of the trainees rated the training as relevant to them. Conclusion: Didactic and hands-on biosafety training is relevant in this era of zoonotic epidemics and pandemic preparedness. During this training program, there was a clear demonstration of knowledge transfer that can change the current practices of participants and improve the safety of infectious diseases research.

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.

Development of squamous cell carcinoma into basal cell carcinoma under treatment with Vismodegib.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in humans. Vismodegib, a Hedgehog pathway inhibitor, has proved its effectiveness in treating non-resectable advanced BCC. AIM: However, its action on squamous cell carcinoma (SCC) is unknown. We present three SCC cases developed into BCC in vismodegib-treated patients. MATERIAL AND METHODS: We have described three cases of patients developing SCC during treatment by vismodegib for BCC. RESULTS: Patient 1 was treated with vismodegib for five facial BCC. Due to the progression of one of the lesions at month 3 (M3), a biopsy was performed and showed SCC. Patient 2 was treated with vismodegib for a large facial BCC. A biopsy was performed at M2 on a BCC area not responding to treatment and showed SCC. Patient 3 was treated with vismodegib for a BCC on the nose. Due to vismodegib ineffectiveness, a biopsy was performed and showed SCC. DISCUSSION: Two similar cases have been described in the literature. This could be due to the appearance of the squamous contingent of a metatypical BCC or to the squamous differentiation of stem cells through inhibition of the hedgehog pathway. CONCLUSION: In practice, any dissociated response of a BCC to vismodegib should be biopsied.

Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib.

Vemurafenib is indicated for the treatment of patients with BRAF (V600)-mutant metastatic melanoma. We studied for the first time the characteristics of brain metastases developed during treatment with vemurafenib in real-life conditions. We included all patients treated over 3 years with vemurafenib in our department for metastatic melanoma without initial brain involvement. Our primary endpoint was to assess the incidence of brain metastases in these patients. Our secondary endpoints were to identify the risk factors for metastases occurrence and their characteristics and course. In our retrospective cohort of 86 patients, 20% had developed brain metastases on average 5.3 months after vemurafenib initiation. The median follow-up was 9 months (1-26 months). Radiological examinations revealed multiple brain metastases in 41% of patients. The only risk factor for metastasis occurrence identified was a high number of metastatic sites when initiating vemurafenib (p = 0.045). Metastasis development was associated with a trend toward a decrease in overall survival from 12.8 to 8.5 months (p = 0.07) and a significant decrease in progression-free survival from 7 to 5 months (p = 0.04). Among the patients who developed brain metastases, 82% died, of whom 64% within 3 months, versus 58% of patients without brain metastases over the same period. The extra-cerebral disease was well controlled in 59% of patients during brain progression. In vemurafenib-treated melanoma patients, brain metastases are frequent and associated with a particularly poor prognosis. Because of their high frequency in patients with controlled extra-cerebral disease, brain explorations should be systematically performed during treatment.

Melanoma and rituximab: an incidental association?

Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed.

Onychopathy induced by temsirolimus, a mammalian target of rapamycin inhibitor.

Temsirolimus belongs to the mammalian target of rapamycin (mTOR) inhibitors, targeted therapies for which indications are booming in oncology. While their tolerance is usually good, mucocutaneous toxicity is the most common, including stomatitis, rashes, edemas, pruritus, dry skin and nail disorders. The latter are common in clinical practice but have not yet been well characterized. We report 2 cases of patients who developed, after 6-7 months with temsirolimus, a dystrophy of the 20 nails with fragility, distal onycholysis, yellow discoloration, associated in 1 case with painful paronychia. Topical steroids improved the paronychia, without changing the nail dystrophy. To our knowledge, the occurrence of yellow nail discoloration with temsirolimus has never been reported before. We review the cutaneous and mucosal toxicities induced by temsirolimus and everolimus, two mTOR inhibitors used as anticancer agents and by their parent molecule sirolimus.

[Lymphomatoid granulomatosis revealed by cutaneous lesions]. / Granulomatose lymphomatoïde de révélation cutanée.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein Barr virus (EBV)-related lymphoproliferative disorder. It most frequently involves the lungs, skin and central nervous system and arises preferentially in patients with immune disorders. Here we report a case revealed by cutaneous lesions in an immunocompetent patient. CASE REPORT: A 56-year-old man consulted for erythematous nodules of the trunk associated with malaise and marked weight loss (14kg). In a few days the nodules became necrotic. Two weeks later a cough appeared and the chest computerized tomography showed multiple poorly defined nodular opacities with a peribronchovascular distribution. Cutaneous and pulmonary biopsies showed an infiltrate composed of medium-sized atypical lymphocytes T and B. EBV was present in the infiltrate (in situ hybridization) with a high EBV load in plasma. All of these data helped confirm the diagnosis of lymphoid granulomatosis. Despite aggressive treatment with polychemotherapy, the patient died after 2 months. DISCUSSION: Lymphomatoid granulomatosis represents a diagnostic challenge. In most cases, the presenting symptoms are not specific: malaise, weight loss, fever and cough. Moreover histology is difficult because of the T-cell-rich background. It is essential to consider this diagnosis in cases of cutaneous and pulmonary symptoms.

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.

Innate immunity: a crucial target for zinc in the treatment of inflammatory dermatosis.

BACKGROUND: Zinc is a cofactor of many metalloenzymes explaining that it plays a crucial role in cell proliferation and also in the regulation of immune system. It has been shown by different data that it could play a crucial role not only in the regulation of adaptative immunity but also in innate immunity which plays a crucial role in skin. OBJECTIVES: In this article, we proposed an overview of published information in the literature, on zinc and cutaneous innate immunity. METHODS: At the basic level, we gave a synthesis of data related to zinc's cutaneous targets in innate immunity, and then at clinical level selected studies on cutaneous disorders where zinc could be a therapeutic approach and discussed the targets of zinc in these pathologies. RESULTS/CONCLUSION: The specific activity of zinc salts on the innate immunity of the skin with different targets can explain why zinc is more specifically involved in cutaneous affection in which inflammation plays a particular important role, such as inflammatory acne, acrodermatitis enteropathica, hidradenitis suppurativa, folliculitis decalvans.

[Thalidomide in the treatment of chronic discoid lupus erythematosus]. / Lupus érythémateux chronique: traitement par thalidomide.

INTRODUCTION: Thalidomide is the second line treatment of chronic lupus erythematosus. The efficacy of this treatment, the minimal effective doses and tolerance are poorly documented in the literature. PATIENTS AND METHODS: We present the data of a single-center retrospective studied among 18 patients with chronic lupus erythematosus, treated with thalidomide from 1998 to 2003. Inclusion criteria were: the presence of clinical lesions evoking the disease, confirmed by histological examination and direct immunofluorescence and treatment with thalidomide for more than 2 months. RESULTS: Mean age on diagnosis was of 35.8 years. Thalidomide had been initiated a mean of 10.6 years after diagnosis of chronic lupus erythematosus. In 13 out of 18 patients, thalidomide had been prescribed because of failure with prior treatments. Fifteen patients were improved by thalidomide (83.3 p. 100), with 11 (61 p. 100) complete and 4 (22 p. 100) partial remissions. Two (11 p. 100) patients were stabilized and treatment failed in one. The mean initial dose was of 100 mg/d (50-150), and maintenance dose was of around 50 mg/d (56 mg/d). The mean follow-up with thalidomide was of 19.4 months. Only one withdrawal due to side effects was reported. The most frequent side effects were: asthenia (33 p. 100), paresthesia (22 p. 100) and weight gain (16.6 p. 100). No side effects were reported in 10 out of 18 patients. DISCUSSION: This study confirms the efficacy of low dose thalidomide in the treatment of chronic lupus erythematosus. In our experience, tolerance to this treatment is good, the most frequent side effect was asthenia, but usually mild. No significant peripheral neuropathy was noted. The fear of side effects, notably neurological, should not delay initiation of thalidomide in the case of failure with current treatments.

Biclonal immunoglobulin M dysglobulinaemia: evolving aspects in a case of primary Sjögren's syndrome.

The observation of suggestive clinical symptoms in a patient suffering from a Gougerot-Sjögren syndrome led to a search for a cryoglobulin. Unusual physico-chemical features of this cryoglobulin were discovered, using standard electrophoresis, immunoelectrophoresis, immunofixation and electroimmunotransfer. The main unusual finding was that the cryoprecipitate was made up of a biclonal IgM kappa associated to polyclonal IgG. Therefore, we suggest that this new form of cryoglobulin be classified as a subtype IIb, thus distinguishing two subtypes in the usual classification.