Iontophoresis of treprostinil promotes wound healing in a murine model of scleroderma-related ulcers.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, chronic disease characterized by fibrosis, vascular alterations and digital ulcerations. Few drugs have shown efficacy to enhance wound healing of existing SSc-related ulcers. Local delivery of treprostinil, a prostacyclin analogue, may improve wound healing. The present work aimed first at developing a mouse model of SSc-related ulcerations and second at assessing the effect of iontophoresis of treprostinil on wound healing. METHODS: We used two murine models of SSc: chemically induced with HOCl, and urokinase-type plasminogen activator receptor (uPAR)-deficient. Excisional wounding was performed on the dorsal midline with a biopsy punch. Animals were randomized into three groups: treated with electrostimulation alone, with treprostinil iontophoresis or untreated. We assessed wound healing over time, as well as skin microvascular reactivity, inflammation, microvessel density and collagen distribution, before wounding and after re-epithelialization. RESULTS: uPAR-/- mice, but not HOCl-treated mice, showed impaired wound healing and decreased microvascular reactivity compared with their controls. Treprostinil iontophoresis improved wound healing and microvascular density and decreased inflammation in uPAR-/- mice, while electro-stimulation did not. However, treprostinil had no effect on microvascular reactivity and collagen distribution. CONCLUSION: This study suggests that excisional wounds in uPAR-/- mice are a relevant model of SSc-related ulcers. In addition, treprostinil iontophoresis enhances wound healing in this model. Further work in now needed to show whether this effect translates in humans.

Skin necrosis and calcifications after extravasation of vancomycin: a localised form of calciphylaxis?

Vancomycin is a tricyclic glycopeptide antibiotic produced from Streptococcus orientalis. There is much variation in the literature with regard to the recommended dose, dilution rate and type of infusion. Given the vesicant properties of vancomycin at supratherapeutic doses (>10mg/ml), tissue damage including blistering and necrosis have been reported. We report a rare case of bilateral cutaneous necrosis induced by accidental extravasation of vancomycin when being intravenously administered. The skin surrounding the injection site was marked by the appearance of subcutaneous calcifications. The development of iatrogenic skin calcinosis has not yet been described for the extravasation of vancomycin. The mechanism underlying the calcinosis observed in our case remains unclear, but we hypothesised a form of localised calciphylaxis induced by a local triggering factor. The ulcers progressed to re-epithelialisation following necrosis debridement and local conservative treatments. Given the increased prevalence of meticillin-resistant Staphylococcus aureus, which has prompted clinicians to gradually increase vancomycin dosage, clinicians should be aware of the high risk of skin toxicity in cases of vancomycin high-dose extravasation.

Safety Profile of Sclerosing Agents: An Analysis From the World Health Organization Pharmacovigilance Database VigiBase.

BACKGROUND: Several sclerosing agents are used to treat chronic venous diseases. Although they do not seem to differ in terms of efficacy, their safety profiles might differ. OBJECTIVE: To compare the safety profile of sclerosing agents through an analysis of the World Health Organization pharmacovigilance database. METHODS: The authors performed a disproportionality analysis using the proportional reporting ratio (PRR) method to compare pharmacovigilance signals between each sclerosing agent among 6 adverse event syndromes of interest: hypersensitivity reactions, arterial thromboembolic disorders, venous thromboembolic disorders, cardiac arrhythmias, visual/neurological disturbances, and skin ulcerations. The cutoff for signal detection was defined by a logPRR lower boundary 95% confidence interval (CI) ≥0 and number of cases n ≥3. RESULTS: Of 1,227 Individual Case Safety Reports (ICSRs) identified, after removal of ICSRs with unselected indications, the authors selected 472 reports for the analysis. The authors found that polidocanol is associated with more reporting of venous embolic/thrombotic events (logPRR = 1.38 [95% CI 1.27-1.49]), ethanolamine with the higher pharmacovigilance disproportionality signal of cardiac arrhythmias (logPRR = 0.80 [95% CI 0.51-1.09]), and STS with more reporting of allergic reactions (logPRR = 1.79 [95% CI 1.59-1.98]). CONCLUSION: The safety profile of sclerosing agents significantly differs and should guide benefit-risk ratio assessment of such agents.

Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design.

BACKGROUND: Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. OBJECTIVE: The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. METHODS/DESIGN: This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). DISCUSSION: The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Long-term outcomes of isolated superficial vein thrombosis in patients with active cancer.

BACKGROUND: Cancer patients who develop a deep-vein thrombosis (DVT) or a pulmonary embolism (PE) are at higher risk of death than similar cancer patients who do not develop DVT or PE. The impact of isolated superficial venous thrombosis (SVT) (i.e. without DVT or PE) on the prognosis of cancer patients is unknown. METHODS: Data from the OPTIMEV, multicentre, observational study, to compare at 3 years the incidences of death, DVT-PE recurrence and bleeding of cancer patients with objectively confirmed SVT vs. cancer patients with DVT (matched 1:2 on age, sex, cancer stage) and vs. patients with SVT without cancer (matched 1:3 on age and sex). RESULTS: Cancer patients with SVT (n = 34) had a high risk of death (23.2%patient-year(PY)), that was similar to that of cancer patients with DVT (aHR = 1.0[0.6-1.9]) and higher to that of SVT patients without cancer (aHR = 9.0[3.5-23.1]). Cancer patients with SVT received anticoagulants for a median duration of 45 days and had a high risk of DVT-PE recurrence (6.0%PY), similar to that of cancer patients with DVT (adjusted cause-specific HR (aCHR) = 1.5[0.4-5.8]) and higher to that of SVT patients without cancer (aCHR = 2.9[0.7-11.9]). In our population, venous thrombosis on varicose veins was associated with a lower risk of death (aHR = 0.6[0.3-1.0]) and DVT-PE recurrence (aCHR = 0.6[0.2-1.7]). CONCLUSION: Our results suggest that cancer patients with SVT have a poor prognosis, similar to that of patients with cancer-related DVT. The high rate of DVT-PE recurrence suggests that such patients may need longer duration of anticoagulant treatment.

Impact of an educational program on the quality of life of patients with lymphedema: A preliminary evaluation.

OBJECTIVE: We report on the preliminary evaluation of a well-designed program, Living with Lymphedema. This longitudinal cohort study assessed patients' quality of life using questionnaires. Our main objective was to evaluate the satisfaction of the patients and their adherence to the program. This was done using a specific questionnaire of satisfaction as well as by noting patients' adherence to the program (number of patients attending all three consultations). The secondary objective was to assess the effect of the program on the patient's quality of life. The assessment criteria were the evolution of the Medical Outcomes Study 36-Item Short Form Health Survey and EuroQol questionnaire scores between the first (C1) and third (C3) consultations. METHODS: The Living with Lymphedema program targeted all patients with lymphedema in the Grenoble (France) conurbation and within the GRANTED health care network that includes vascular medicine specialists, primary care physicians, physical therapists, and dietitians in the Alpine region of France. All studied patients were ambulatory patients. The GRANTED network took care only of the educational aspect of the disease. All patients with primary or secondary lymphedema were offered the Living with Lymphedema program, whatever their age and the location of the lymphedema (upper or lower limbs). The collection of patient data conformed to the ethical and administrative regulations of the regional health authority. Grenoble Institutional Review Board (CPP Sud-Est V; No. 5891) approval for the study was specifically obtained for this evaluation on December 24, 2012. The program was built around one-to-one consultations, group workshops, and more specialized appointments. It was complementary to the routine medical care received by the patient (not evaluated in this study). It proposed three individual "educational" consultations, seven group workshops, and two specialized consultations with a dietitian. All the consultations or workshops were led by certified professionals trained in therapeutic education. RESULTS: The cohort was the 34 patients included in the program. We found a significant improvement in the physical dimension of the Medical Outcomes Study 36-Item Short Form Health Survey score (P = .01) between C1 and C3 but not for the psychic dimension. Visual analog scale scores of the ability to cope with the lymphedema showed a statistically significant improvement between C1 and C3 (P = .05). No difference was observed in adherence to compression therapy. CONCLUSIONS: This therapeutic educational program showed a significant improvement in several criteria of quality of life and in the autonomy of patients with lymphedema.

A Femoral Common Vein Aneurysm in a Patient with Neurofibromatosis Syndrome Type 1.

Neurofibromatosis type I (NFI), also called Von Recklinghausen disease, is an autosomal dominant disease secondary to a genetic mutation on the long arm of chromosome 17. This disorder affects neural crest cells. Cutaneous clinical forms are the most frequent with multiple benign skin neurofibromas, associated with café au lait skin spots and iris hamartomas. Vascular abnormalities in NF1 are rare but have also been well described. The most frequent abnormalities are characterized by arterial aneurysm degeneration, stenosis, and malformations. Venous locations are rare, but some cases of venous aneurysms were described with ruptures as complications. We present a rare case of thrombosed venous femoral aneurysm associated with a pulmonary embolism in a patient affected by NF1.

Drug-induced Raynaud's phenomenon: beyond ß-adrenoceptor blockers.

AIM: Drug-induced Raynaud's phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or ß-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS: A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS: We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by ß-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION: Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction.

Vascular endothelial-cadherin is the most important transmembrane component of endothelial adherens junctions, exclusively expressed by endothelial cells in all types of vessels. Targeting either the extracellular domain or the cytoplasmic tail deleteriously affects the junctional strength and leads to vascular permeability. Recently, cytokine-induced phosphorylation of the vascular endothelial-cadherin cytoplasmic domain was reported to trigger cleavage of its extracellular domain, producing the soluble form of the protein - soluble vascular endothelial-cadherin. Hence, the presence of soluble vascular endothelial-cadherin or auto-antibodies to human vascular endothelial-cadherin in human serum could signalize the presence of vascular abnormalities. This systematic review covers many human studies reporting increased levels of soluble vascular endothelial-cadherin, as well as auto-antibodies to human vascular endothelial-cadherin, which could be promising biomarkers of endothelial dysfunction in a large panel of diseases.

A multicenter randomized controlled trial evaluating balneotherapy in patients with advanced chronic venous insufficiency.

BACKGROUND: Apart from compression therapy, physical therapy has scarcely been evaluated in the treatment of chronic venous disorders (CVDs). Spa treatment is a popular way to administer physical therapy for CVDs in France, but its efficacy has not yet been assessed in a large trial. The objective was to assess the efficacy of spa therapy for patients with advanced CVD (CEAP clinical classes C4-C5). METHODS: This was a single-blind (treatment concealed to the investigators) randomized, multicenter, controlled trial (French spa resorts). Inclusion criteria were primary or post-thrombotic CVD with skin changes but no active ulcer (C4a, C4b, or C5). The treated group had the usual 3-week spa treatment course soon after randomization; the control group had spa treatment after the 1-year comparison period. All patients continued their usual medical care including wearing compression stockings. Treatment consisted of four balneotherapy sessions per day for 6 days a week. Follow-up was performed at 6, 12 and 18 months by independent blinded investigators. The main outcome criterion was the incidence of leg ulcers at 12 months. Secondary criteria were a modified version of the Venous Clinical Severity Score, a visual analog scale for leg symptoms, and the Chronic Venous Insufficiency Questionnaire 2 and EuroQol 5D quality-of-life autoquestionnaires. RESULTS: Four hundred twenty-five subjects were enrolled: 214 in the treatment group (Spa) and 211 in the control group (Ctr); they were similar at baseline regarding their demographic characteristics, the severity of the CVD, and the outcome variables. At 1 year, the incidence of leg ulcers was not statistically different (Spa: +9.3%; 95% confidence interval [CI], +5.6 - +14.3; Ctr: +6.1%; 95% CI, +3.2 - +10.4), whereas the Venous Clinical Severity Score improved significantly in the treatment group (Spa: -1.2; 95% CI, -1.6 - -0.8; Ctr: -0.6; 95% CI, -1.0 - -0.2; P = .04). A significant difference favoring spa treatment was found regarding symptoms after 1 year (Spa: -0.03; 95% CI, -0.57 - +0.51; Ctr: +0.87; 95% CI,+0.46 - +1.26; P = .009). EuroQol 5D improved in the treatment group (Spa: +0.01; 95% CI, -0.02 - +0.04) while it worsened (Ctr: -0.07; 95% CI, -0.10 - -0.04) in the control group (P < .001). A similar pattern was found for the Chronic Venous Insufficiency Questionnaire 2 scale (Spa: -2.0; 95% CI, -4.4 - +0.4; Ctr: +2.4; 95% CI, +0.2 - +4.7; P = .008). The control patients showed similar improvements in clinical severity, symptoms, and quality of life after their own spa treatment (day 547). CONCLUSIONS: In this study, the incidence of leg ulcers was not reduced after a 3-week spa therapy course. Nevertheless, our study demonstrates that spa therapy provides a significant and substantial improvement in clinical status, symptoms, and quality of life of patients with advanced venous insufficiency for at least 1 year.

Recanalization and stenting of a post-thrombotic iliac vein in a patient with Behçet's disease.

Vascular lesions are frequent in Behçet's disease, and among them, deep venous thrombosis may occur in up to one-third of patients. Treatment is based on immunosuppressive drugs in addition to anticoagulants. We report the case of a young woman who presented with an acute iliofemoral venous thrombosis. Acute treatment with endovascular thrombectomy and catheter-directed fibrinolysis failed, probably because of the inflammatory status of the vessel wall. Recanalization with stenting of the obstructed common femoral and iliac veins 1 year later was successful under immunosuppressive therapy. This case suggests that endovascular treatment of venous thrombosis in Behçet's disease may be conducted successfully in nonactive venous lesions under immunosuppressive therapy.

Photodynamic therapy can improve warts' discomfort in renal transplant patients prospective multicenter study.

Many studies have been conducted showing that aminolevulinic acid (ALA)-photodynamic therapy (PDT) can be an alternative treatment for recalcitrant warts. Recently, we performed a study evaluating methyl-aminolevulinic acid (MAL)-PDT for the treatment of hand warts in a population of renal transplant patients. Two symmetrical targets were selected on each hand and randomly assigned to chemical keratolytic treatment followed by three cycles of ALA-PDT (75 J cm(-2) red light). Patients were evaluated after 3 months and a second run of PDT was performed if the total area and number of warts decreased less than 50%, with evaluation every 3 months for 1 year. Twenty patients were included and 16 were evaluable (9 M, 7 F). After 6 months the reduction of warts' area was 48.4% on the treated side versus 18.4% in the control area (P = 0.021). The decrease in the total number of warts was 41%versus 19.4% (P = NS). The global tolerance of the treatment was good with acceptable pain during irradiation. These results suggest that ALA-PDT is a safe and efficient treatment for transplanted patient warts. The improvement between treated and control zone is 20% due to the decrease in untreated warts' area and number.

Treatment of cutaneous calcinosis in CREST syndrome by extracorporeal shock wave lithotripsy.

We describe the unusual case of a 78-year-old woman consulting for extensive and painful wound leg ulcerations and calcifications secondary to CREST syndrome that was treated by extracorporeal shock wave lithotripsy. This treatment was considered because of the severity of our patient's symptoms and her failure to respond to various medical and surgical treatment.

[Onychomatricoma, a rare lesion of the nail]. / L'onychomatricome, une lésion rare de l'ongle.

Onychomatricoma is a rare fibroepithelial lesion of the nail matrix with peculiar clinical and histological features. Clinically, it is characterized by a longitudinal band of yellow thickening of the nail plate with transverse overcurvature and splinter hemorrhages. Nail avulsion exposes a villous tumor of the matrix with filamentous digitations extending into multiple holes of the nail plate. Histologically, a thick keratogenous zone forms a thickened nail plate. The lesion in its proximal portion is characterized by deep epithelial invaginations and by a stroma organized in two layers. The distal zone corresponds to multiple fibroepithelial projections extending into the nail plate. The diagnosis can be difficult in the presence of misleading clinical features or when the specimen is incomplete or examined with an improper orientation. Surgical resection is the recommended treatment.