Dupilumab therapy of atopic dermatitis of the elderly: a multicentre, real-life study.

BACKGROUND: Treatment of moderate-to-severe atopic dermatitis (AD) in the elderly may be challenging, due to side-effects of traditional anti-inflammatory drugs and to comorbidities often found in this age group. Furthermore, efficacy and safety of innovative drugs such as dupilumab are not yet well known. OBJECTIVES: A multicentre retrospective, observational, real-life study on the efficacy and safety of dupilumab was conducted in a group of patients aged ≥65 years and affected by severe AD. Their main clinical features were also examined. METHODS: Data of elderly patients with severe (EASI ≥24) AD treated with dupilumab at label dosage for 16 weeks were retrospectively collected. Treatment outcome was assessed by comparing objective (EASI) and subjective (P-NRS, S-NRS and DLQI) scores at baseline and after 16 weeks of treatment. RESULTS: Two hundred and seventy-six patients were enrolled in the study. They represented 11.37% of all patients with severe AD. Flexural eczema was the most frequent clinical phenotype, followed by prurigo nodularis. The coexistence of more than one phenotype was found in 63/276 (22.82%) subjects. Data on the 16-week treatment with dupilumab were available for 253 (91.67%) patients. Efficacy of dupilumab was demonstrated by a significant reduction of all the scores. No statistically significant difference regarding efficacy was found in elderly patients when compared to the group of our AD patients aged 18-64 years, treated with dupilumab over the same period. Furthermore, only 18 (6.52%) patients discontinued the drug due to inefficacy. Sixty-one (22.51%) patients reported adverse events, conjunctivitis and flushing being the most frequent. One (0.36%) patient only discontinued dupilumab due to an adverse event. CONCLUSIONS: Therapy with dupilumab led to a significant improvement of AD over a 16-week treatment period, with a good safety profile. Therefore, dupilumab could be considered as an efficacious and safe treatment for AD also in the elderly.

Brodalumab for the treatment of moderate-to-severe plaque-type psoriasis: a real-life, retrospective 24-week experience.

BACKGROUND: Brodalumab was efficacious and safe in moderate-to-severe plaque-type psoriasis in the AMAGINE trials; published reports under real-life conditions are limited. OBJECTIVES: To evaluate the effectiveness and safety of brodalumab in patients with moderate-to-severe plaque-type psoriasis in a real-world setting. METHODS: This observational, retrospective study enrolled adult patients (≥18 years) with moderate-to-severe plaque-type psoriasis who underwent 24 weeks of treatment with brodalumab at 17 Italian dermatological centres. Baseline data included demographics, comorbidities, age of onset and duration of psoriasis and previous treatments. Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA), static PGA of Genitalia, Dermatology Life Quality Index and patient satisfaction were assessed at weeks 0, 4, 12 and 24; adverse events were recorded. RESULTS: Seventy-eight patients (mean age 47.9 years, 71.8% male, average disease duration 16.8 years) were enrolled. A rapid and significant reduction in mean PASI score was observed after 4 weeks of treatment, decreasing further at weeks 12 and 24 (all P < 0.0001 vs. baseline). A higher number of cardiometabolic comorbidities and previous therapies were negatively associated with the achievement of PASI 90 at all assessments. Brodalumab was effective in bio-experienced patients, including those who had failed on anti-interleukin (IL)-17 therapies. Quality of life and patient satisfaction increased significantly during treatment (P < 0.0001 and P < 0.01 vs. baseline, respectively). Treatment was interrupted in 9 (11.5%) patients due to adverse events (n = 4), lack of efficacy (n = 3), lost to follow-up (n = 1) and surgical procedure (n = 1). CONCLUSIONS: Brodalumab is effective and safe in the treatment of moderate-to-severe psoriasis in a real-world setting, including in patients with failure to anti-IL17 therapies.

Wide local excision vs. Mohs Tübingen technique in the treatment of dermatofibrosarcoma protuberans: a two-centre retrospective study and literature review.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade mesenchymal skin tumour, characterized by slow infiltrative growth and common local recurrence, with infrequent distant metastases. OBJECTIVE: The aim of this study is to better clarify clinicopathological characteristics of this tumour and to evaluate the cure rates of Mohs Tübingen technique (MTT) and wide local excision (WLE). Eventually, we perform a literature review to compare our experience with published data. METHODS: A retrospective review was conducted on 135 patients diagnosed, treated and followed up between 1997 and 2014 at two different institutions. Sixty-two patients underwent to WLE and 73 to MTT. The primary end-points were the following: percentage of recurrences, time to progression and recurrence annual risk rate. Then, the PubMed database was searched for DFSP case series treated with standard surgical resection (SSR), WLE, Mohs' micrographic surgery (MMS) and MTT. The annual risk rate of recurrence calculated and reported for the four separate procedures was pooled to compare them. RESULTS: Five of the 62 patients with WLE (8.1%) experienced recurrences after a mean follow-up of 4.7 years; the percentage of recurred patients 9 years after MTT was 5.5%, and the annual recurrence risk rate of 0.6%. Pooling these data with those from literature, the recurrence rate varies from 26% to 60% for SSR, from 0% and 41% for WLE, from 0% and 8.3% for MMS and from 0% to 5.5% for MTT. The lowest annual recurrence risk rate was found for MTT. CONCLUSION: Significantly lower recurrence rates were recorded in patients treated with classic or Tübingen Mohs' technique. To the best of our knowledge, our case series is the widest treated with MTT ever described in the literature; these data may be useful to guide clinicians in the choice of the gold standard treatment for Dermatofibrosarcoma protuberans.

[Epidemiology of sexting]. / Sexting: epidemiologia del fenomeno.

AIM: Aim of the present study was to assess the prevalence of sexting, defined as "the sharing of images or videos of sexually explicit content", identifying the age groups involved and assessing the possible cultural ties. The study also aimed at providing a clear picture of the phenomenon to educators and parents, an essential starting point for planning any effective educational program. METHODS: We performed a literature search on Medline (PubMed) database. In addition, the 2011 and 2012 surveys released by Eurispes and Telefono Azzurro were also consulted. "Google Trends" application provided additional details. RESULTS: In Italy teenagers from 12 to 18 years who received sexually oriented material increased from 10.2% in 2011 to 25.9% in 2012. In the USA 69.4% declared having received sexually oriented material, while 66.7% reported having sent it. In Italy, 1 out of 10 teenagers (age range 16-18) found himself in danger for having posted his nude photos online. CONCLUSION: The practice of sexting involves a wide age range with different legal implications. Teenagers practice sexting to attract attention and prove to be involved in a relationship. Sexting usually does not have any consequence but in rare cases, about 4%, malicious behavior such as sexting for money, to tease or take someone under threat has been reported. Moreover, during the past decade the cases of online harassment increased, especially involving young women. Only by closely monitoring the phenomenon and studying its deeper motivations it could be possible to plan effective educational programs, integrating sexting and the correct use of new media into a structured sexual education project.

Pigmented basal cell carcinomas in Gorlin syndrome: two cases with different dermatoscopic patterns.

We describe two nonconsanguineous white patients with multiple pigmented basal cell carcinomas (BCCs) that were histopathologically confirmed. The first patient had calcification of the cerebral falx, multiple keratocysts in the jaw, and other malformations of the cranial and finger bones. The second patient presented with multiple dermoid cysts, calcification of the cerebral falx, keratocysts of the mandible, and agenesis of left kidney. Both patients had palmar pits. Both denied any family history of cutaneous tumours. On dermatoscopic examination of patient 1, multiple, bluish, confluent and large globules were seen. The second patient had blue ovoid globules, arborizing vessels, and areas shaped like maple leaves and spoke-wheels. Based on the clinical and radiological features we diagnosed both patients as having Gorlin syndrome (GS). To our knowledge, there are no previous reports of white patients with GS showing only pigmented BCCs. The dermatoscopic patterns were different in the two patients, and to our knowledge, this is the first report of a patient with GS showing a spoked-wheel dermatoscopic pattern.

Calcipotriol induces apoptosis in psoriatic keratinocytes.

In recent years, vitamin D3 analogues have become one of the most widely prescribed topical treatments for mild or moderate chronic plaque psoriasis. These molecules are effective and safe, but their exact mechanism of action is not completely understood. In vitro studies have shown that D3 analogues decrease proliferation and induce differentiation of keratinocytes, and have strong immunomodulating effects, but there are no conclusive data about apoptosis. The aim of this study was to evaluate differences in apoptotic response between lesional and perilesional keratinocytes of patients with psoriasis before and after treatment with calcipotriol, a synthetic vitamin D3 analogue. Keratinocytes were isolated from psoriatic plaques including lesional and perilesional skin, and cultured. Cells were treated with calcipotriol for 20 h and examined under confocal microscopy after staining with propidium iodide. The number of apoptotic cells after incubation with calcipotriol was significantly higher in lesional than in perilesional keratinocytes (P < 0.05) or non-treated psoriatic keratinocytes (P < 0.05). In conclusion, calcipotriol seems to induce apoptosis in psoriatic keratinocytes.

Is there an easier way to autograft skin in chronic leg ulcers? 'Minced micrografts', a new technique.

BACKGROUND: Chronic venous leg ulcers represent an urgent and increasing problem for public health. The use of skin autografts results in a greater therapeutic success in healing chronic ulcers. OBJECTIVE: A simple method of skin autografting that could permit a wider use of skin grafts in outpatients is needed. A new technique allowing skin autografting in a simple one-step process, without complex surgical procedures or expensive technical supplies, is presented. METHODS: A small, full-thickness skin specimen taken from the patient is finely minced and spread on his leg ulcer bed allowing to cover a surface many times wider than the sample itself. RESULTS: This method induces faster re-epithelization of chronic leg ulcers that failed to heal despite good conservative local therapy and give the possibility to repair very large ulcers with small fragments of skin. A clinical case is shown as an example out of 20 ulcers we recently treated. CONCLUSION: Our preliminary report shows that this technique results in a greater therapeutic success (18 of 20 cases) in healing chronic leg ulcers, a common pathology that often affects outpatients treated for very long periods at home or in the Dermatologist's office. In our experience, this new and successful reparative possibility makes 'mince grafting' a recommendable procedure.

[Dermatofibrosarcoma protuberans: surgical treatment using the Tübingen technique (31 cases)]. / Dermatofibrosarcome de Darier-Ferrand: traitement par la technique chirurgicale de Tübingen (31 cas).

BACKGROUND: Dermatofibrosarcoma protuberans is a rare cutaneous sarcoma that progresses slowly. Although it exhibits pronounced local aggressiveness, it rarely metastasises. The condition is difficult to treat on account of asymmetric and unpredictable growth as well as the frequency of relapse. Treatment is primarily surgical. PATIENTS AND METHODS: We report 31 cases of dermatofibrosarcoma protuberans operated at the Dermatology Clinic of Novara between 1997 and 2004 using the Tübingen technique. An immunohistochimical study was performed and screening was carried out for possible extension of the neoplasm into muscle. RESULTS: Muscular involvement was seen in 4 cases. No relapses were seen over a median survival period of 3 years and no patients were lost to follow-up. DISCUSSION: The Mohs technique is the surgical method of reference and allows tumour eradication with sparing of healthy tissue. The Tübingen method constitutes an alternative approach requiring fewer histological sections. The results obtained in our series were good and no relapses were seen over a median survival period of 3 years.

[Cutaneous spreading of a chordoma]. / Extension cutanée d'un chordome.

INTRODUCTION: Chordomas are rare extradural bone tumors arising from notochord remnants, the embryonic structure forming the original axis of the spine. They represent 0.1p. 100 of all intra-cranial tumors. The chordoma is a locally malignant cancer that tends to invade the surrounding tissues. Its localization in the skin is exceptional. OBSERVATION: A 56 year-old man developed a nut-sized vegetating nodule on the nasal groove. This lesion appeared a few months following surgery for a frontoglabellar relapse of a chordoma that had developed six years earlier at the base of the skull. DISCUSSION: We report this case because of the rareness of cutaneous involvement and the particular conditions in which it occurred. It may have been due to tumoral seeding during the previous surgical interventions.

The heme-globin and dimerization equilibria of recombinant human hemoglobins carrying site-specific beta chains mutations.

The heme-globin and dimer-tetramer equilibria of ferric recombinant human hemoglobins with site-specific beta chain mutations at the heme pocket or at either the a1beta1 or the alpha1beta2 interfaces have been determined. The heme pocket mutation V67T leads to a marked stabilization of the beta chain heme and does not affect the dimer-tetramer association constant, K2,4. In the C112 mutants, the intrinsic rate of beta chain heme loss with respect to recombinant HbA (HbA-wt) is significantly increased only in C112G with some heme released also from the alpha chains. Gel filtration experiments indicate that the K2,4 value is essentially unaltered in C112G and C112L, but is increased in C112V and decreased in C112N. Substitution of cysteine 93 with A or M leads to a slight decrease of the rate of beta chain heme release, whereas the obvserved K2,4 value is similar to that obtained for HbA-wt. Modifications in oxygen affinity were observed in all the mutant hemoglobins with the exception of V67T, C93A, and C112G. The data indicate that there is no correlation between tetramer stability, beta chain heme affinity, and hemoglobin functionality and therefore point to a separate regulation of these properties.

Burow's triangle advancement flaps for excision of two closely approximated skin lesions.

The Burow's triangle advancement flap can be adapted to simultaneously remove two closely approximated cutaneous lesions. Possible technical variants and their limitations are discussed. Four clinical cases are presented. This technique gives good cosmetic results and reduces operating time.

Immobilized human hemoglobin, a versatile matrix for analytical and biotechnological applications.

The analytical and biotechnological applications of human hemoglobin immobilized covalently on CNBr-Sepharose 4B are reviewed. Hemoglobin is bound to the matrix as alphabeta dimers via either chain. The immobilized alphabeta dimers maintain the capacity to interact reversibly with soluble ones under conditions where the soluble protein is in self-association equilibrium. Under these conditions, therefore, immobilized dimers bind part of the soluble protein. In turn, the binding process can be used to assess the specific features of the equilibrium on solid-phase and to extract selectively hemoglobin from a variety of biological specimens of practical interest. A different application of immobilized alphabeta dimers concerns their use in the determination of the equilibrium and kinetic stability of the heme-globin linkage, a property that is directly correlated with the stability of the hemoglobin molecule. The advantages and limitations attendant the use of the immobilized protein relative to the soluble one are discussed.

Immobilized apo-myoglobin, a new stable reagent for measuring rates of heme dissociation from hemoglobin.

Apo-myoglobin covalently linked on CNBr-activated Sepharose 4B is proposed as a new heme acceptor for investigating the heme transfer reaction from hemoproteins. Immobilized apo-myoglobin has the desirable properties of an ideal heme acceptor in that it is characterized by a high affinity for ferric heme, a high stability towards denaturation even at physiological temperatures and can be lyophilized for long-term storage. The study of heme release from myoglobin at pH 5.0 and 37 degrees C indicates that heme affinity is increased at least 10-fold relative to the soluble protein. Experiments with human hemoglobin allowed the estimation of the heme release rates from both alpha and beta chains and brought out the greater temperature sensitivity of the alpha chain heme-globin linkage.

Stability of the heme-globin linkage in alphabeta dimers and isolated chains of human hemoglobin. A study of the heme transfer reaction from the immobilized proteins to albumin.

The stability of the heme-globin linkage in alphabeta dimers and in the isolated chains of human hemoglobin has been probed by studying the transfer of heme from the proteins immobilized onto CNBr-activated Sepharose 4B to human albumin. The kinetic and equilibrium features of the reaction have been measured spectrophotometrically given the stability of the heme donors and the ease with which heme donor and acceptor can be separated. Isolated alpha and beta chains transfer heme to albumin at similar rates (1 6 x 10(-2) s-1 at pH 9.0 and 20 degrees C) in the ferrous CO-bound and in the ferric state. In alpha beta dimers the heme-globin linkage is strengthened considerably, albeit to a different extent in the ferrous CO-bound and ferric met-aquo derivatives. Only in the latter heme is lost at a measurable rate, 0.065 +/- 0.011 x 10(-2) s-1 for alpha heme and 2.8 +/- 0.6 x 10(-2) s-1 for beta heme at pH 9.0 and 20 degrees C, which is very close to the rate measured with soluble met-aquo-hemoglobin at micromolar concentrations. These results indicate that in human hemoglobin the heme-globin linkage in the alpha chains is stabilized by interactions between unlike chains at the alpha1 beta1 interface, whereas heme binding to the beta chains is stabilized by interactions at the alpha1beta2 interface. These long range factors have to be taken into account in addition to the local factors at the heme pocket when evaluating the effect of point mutation and chemical modification.

Detection of undegraded beta-lactoglobulins and evaluation of the molecular weight of peptides in hydrolysate cow's milk formulae.

Hydrolysate formulae have been developed with the purpose of reducing the allergenicity of cow's milk proteins, thus providing a suitable formula for feeding babies with cow's milk allergy. More recently, hydrolysate formulae have also been used with babies at high risk of atopy in order to prevent cow's milk allergy. The aim of the present study was to investigate the presence of intact cow's milk proteins and the molecular weights of peptides in several batches of two extensively hydrolyzed formulae and two partially hydrolyzed formulae. The results show the presence of a significant amount of intact beta-lactoglobulin in one partially hydrolyzed formula and of peptides with high molecular weights (>16,900 D) in the two partially hydrolyzed formulae. In conclusion, the present study confirms that partially hydrolysed formulae contain a large proportion of peptides with high molecular weights: in addition, undegraded beta-lactoglobulin was detected in a partially hydrolyzed whey formula. These data strongly indicate that partially hydrolyzed formulae may be not only allergenic in an already sensitized individual, but also immunogenic in a predisposed baby.

Preparative and analytical applications of immobilized haemoglobin.

New applications of haemoglobin immobilized on Sepharose 4B are proposed for the removal of cell-free, potentially toxic haemoglobin from either natural biological specimens or artificial haemoglobin-containing systems (e.g., blood substitutes, haemosomes) to be employed for biomedical purposes. In a model study, an affinity column of immobilized haemoglobin was used to remove free haemoglobin from blood serum in which controlled haemolysis had been induced. The affinity column retains all the free haemoglobin, does not retain the haemoglobin-haptoglobin complex(es) and leaves the composition of the serum samples unaltered. When immobilized met-haemoglobin is used, haem is transferred readily to albumin, with which it forms a complex. This observation on the one hand shows that immobilized oxyhaemoglobin should be preferred for preparative purposes, and on the other opens the way to the characterization of the haem transfer reaction to albumin by means of immobilized met-haemoglobin. This reaction is difficult to study in solution owing to the overlap of the met-haemoglobin and methaemalbumin spectra.

The dimer-tetramer equilibrium of recombinant hemoglobins. Stabilization of the alpha 1 beta 2 interface by the mutation beta(Cys112-->Gly) at the alpha 1 beta 1 interface.

The dimer-tetramer association constants of several recombinant human hemoglobins (in the CO form) have been measured by differential gel filtration. Recombinant human hemoglobin prepared from recombinant beta-chains, and mutant hemoglobins where the substitution was on the surface, beta(Thr4-->Asp), in the heme pocket, beta(Val67-->Thr), at the 2,3-DPG binding site, beta(Val1-->Met+His2del), had a twofold smaller association with respect to natural hemoglobin. In a mutant at the alpha 1 beta 2 interface, beta(Cys93-->Ala), the association constant was decreased three-fold. Conversely, in a mutant at the alpha 1 beta 1 interface, beta(Cys112-->Gly), the association constant was two- and four-fold increased with respect to natural and recombinant human hemoglobin. These differences are energetically very small, consistent with the correct folding of the recombinant hemoglobins. The stabilization of the tetrameric structure by a mutation at the alpha 1 beta 1 interface indicates that structural changes in this interface can be propagated through the protein to the alpha 1 beta 2 interface and, thereby, exert an effect on the allosteric equilibrium.

Selective removal of beta-lactoglobulin directly from cow's milk and preparation of hypoallergenic formulas: a bioaffinity method.

beta-Lactoglobulin, a major allergen of cow's milk, can pass into the breast milk of mothers consuming dairy products and thus sensitize a predisposed infant with a family history of atopic allergy. beta-Lactoglobulin coupled to Sepharose 4B can be used as a specific affinity matrix to remove beta-lactoglobulin from milk without the use of buffer systems. The tendency of beta-lactoglobulin to polymerize reversibly in milk promotes binding of the soluble protein to the coupled protein and a significant retardation in its elution with respect to the other milk proteins. The matrix can be regenerated with water and used repeatedly. These unique characteristics can be exploited in bioreactors designed to treat milk for the preparation of new hypoallergenic hyposensitizing milk formulas to be used by lactating mothers.

Immobilized hemoglobin in the purification of hemoglobin-based oxygen carriers.

Chemically modified hemoglobins can be used as oxygen carriers in cell-free fluids provided that they have a low oxygen affinity and are stable towards dissociation into subunits. The latter species are undesirable because they are filtered rapidly through the kidneys, have renal toxicity and are characterized by a high oxygen affinity. A most important step in the preparation of hemoglobin-based oxygen carriers is therefore their purification from any dissociable material. Hemoglobin immobilized as alpha beta dimers on Sepharose lends itself naturally to this purpose as it is able to interact in a specific and reversible way with soluble alpha beta dimers. Hemoglobin affinity columns are very effective in the purification of cross-linked and pseudo-cross-linked human and bovine hemoglobin. The applicability of the technique is enhanced by the ease with which alpha beta dimers from different species cross-interact to yield hybrid alpha 2 beta 2 tetramers. It is shown that hemoglobin affinity columns may provide analytical information on the cross-linking reaction itself.