T follicular helper phenotype mycosis fungoides associated with acanthosis nigricans.

The association between acanthosis nigricans (AN) and mycosis fungoides (MF) has rarely been described, but it is known that MF may appear as AN-like vegetating and papillomatous plaques in skin folds, or may be associated with paraneoplastic AN. There have also been recent descriptions of a form of "intertriginous MF" that is characterized by skin fold involvement and the expression of T follicular helper (TFH) markers, and that often has an aggressive course. We describe the case of a 48-year-old man affected by MF associated with AN, whose lesions were characterized by a TFH immunophenotype and the expression of the GATA-3 nuclear master regulator that may be related to a TFH-2 subpopulation or possible disease progression.

Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model.

Cutaneous lesions are one of the hallmarks of tuberous sclerosis complex (TSC), a genetic disease in which mTOR is hyperactivated due to the lack of hamartin or tuberin. To date, novel pharmacological treatments for TSC cutaneous lesions that are benign but still have an impact on a patient's life are needed, because neither surgery nor rapamycin administration prevents their recurrence. Here, we demonstrated that primary TSC2-/meth cells that do not express tuberin for an epigenetic event caused cutaneous lesions and follicular neogenesis when they were subcutaneously injected in nude mice. Tuberin-null cells localized in the hair bulbs and alongside mature hairs, where high phosphorylation of S6 and Erk indicated mTOR hyperactivation. Interestingly, 5-azacytidine treatment reduced hair follicles, indicating that chromatin remodeling agents might be effective on TSC lesions in which cells lack tuberin for an epigenetic event. Moreover, we demonstrated that the primary TSC2-/meth cells had metastatic capability: when subcutaneously injected, they reached the bloodstream and lymphatics and invaded the lungs, causing the enlargement of the alveolar walls. The capability of TSC2-/meth cells to survive and migrate in vivo makes our mouse model ideal to follow the progression of the disease and test potential pharmacological treatments in a time-dependent manner.

Disease severity and quality of life in children with atopic dermatitis: PO-SCORAD in clinical practice.

BACKGORUND: Atopic dermatitis (AD) can significantly compromise the quality of life (QoL). The aim of our investigation was to evaluate whether QoL correlates with AD severity, evaluated through the physician and the patient perspective, in a sample of Italian children. METHODS: Forty children with AD were evaluated. Disease severity was assessed by the physician and the patients (or their parents) using the SCORAD and the patient-oriented SCORAD (PO-SCORAD) tools, respectively. Patients or their parents completed specific QoL questionnaires (IDQOL/CDLQI). Spearman's correlation coefficient and non-parametric analysis of covariance were used to analyze the data. RESULTS: SCORAD e PO-SCORAD were moderately but significantly correlated (ρ Spearman=0.55, P<0.01). QoL scores ranged from 1 to 23, with a median score of 4.0 (higher scores represent more impaired QoL). After adjustment for age and sex, children with SCORAD>40 had significantly higher QoL scores (more impaired QoL) than those with SCORAD≤40 (median QoL of 5 and 4, respectively, P=0.048). Even higher differences emerged when AD severity was self-assessed (median QoL of 6 and 3.5 for children with PO-SCORAD>40 and PO-SCORAD≤40, respectively, P=0.01). AD children with concomitant food allergy had a significantly more impaired QoL than those with AD only (P=0.040). No significant difference in QoL was observed according to sex or age. CONCLUSIONS: In our sample of AD children, QoL appeared slightly-moderately altered, and increasing disease severity was associated with greater impairment in QoL. SCORAD and PO-SCORAD were fairly correlated and the association of QoL was somewhat stronger with the PO-SCORAD than the SCORAD Index. This supports the usefulness of PO-SCORAD for the self-assessment of AD in children, and suggests the importance to integrate physician and patient perspectives in the management of AD.

Autoantibody Profile of a Cohort of 78 Italian Patients with Mucous Membrane Pemphigoid: Correlation Between Reactivity Profile and Clinical Involvement.

Direct diagnosis of mucous membrane pemphigoid (MMP) is not easy. Circulating autoantibodies targeting bullous pemphigoid antigens of 180 kDa and 230 kDa (BP180 and BP230), α6ß4 integrin, laminin 332 and type VII collagen (Col VII) are not always present. The aims of this study were to characterize the humoral immune response of a cohort of Italian patients with MMP, its association with clinical involvement and severity, and to design an algorithm for efficient serological diagnosis. Seventy-eight MMP sera were studied retrospectively by indirect immunofluorescence on salt-split skin, enzyme-linked immunosorbent assay (ELISA) and immunoblotting. Indirect immunofluorescence on salt-split skin resulted in the most sensitive approach for diagnosis of MMP. BP180 was the major autoantigen in MMP patients with oral and cutaneous involvement. Significant associations were found between BP180 reactivity and oral and cutaneous localization of the lesions (p = 0.006), and between Col VII positivity and Setterfield severity score (p = 0.020).

Atopic dermatitis: recent insight on pathogenesis and novel therapeutic target.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It affects infancy, but it is also highly prevalent in adults and it is one of the disease burdens for the patients and their families. Nowadays, AD is recognized as a heterogenous disease with different subtypes with variable clinical manifestations which is affected by the impairments of the skin barrier. The severity of AD dictates the level of treatment. Current AD treatment focuses on restoration of the barrier function, mainly through the use of moisturizers and corticosteroids to control the inflammation, topical calcineurin inhibitors, and immunosuppresive drugs in the most severe cases. However, targeted disease-modifying therapies are under investigation. The most recent findings on the skin microbial dysbiosis is a promising future direction for the development of new treatments. We need to improve the understanding of the complex microbiome-host interactions, the role of autoimmunity, the comparative effectiveness of therapies and the ways to appropriately implement the educational strategies.

Functional characterisation of a novel mutation affecting the catalytic domain of MMP2 in siblings with multicentric osteolysis, nodulosis and arthropathy.

Multicentric osteolysis, nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder. To date, 13 mutations of the matrix metalloproteinase 2 (MMP2) gene have been detected in 26 patients with MONA and other osteolytic syndromes. Here, we describe the molecular and functional analysis of a novel MMP2 mutation in two adult Italian siblings with MONA. Both siblings displayed palmar-plantar subcutaneous nodules, tendon retractions, limb arthropathies, osteolysis in the toes and pigmented fibrous skin lesions. Molecular analysis identified a homozygous MMP2 missense mutation in exon 8 c.1228G>C (p.G410R), not detected in 260 controls and predicted by several bioinformatic tools to be pathogenic. By protein modelling, the mutant residue was predicted to affect the main chain conformation of the catalytic domain. Gelatin zymography, the gold standard test for MMP2 function, of serum-free conditioned medium from G410R-MMP2-expressing human embryonic kidney (HEK) cells, showed a complete loss of gelatinolytic activity. The novel mutation is located in the catalytic domain, as are 3 (p.E404K, p.V400del and p.G406D) of the other 13 MMP2 mutations described to date; however, p.G410R underlies a phenotype that is only partially overlapping that of other MMP2 exon 8 mutation carriers. Our results further delineate the complexity of genotype-phenotype correlations in MONA, broaden the repertoire of reported MMP2 mutation and enhance the comprehension of the protein motifs crucial for MMP2 catalytic activity.

Dermatological findings in Rubinstein-Taybi Syndrome.

Rubinstein-Taybi Syndrome is a rare congenital multisystem syndrome inherited in an autosomal dominant pattern caused by mutations in CREBBP and EP300 genes in approximately 60% and 10% respectively. These genes encode two highly evolutionarily conserved, ubiquitously expressed, and homologous lysine-acetyltransferases, that are involved in number of basic cellular activities, such as DNA repair, cell proliferation, growth, differentiation, apoptosis of cells, and tumor suppression. It is mainly characterized by global developmental delay, moderate to severe intellectual disability, postnatal retardation, microcephaly, skeletal anomalies including broad/short, angled thumbs and/or large first toes, short stature, and dysmorphic facial features. There is an increased risk to develop tumors mainly meningiomas and pilomatrixomas, without a clear genotype-phenotype correlation. Although not considered as characteristic manifestations, numerous cutaneous anomalies have also been reported in patients with this entity. Both susceptibility to the formation of keloids and pilomatricomas are the most often associated cutaneous features. In this review, we discuss the genetics, diagnosis, and clinical features in Rubinstein-Taybi Syndrome with a review of the major dermatological manifestations.

Comma hairs in tinea capitis: a useful dermatoscopic sign for diagnosis of tinea capitis.

Diagnosis of tinea capitis (TC) can be challenging for dermatologists, especially in noninflammatory TC caused by anthropophilic dermatophytes and in black patients, in whom erythema of the scalp is difficult to appreciate. The finding of a typical TC dermoscopic pattern may lead more quickly to a correct diagnosis.

Machine learning for the identification of decision boundaries during the transition from radial to vertical growth phase superficial spreading melanomas.

The objective of this study was to compute threshold values for the diameter of superficial spreading melanomas (SSMs) at which the radial growth phase (RGP) evolves into an invasive vertical growth phase (VGP). We examined reports from 1995 to 2019 of 834 primary SSMs. All the patients underwent complete surgical removal of the tumor and the diagnosis was confirmed after histologic examination. Machine learning was used to compute the thresholds. For invasive non-naevus-associated SSMs, a threshold for the diameter was found at 13.2 mm (n = 634). For the lower limb (n = 209) the threshold was at 9.8 mm, whereas for the upper limb (n = 117) at 14.1 mm. For the back (n = 106) and the trunk (n = 173), the threshold was at 16.2 mm and 17.1 mm, respectively. When considering non-naevus-associated and naevus-associated SSMs together (n = 834) a threshold for the diameter was found at 16.8 mm. For the lower limb (n = 248) the threshold was at 11.7 mm, whereas for the upper limb (n = 146) at 16.4 mm. For the back (n = 170) and the trunk (n = 236), the threshold was at 18.6 mm and 14.1 mm, respectively. Thresholds for various anatomic locations and for each gender were defined. They were based on the diameter of the melanoma and computed to suggest a transition from RGP to VGP. The transition from a radial to a more invasive vertical phase is detected by an increase of tumor size with a numeric cutoff. Besides the anamnestic, clinical and dermatoscopic findings, our proposed approach may have practical relevance in vivo during clinical presurgical inspections.

Plasmacytoid dendritic cells: an overview of their presence and distribution in different inflammatory skin diseases, with special emphasis on Jessner's lymphocytic infiltrate of the skin and cutaneous lupus erythematosus.

BACKGROUND: Plasmacytoid dendritic cells (PDC) play a pivotal role in the induction of autoimmune diseases and other skin diseases. The present study focuses on the distribution patterns of PDC in patients with cutaneous lupus erythematosus (LE) and Jessner's lymphocytic infiltrate (LI) of the skin and compares them with other skin diseases. The goal was to scrutinize the involvement of PDC in LI, and to show that PDC present a specific pattern of distribution in various cutaneous disorders. METHODS: 353 skin biopsies of LE (various subtypes), LI, and other inflammatory skin diseases as well as two halo melanocytic nevi and 10 epithelial tumors were immunohistochemically investigated for the presence of PDC by employing antibodies against CD123 and CD2AP. RESULTS: PDC were constantly detected as distinct perivascular and periadnexal clusters in LE and LI. In other forms of dermatitis, PDC could be found as single cells or scattered throughout the infiltrate or beneath the epidermis. CONCLUSIONS: Our data suggest that the distribution of PDC in tumid LE and LI is identical, and this observation suggests that both designations signify one disease. The distinct PDC arrangement in LE represents as useful diagnostic tool in the differential diagnosis with other forms of dermatitis.

A Systematic Review of Treatment Options and Clinical Outcomes in Pemphigoid Gestationis.

Background: Treatment regimens for pemphigoid gestationis (PG) are non-standardized, with most evidence derived from individual case reports or small series. Objectives: To systematically review current literature on treatments and clinical outcomes of PG and to establish recommendations on its therapeutic management. Methods: An a priori protocol was designed based on PRISMA guidelines. PubMed, Scopus, and Web of Science databases were searched for English-language articles detailing PG treatments and clinical outcomes, published between 1970 and March 2020. Results: In total, 109 articles including 140 PG patients were analyzed. No randomized controlled trials or robust observational studies detailing PG treatment were found. Systemic corticosteroids ± topical corticosteroids and/or antihistamines were the most frequently prescribed treatment modality (n = 74/137; 54%). Complete remission was achieved by 114/136 (83.8%) patients. Sixty-four patients (45.7%) were given more than one treatment modality due to side effects or ineffectiveness. Leaving aside topical corticosteroids as monotherapy ± antihistamines in patients with mild disease, systemic corticosteroids ± topical corticosteroids and/or antihistamines led to complete remission in the highest proportion of patients (83%), while steroid-sparing treatments ± topical corticosteroids and/or antihistamines were associated with the lowest proportion of flares (55.5%). Limitations: The review has been drafted based on a limited number of single case reports and small case series. Underreporting/underdiagnosis of patients with mild-to-moderate PG, partial/absent follow-up, absence of precise description of neonatal outcomes and lack of validated objective scores for measuring disease severity are other limitations of our study. Our systematic review was affected by publication bias. Conclusion: Systemic corticosteroids are the most frequently used treatment for PG. Whilst most patients achieve complete remission, many of them have refractory/persistent disease requiring multiple lines of therapy. Therefore, we provided an algorithm for PG treatment integrating the results of this systematic review with current knowledge available for bullous pemphigoid. High-quality studies will further help assess the effectiveness of different treatment options for PG.

The Many Faces of Covid-19 at a Glance: A University Hospital Multidisciplinary Account From Milan, Italy.

In March 2020, northern Italy became the second country worldwide most affected by Covid-19 and the death toll overtook that in China. Hospital staff soon realized that Covid-19 was far more severe than expected from the few data available at that time. The Covid-19 pandemic forced hospitals to adjust to rapidly changing circumstances. We report our experience in a general teaching hospital in Milan, the capital of Lombardy, the most affected area in Italy. First, we briefly describe Lombardy's regional Covid-19-related health organizational changes as well as general hospital reorganization. We also provide a multidisciplinary report of the main clinical, radiological and pathological Covid-19 findings we observed in our patients.

Vitamin D status and body mass index in children with atopic dermatitis: A pilot study in Italian children.

BACKGROUND: Vitamin D (vitD) is involved in important regulatory functions of the innate and adaptive immune system. So, it has been hypothesized that vitD might influence the course of atopic dermatitis (AD). Also obesity may have impact on immune system. The aim of our study was to investigate vitamin D status and body mass index (BMI) in urban children with AD. METHODS: 52 children with AD and 43 healthy children were enrolled. SCORAD, BMI and serum vitD levels were evaluated. RESULTS: There was an association between vitamin D and the AD occurrence but neither between vitamin D and the AD severity, nor between vitamin D and BMI. A positive correlation was observed between BMI and the AD severity in males. CONCLUSIONS: This study highlights the complex inter-relationships among atopic dermatitis severity, vitamin D and body mass index and suggests the need to investigate the role of genetic factors and/or gender-related differences to possibly identify new prevention strategies.

M1 and M2 macrophages' clinicopathological significance in cutaneous melanoma.

Skin malignant melanoma (MM) is an aggressive cancer with an increasing incidence with limited therapies in advanced stages. Tumor-associated macrophages (TAMs) are the major immune constituent of the MM microenvironment and contribute toward its prognosis. TAMs' characterization and localization in human cancer is important to understand cancer progression and to identify molecular personalized therapies. M2 TAMs in stage I-II MMs are associated with worse prognostic parameters. A comprehensive M1-macrophage and M2-macrophage intratumoral localization and quantification in all stages of skin MMs is documented here with its clinical significance. To highlight immune pathways and possible early indicators of MM progression, we evaluated the number of M1 and M2 TAMs and intratumoral distribution in a large series of skin MMs. CD68 double immunostaining with MRP8-14 or inducible nitric oxide synthase (M1 macrophages) and with CD163 or CD204 (M2 macrophages) was performed in 94 stage I-IV skin MMs with a long duration of follow-up. The accumulation and distribution of M1 and M2 TAMs in intratumoral nests, stroma, and at the invasive front was correlated with clinicopathological variables. Since the early stage of MMs, M1 intratumoral macrophages were fewer than the M2 population; their recruitment was rapidly and progressively overwhelmed by an increase in M2 TAMs during MM progression. Independent of their intratumoral distribution, the accumulation of both M1 and M2 TAMs is associated with poor prognostic indicators and patients' survival. M1-recruited macrophages shift to the M2 phenotype early in MM development, possibly induced by high inducible nitric oxide synthase intratumoral increase peculiarly occurring since the initial MM stages. M2-recruited TAMs overwhelm M1 accumulation in all stages of MM progression, thus favoring neoplastic growth and dissemination. Independent of their intratumoral distribution, the prevalent accumulation of M2 TAMs in MM is statistically confirmed to be a poor indicator of patients' outcome and a potential target of immune therapies.

A rare case of subcutaneous fusariosis in an immunocompetent patient.

Fusarium species can cause diseases in immunocompromised patients, whereas have rarely been reported as pathogens in immunocompetent individuals. Fusarium oxysporum and F. solani species complex are the most frequent pathogenic species. Primary subcutaneous hyalohyphomycosis due to these filamentous fungi is an extremely rare pathology, especially in immunocompetent patients. Only 37 cases of deep Fusarium infection in healthy patient have been reported in international literature. We report a case of subcutaneous infection due to F. solani species complex in a healthy 45-year-old man presenting with painful nodular lesion on the left ankle, appeared seven years earlier.

G protein-mediated signal transduction is affected in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by severe intraepatic cholestasis. Pruritus often occurs during the course of the illness. We designed a study aimed at assessing whether pruritus is associated with dysfunction of signal transduction. Seventeen female patients affected by PBC were enrolled into the study and divided in two groups according to severity of liver disease. Leukocytes were isolated from peripheral blood and Gi, Go and Gs protein expressions were evaluated by western blotting, while G protein function was assessed by measuring cyclic adenosine phosphate formation. The expression of all types of G proteins was increased in leukocytes of PBC patients. The basal adenylate activity was significally higher than control in patients with less severe liver disease, while it was lower than normal in those with severe liver disease. Incubation of patient leukocytes with guanosine triphosphate-gamma-S and Gs protein activators failed to enhance cAMP production, while N-formyl-met-leu-phe was more effective in reducing cAMP production. The expression of all G proteins was non-selectively increased in PBC leukocytes, while adenylate cyclase activity was significantly modified. However, the observed changes in G proteins expression and in adenylate cyclase activity are not related to the presence of pruritus.

An observational study regarding the rate of growth in vertical and radial growth phase superficial spreading melanomas.

The natural history of superficial spreading melanomas (SSMs) involves the progression from a radial growth phase (RGP) to a vertical growth phase (VGP). Currently, a patient's history represents the only method to estimate the rate of tumor growth. The present study aimed to verify whether the estimated rate of growth (ROG) of SSMs with a RGP or VGP exhibited any differences, and to evaluate the possible implications for the most important prognostic determinants. ROG was quantified as the ratio between Breslow's thickness in millimeters (mm) and the time of tumor growth in months, defined as the time between the date that the patient had first noticed the lesion in which melanoma subsequently developed and the date on which the patient first felt this lesion changed. A total of 105 patients (58 male and 47 female) were studied. Of these, 66 had VGP-SSMs, whilst 39 had RGP-only SSMs (RGP-SSMs). No significant differences in age and gender were observed between these groups. The mean Breslow's thickness in patients with VGP-SSMs was significantly greater than in patients with RGP-SSMs (0.78±0.68 vs. 0.48±0.22 mm, P=0.0096). Similarly, the ROG was observed to be higher in VGP-SSM vs. RGP-SSM patients (0.13±0.16 vs. 0.065±0.09 mm/month, P=0.0244). In patients with VGP-SSMs, Breslow's thickness and ROG were significantly higher for tumors with a mitotic rate of ≥1 mitosis/mm2 compared with those with <1 mitosis/mm2 (1.15±0.96 vs. 0.56±0.30 mm, P=0.0005; and 0.188±0.20 vs. 0.09±0.12 mm/month, P=0.0228, respectively). According to these results, two subsets of SSMs exist: The first is characterized by the presence of mitosis and a higher ROG, while the second exhibits a more indolent behavior and is characterized by an RGP only. Given the differences in the Breslow's thickness and ROG, clinicians must be aware of the possible diagnostic delay in these subsets of melanoma that, differently from true nodular melanomas, generally fulfill the classical ABCD clinical criteria.

Bcl-6 gene mutations in primary cutaneous B-cell lymphomas.

We analyzed mutations in the 5' non-coding region of the BCL-6 gene in 46 cases of primary cutaneous B-cell lymphomas (PCBCL), using a polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) method. The results indicate that PCBCL display a low frequency of mutations and support a marginal zone B-cell origin for most of these neoplasms.