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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent and painful nodules and abscesses in intertriginous skin areas, which can progress to sinus tract formation, tissue destruction, and scarring. HS is highly debilitating and severely impairs the psychological well-being and quality of life of patients. The therapeutic approach to HS is based on medical therapy and surgery. First-line medical therapy includes topical antibiotics, systemic antibiotics, and biologics. Main surgical procedures include deroofing, local excision, and wide local excision. Despite the availability of multiple therapeutic options, the rates of disease recurrence and progression continue to be high. In recent years, the possibility of combining biologic therapy and surgery has raised considerable interest. In a clinical trial, the perioperative use of adalimumab has been associated with greater response rates and improved inflammatory load and pain, with no increased risk of postoperative infectious complications. However, several practical aspects of combined biologic therapy and surgery are poorly defined. In June 2022, nine Italian HS experts convened to address issues related to the integration of biologic therapy and surgery in clinical practice. To this purpose, the experts identified 10 areas of interest based on published evidence and personal experience: (1) patient profiling (diagnostic criteria, disease severity classification, assessment of response to treatment, patient-reported outcomes, comorbidities); (2) tailoring surgery to HS characteristics; (3) wide local excision; (4) presurgery biologic treatment; (5) concomitant biologic and surgical treatments; (6) pre- and postsurgery management; (7) antibiotic systemic therapy; (8) biologic therapy after radical surgery; (9) management of adverse events to biologics; and (10) management of postoperative infectious complications. Consensus between experts was reached using the Estimate-Talk-Estimate method (Delphi Method). The statements were subsequently presented to a panel of 27 HS experts from across Italy, and their agreement was assessed using the UCLA Appropriateness Method. This article presents and discusses the consensus statements., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease that negatively impacts the quality of life and work productivity of patients., Objectives: We sought to evaluate the real-world burden of AD patients in Italy., Methods: This sub-analysis of the MEASURE-AD multicountry study conducted between December 2019-2020 included patients diagnosed with moderate-to-severe AD eligible for or receiving systemic therapy in the previous 6 months. During a single visit, physician and patient-reported questionnaires were used., Results: A total of 118 adult patients were enrolled and 57.6% (N = 68) of patients had moderate-to-severe AD at the time of enrolment according to the Eczema Area and Severity Index. Sleep disorders interfered with daily function in the previous week in 58.5% (N = 69) of patients, pruritus was severe in 50% (N = 59) and 42.4% (N = 50) reported a flare lasting >7 days in the previous 6 months. According to the Dermatology Quality of Life Index, 37.3% (N = 44) of patients reported a severe impact of AD and approximately 10% had clinical depression/anxiety. Current drug therapy was considered inadequate in controlling AD in 26.3% (N=31) of patients. Work activity impairment was 38.6±31.7% and monthly AD-related expenses were 148.6±134.6 Euros per patient., Conclusions: This real-life study documents a high burden of disease in patients with moderate-severe AD in Italy.

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAF V600E or NRAS Q61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53 R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs., (© 2023. The Author(s).)

Introduction: Psoriasis affects children with a considerable burden in early life. Treating pediatric psoriasis is challenging also because of the lack of updated specific guidelines. With the recent approval of several biologics for pediatric psoriasis and the ongoing COVID-19 pandemic, the management of young psoriatic patients is facing major changes. A revision of treatment recommendations is therefore needed., Methods: In September 2021, a board of six Italian dermatologists convened to update treatment recommendations. The board issued evidence- and consensus-based statements covering relevant areas of pediatric psoriasis, namely: assessment of psoriasis severity, management of children with psoriasis, and treatment of pediatric psoriasis. To reach consensus, the statements were submitted to a panel of 24 experts in a Delphi process performed entirely via videoconference. A treatment algorithm was produced., Results: There was full consensus that psoriasis severity is determined by the extension/severity of skin lesions, site of lesions, and impact on patient quality of life. Agreement was reached on the need for a multidisciplinary approach to pediatric psoriasis and the importance of patient/parents education. The relevance of vaccinations, including COVID-19 vaccination, for psoriatic children was acknowledged by all participants. Management issues that initially failed to reach consensus included the screening for psoriasis comorbidities and early treatment with biologics to prevent them and the use of telemedicine to facilitate patient follow-up. There was full consensus that topical corticosteroids are the first choice for the treatment of mild pediatric psoriasis, while phototherapy and systemic therapy are used in children with moderate-severe psoriasis. According to the proposed treatment algorithm, biologics are the first line of systemic therapy., Conclusions: Targeted systemic therapies are changing the treatment of moderate-severe pediatric psoriasis, while topical corticosteroids continue to be the first choice for mild disease. Children-centered research is needed to further improve the treatment of pediatric psoriasis., (© 2022. The Author(s).)

Background: Some biologics for psoriasis, especially anti-tumor necrosis factor (TNF)-α therapies, may re-activate latent tuberculosis (TBC) infection with consequent morbidity and mortality. However, there is a low reported incidence of conversion to positive TBC status among patients with psoriasis treated with second-generation biologic therapies, particularly anti-interleukin (IL)-17 therapies such as secukinumab., Objectives: To evaluate the safety profile of secukinumab in psoriasis patients with latent TBC infection., Methods: Real-life data were collected by retrospective chart review on patients with moderate-to-severe psoriasis who showed positivity for TBC screening at baseline and underwent secukinumab treatment for psoriasis at six Italian centers. Patients received secukinumab 300 mg at week 0/1/2/3/4, then every 4 weeks., Results: Fifty-nine patients were enrolled; 30.5% also had psoriatic arthritis and other comorbidities were common. At baseline, the mean psoriasis duration was 14.5 years. Ten (17%) patients did not undergo prophylaxis before starting secukinumab. Conversely, isoniazid ± rifampicin or rifampicin alone prophylaxis was administered in 49/59 (83.1%) patients. After a mean treatment duration of 84 weeks, there were no cases of TBC reactivation and no unexpected safety signals., Conclusions: Secukinumab use over an extended period was safe in psoriasis patients with latent TBC, even in patients who did not receive chemoprophylaxis.

Differential genetically determined expression of transforming growth factor-β (TGF-β pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular "milieu" involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-β and VEGF-A genes in 70 NMSC patients and 161 healthy controls, typed for TGF-β1 rs1800471 , TGF-β2 rs900 , TGF-βR1 rs334348 and rs334349 , TGF-βR2 rs4522809 and VEGF-A rs3025039 SNPs. TGF-βR2 rs1800629G allele and related genotypes were found to be associated with a possible protective role against NMSC, whereas VEGF-A rs3025039T was associated with an increased risk. To evaluate the effect of genotype combinations on NMSC susceptibility, we determined the frequencies of 31 pseudo-haplotypes due to non-random linkage among alleles of loci not lying on the same chromosome. Two pseudo-haplotypes that imply a minor allele of TGF -βR2 or minor allele of VEGF-A SNPs combined with major alleles of the other SNPs were, respectively, associated with a protective effect, and susceptibility to NMSC. In addition, a pseudo-haplotype involving minor alleles of TGF-β2 rs900 , TGF-βR1 rs334348 and rs4522809 SNPs might be a susceptibility marker for NMSC. In conclusion, our data suggest that a complex interplay among the genetic polymorphisms of TGF-β , TGF-β receptors and VEGF-A genes might influence the net effect of genetic background of the patients on NMSC development. This might be relevant in the risk evaluation, diagnosis and treatment of NMSC.

Background and Objective: Biologics for psoriasis, especially anti-tumor necrosis factor-α therapies, may reactivate hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, as well in inactive carriers or patients with occult infection. However, some biologics, including anti-interleukin-17 therapies such as secukinumab, seem to be less likely to cause hepatitis reactivation. This study assessed the safety of secukinumab treatment in patients with psoriasis with HBV or HBC infection., Methods: This was a retrospective cohort study of patients with moderate-to-severe psoriasis treated with secukinumab at seven Italian centers. Patients serologically positive for one or more of the following viral hepatitis markers were included: HCV antibody (± HCV-RNA positivity) and/or hepatitis B surface antigen, and/or HBV core antibody and/or HBV surface antibody (± HBV-DNA positivity). Patients received secukinumab 300 mg subcutaneously at week 0/1/2/3/4 then every 4 weeks; prophylactic therapy before starting secukinumab was prescribed where indicated. The primary study endpoint was the reactivation of hepatitis viral infection, defined as conversion to HBV-DNA or HCV-RNA positivity, with or without elevation of transaminases., Results: Sixty patients (17 with concomitant psoriatic arthritis) were included. Thirteen subjects were hepatitis B surface antigen positive, 19 were HBV core antibody positive, and 30 were positive for the HCV antibody; however, all were HCV-RNA negative. After 53.5 ± 37.5 weeks of secukinumab therapy, hepatitis reactivation occurred in only one patient, who had a reactivation of both hepatitis B and hepatitis C. This patient had not undergone hepatitis B prophylaxis or hepatitis C treatment before secukinumab., Conclusions: These real-world data support the safety of secukinumab in patients with positive markers of HBV or HCV infection, when administered together with dedicated prophylaxis., (© 2022. The Author(s).)

Competing Interests: A.C. served as advisory board member and consultant receiving fees and speaker's honoraria or has participated in clinical trials for AbbVie, Almirall, Biogen, Fresenius Kabi, Leo Pharma, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme, and UCB Pharma. G.F. acted as speaker and consultant for AbbVie and Leo Pharma. G.G. has been principal investigator in clinical trials sponsored by and/or and has received personal fees from AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Eli Lilly, Leo Pharma, Novartis, OM Pharma, Pfizer, Regeneron, Samsung, and Sandoz. A.O. has been a scientific consultant/speaker/clinical study investigator for AbbVie, Celgene, Janssen, Leo Pharma, Eli Lilly, MSD, Novartis, Pfizer, Sanofi, Alfasigma, and Almirall. M.T.R. has received personal fee for advisory board meeting from Sanofi, AbbVie, Novartis, and Cantabria. L.B. reports personal fees from speaker and as consultant for AbbVie, Novartis, Janssen-Cilag, Pfizer, UCB, and Leo Pharma, outside the submitted work. L.S. has been principal investigator in clinical trials sponsored by and/or received personal fees from AbbVie, Almirall, Celgene, Eli Lilly, Janssen, Novartis, and Sanofi-Genzyme. G.P. has been principal investigator in clinical trials sponsored by and/or received personal fees from AbbVie, Almirall, Eli Lilly, Leo Pharma, Novartis, and Sanofi. A.P. has served as a speaker and received honoraria from Sanofi-Genzyme for lectures, research grants, and as an advisory board member. C.F. has been speaker for Sanofi and AbbVie. M.C.F. has served on advisory boards, received honoraria for lectures, and research grants from Almirall, AbbVie, Galderma, Leo Pharma, Mylan, Medac Pharma, Celgene, Pierre Fabre, UCB, Eli Lilly, Pfizer, Janssen, Novartis, Sanofi Genzyme, Roche, Sun Pharma, and MSD. F.R. has served on advisory board, received honoraria for lectures and research grants from Novartis, AbbVie, Janssen-Cilag, Eli Lilly, Leo Pharma, and Sanofi-Genzyme. P.A. has received speaker honoraria from Sanofi, AbbVie, Janssen, Celgene, Novartis, and Sandoz. G.M. has been a scientific consultant/clinical study investigator for AbbVie, Eli Lilly, Janssen-Cilag, Leo Pharma, and Novartis. C.P. has been a consultant and held sponsored conferences for AbbVie, Novartis, Pfizer, and Sanofi. I.Z. has been a consultant and/or speaker for Novartis, Celgene, and Amgen. K.P. reports grants and personal fees for advisory board meeting from Almirall, AbbVie, Biogen, Lilly, Celgene, Galderma, Leo Pharma, Novartis, Pierre Fabre, Sanofi, Sandoz, Sun Pharma, and Janssen. S.F. has been principal investigator in clinical trials by AbbVie and Sanofi-Genzyme, has served on advisory board, received honoraria for lectures and research grants from Novartis, Menarini, and Almirall. The remaining authors have no funding or conflicts of interest to declare.

Breast cancer (BC) is the second cause of cancer-related deceases in the worldwide female population. Despite the successful treatment advances, 25% of BC develops resistance to current therapeutic regimens, thereby remaining a major hurdle for patient management. Current therapies, targeting the molecular events underpinning the adaptive resistance, still require effort to improve BC treatment. Using BC sphere cells (BCSphCs) as a model, here we showed that BC stem-like cells express high levels of Myc, which requires the presence of the multifunctional DNA/RNA binding protein Sam68 for the DNA-damage repair. Analysis of a cohort of BC patients displayed that Sam68 is an independent negative factor correlated with the progression of the disease. Genetic inhibition of Sam68 caused a defect in PARP-induced PAR chain synthesis upon DNA-damaging insults, resulting in cell death of TNBC cells. In contrast, BC stem-like cells were able to survive due to an upregulation of Rad51. Importantly, the inhibition of Rad51 showed synthetic lethal effect with the silencing of Sam68, hampering the cell viability of patient-derived BCSphCs and stabilizing the growth of tumor xenografts, including those TNBC carrying BRCA mutation. Moreover, the analysis of Myc, Sam68 and Rad51 expression demarcated a signature of a poor outcome in a large cohort of BC patients. Thus, our findings suggest the importance of targeting Sam68-PARP1 axis and Rad51 as potential therapeutic candidates to counteract the expansion of BC cells with an aggressive phenotype., (© 2022. The Author(s).)

Background: It is generally acknowledged that the first morphological change of hidradenitis suppurativa/acne inversa (HS/AI) consists of infundibular plugging of the folliculosebaceous apocrine apparatus, which is followed by acute and chronic inflammation, cysts with sinus formation, and fibrosis. Alternatively, it has been hypothesized that HS/AI is primarily a neutrophilic autoinflammatory disease and that the follicular plugging typical of this disease is secondary to inflammation., Objective: To review the sequence of the changes that mark the disease development, we have performed a histopathologic study on the surgical material from a series of axillary and inguinal/perineal cases., Methods: The histologic material from surgery on Hurley's second and third stage HS/AI was retrieved and collected with the patients' clinical images. The virtually uninvolved skin peripheral to the lesions was studied together with the main inflammatory foci on vertical sections stained with hematoxylin-eosin and immunohistochemistry for the follicle sheaths., Results: The fully developed lesions showed acute and chronic, suppurative and granulomatous inflammation overlapping fibrosis, cysts, and sinuses. Instead, the skin adjacent to florid inflammation showed plugging and dysmorphic alterations of the hair follicles associated with immunopathological changes of the inner root sheath keratin expression., Conclusion: Our observations coincide with the classical pathological studies on the progressive changes of HS/AI; however, in our specimens, the virtually normal skin peripheral to the fully developed lesions show seemingly initial follicular changes that suggest development error. This finding would support the hypothesis of combined mutation-induced epithelial differentiative defects and immunological derangement in HS/AI pathogenesis., (© 2021. Springer-Verlag GmbH Austria, ein Teil von Springer Nature.)

Background: Cyclosporine A (CsA) is one of the systemic therapeutic options for moderate-to-severe psoriasis, based on its efficacy and rapidity of action. The current study investigated the response to CsA in patients with moderate-to-severe plaque psoriasis., Materials and Methods: TRANSITION was an observational, cross-sectional, multicentre study which evaluated the proportion of partial- and suboptimal-responders among patients with moderate-to-severe plaque psoriasis treated with continuous CsA for ≥12 weeks. Patients demonstrating a Psoriasis Area and Severity Index (PASI) response of ≥90, ≥75 and <90, ≥50 and <75 and <50 were defined as responders, suboptimal-responders, partial-responders, and non-responders, respectively., Results: A total of 196 patients (mean age, 46.6 years; 62.8% males) from 14 sites in Italy were evaluated. At the study visit, the mean (SD) PASI score was 4.2(5.5) compared with 15.3(7.1) prior to the last CsA cycle. For response categories, 39.8%, 22.4%, 16.8%, and 20.9% of patients were responders, suboptimal-responders, partial-responders, and non-responders to CsA treatment. Overall, 28.6% of patients permanently discontinued treatment with CsA (lack of efficacy [10.2%], poor tolerability and voluntary discontinuation [3.6% each], and other [11.7%])., Conclusion: Patients were only partially satisfied with CsA treatment, reporting measurable impact on quality of life. Only 40% patients showed a satisfactory response to CsA.

Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression.

Objective: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy., Design: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance., Results: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy., Conclusions: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually occurs after puberty with painful, deep-seated, inflamed nodules and sinus tracts in the apocrine gland-bearing areas of the body, most commonly the axillae and inguinal and anogenital regions, with a relevant impact on patients' quality of life (QoL)., Objective: To evaluate how the burden of HS disease impacts on patient well-being and working activities in a large Italian population over a period of 9 months., Methods: A multicenter, prospective, epidemiologic cohort study was conducted in adult Italian patients with HS. HS severity was assessed through Hurley stage and HS Physician's Global Assessment (HS-PGA), clinical improvement by HS Clinical Response (HiSCR) and partial response, and disease burden through QoL questionnaires (HIDRAdisk, Skindex-16, Dermatology Life Quality Index [DLQI]), and Work Productivity and Activity Impairment - General Health (WPAI:GH)., Results: A total of 308 patients (56.2% women; mean age 35.2 ± 12.9 years) were enrolled in 27 dermatologic clinics. Men were older (37.4 years vs. 33.5), more smoking addicted (74.1% vs. 60.1%), and alcohol consumer (34.1% vs. 13.9%), while more women were obese (34.10% vs. 22.22%). At baseline, most patients had a Hurley severity stage of 2 (43.9%), a moderate HS-PGA score (57.1%), and poor QoL (HIDRAdisk: 65.7 ± 23.3, Skindex-16: 60.3 ± 26.9, and DLQI: 10.8 ± 8.1). Patients with more severe disease showed worse QoL. Mean values for the variables related to HS severity decreased during the study period. The achievement of HiSCR and partial response increased during the study., Conclusion: This study offers insight into the disease burden of HS in an Italian population. Our results underline the impact of QoL evaluation, also with the use of the HIDRAdisk, in clinical routine as a support to validated severity clinical and instrumental indexes for a "360-degree" assessment of HS patient's burden of disease., (© 2021 S. Karger AG, Basel.)

Metastatic disease represents the major cause of death in oncologic patients worldwide. Accumulating evidence have highlighted the relevance of a small population of cancer cells, named cancer stem cells (CSCs), in the resistance to therapies, as well as cancer recurrence and metastasis. Standard anti-cancer treatments are not always conclusively curative, posing an urgent need to discover new targets for an effective therapy. Kinases and phosphatases are implicated in many cellular processes, such as proliferation, differentiation and oncogenic transformation. These proteins are crucial regulators of intracellular signaling pathways mediating multiple cellular activities. Therefore, alterations in kinases and phosphatases functionality is a hallmark of cancer. Notwithstanding the role of kinases and phosphatases in cancer has been widely investigated, their aberrant activation in the compartment of CSCs is nowadays being explored as new potential Achille's heel to strike. Here, we provide a comprehensive overview of the major protein kinases and phosphatases pathways by which CSCs can evade normal physiological constraints on survival, growth, and invasion. Moreover, we discuss the potential of inhibitors of these proteins in counteracting CSCs expansion during cancer development and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Turdo, D’Accardo, Glaviano, Porcelli, Colarossi, Colarossi, Mare, Faldetta, Modica, Pistone, Bongiorno, Todaro and Stassi.)

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease., (© 2021. The Author(s).)

Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus , respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.

Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaggianesi, Di Franco, Pantina, Porcelli, D'Accardo, Verona, Veschi, Colarossi, Faldetta, Pistone, Bongiorno, Todaro and Stassi.)

Background: Few and small studies have described the management of immunomodulant/immunosuppressive therapies or phototherapy in atopic dermatitis (AD) patients during coronavirus disease 2019 (COVID-19) pandemic., Methods: A national registry, named DA-COVID-19 and involving 35 Italian dermatology units, was established in order to evaluate the impact of COVID-19 pandemic on the management of adult AD patients treated with systemic immunomodulant/immunosuppressive medications or phototherapy. Demographic and clinical data were obtained at different timepoints by teledermatology during COVID-19 pandemic, when regular visits were not allowed due to sanitary restrictions. Disease severity was assessed by both physician- and patient-reported assessment scores evaluating itch intensity, sleep disturbances, and AD severity., Results: A total of 1831 patients were included, with 1580/1831 (86.3%) continuing therapy during pandemic. Most patients were treated with dupilumab (86.1%, 1576/1831) that was interrupted in only 9.9% (156/1576) of cases, while systemic immunosuppressive compounds were more frequently withdrawn. Treatment interruption was due to decision of the patient, general practitioner, or dermatologist in 39.9% (114/286), 5.6% (16/286), and 30.1% (86/286) of cases, respectively. Fear of increased susceptibility to SARS-CoV-2 infection (24.8%, 71/286) was one of the main causes of interruption. Sixteen patients (0.9%) resulted positive to SARS-CoV-2 infection; 3 of them (0.2%) were hospitalized but no cases of COVID-related death occurred., Conclusions: Most AD patients continued systemic treatments during COVID pandemic and lockdown period, without high impact on disease control, particularly dupilumab-treated patients., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The current medical treatments of androgenetic alopecia (AGA) have hardly achieved a satisfying clinical improvement. Biologic regenerative therapies, such as platelet-rich plasma (PRP) injections in the scalp, have been proposed recently. This multidisciplinary prospective study aims to explore the efficacy and safety of autologous PRP injections into the scalp of patients with AGA. Fifty-four patients with AGA (35 men and 19 women) were enrolled. Non-activated autologous PRP was injected into the androgen-related areas of the scalp. The study protocol consisted of three sessions of injections at 3-month interval. The effects were assessed by means of noninvasive methods. Safety profile, patient satisfaction, and Dermatology Life Quality Index were assessed. Increase in hair thickness was observed 1 month after the first PRP injection, and hair loss reduction was found after 3 months. In most patients, the improvement was progressively evident until the 12th month. Hair growth/production showed differences between women and men. The safety profile was satisfactory. This study confirms that PRP injections are effective in reducing thinning of the scalp hair and suggests more efficacy in women.

Background : The susceptibility of patients with chronic plaque psoriasis and the risks or benefits related to the use of biological therapies for COVID-19 are unknown. Few data about prevalence, clinical course and outcomes of COVID-19 among psoriatic patients were reported. The aims of this study were 1) to assess the prevalence and severity of COVID-19 in psoriatic patients treated with biologic agents during the first phase of the emergency (22 February to 22 April 2020) in Italy, and 2) to report the clinical outcomes of patients who have been exposed to individuals with confirmed SARS-CoV-2 infection. Methods : Patients with moderate-to-severe chronic plaque psoriasis, aged ≥18 years and undergoing treatment with biologic agents as of 22 February 2020, were eligible to be included in PSO-BIO-COVID study. Demographic and clinical characteristics of patients using any biologic for psoriasis treatment between 22 February and 22 April 2020 were registered. Results : A total of 12,807 psoriatic patients were included in the PSO-BIO-COVID study. In this cohort 26 patients (0.2%) had a swab confirmation of SARS-CoV-2 infection. Eleven patients required hospitalization and two died. Conclusion : The incidence of COVID-19 observed in our cohort of psoriatic patients (0.2%) is similar to that seen in the general population (0.31%) in Italy. However, the course of the disease was mild in most patients. Biological therapies may likely lessen 'cytokine storm' of COVID-19, which sometimes lead to multiple organ failure, ARDS, and death.

Background: The anti-tumour necrosis factor (TNF)-α adalimumab is the only licenced biologic for moderate-to-severe hidradenitis suppurativa (HS). No predictors of response have been identified so far., Objectives: To identify clinical parameters predicting response to adalimumab and confirm its efficacy/safety., Methods: The data of 389 patients with HS treated with adalimumab in 21 Italian centres were reviewed. Sex, age at onset/diagnosis/baseline, body mass index, smoking, phenotype, previous treatments, concomitant antibiotics and 'therapeutic delay', defined as the time from HS onset to adalimumab initiation, were assessed. Response to adalimumab and its impact on quality of life (QoL) were evaluated using the Hidradenitis Suppurativa Clinical Response (HiSCR) and the Dermatology Life Quality Index (DLQI) or the Visual Analogue Scale for pain (VAS pain), respectively. Logistic regression analysis was performed., Results: The therapeutic delay correlated to lack of response to adalimumab at week 16 [odds ratio (OR) 1·92 for therapeutic delay > 10 years; 95% confidence interval (CI) 1·28-2·89; P = 0·0016). HiSCR was achieved in 43·7% and 53·9% patients at week 16 and 52, respectively. Significant reductions in both DLQI and VAS pain were found between week 16 vs. baseline (P < 0·0001 for both) and week 52 vs. baseline (P < 0·0001 for both). Previous immunosuppressants inversely correlated to HiSCR at week 52 (OR = 1·74, 95% CI 1·04-2·91, P = 0·0342)., Conclusions: Inverse correlation between therapeutic delay and clinical response was found, supporting early adalimumab use and providing evidence for a 'window of opportunity' in HS treatment. Adalimumab efficacy and safety were confirmed, along with patients' QoL improvement. Immunosuppressants could negatively influence the response to adalimumab inducing a switch to non-TNF-α-driven pathways., (© 2020 British Association of Dermatologists.)

Prolidase deficiency is a rare disorder inherited through an autosomal recessive gene. The hallmark of the disorder are iminodipeptiduria, chronic skin ulcers, recurring infections, mental retardation and characteristic facial appearance, although prolidase deficiency can occur with no clinical manifestation. The primary biological function of the enzyme involves the metabolism of collagen degradation products and the recycling of proline for collagen resynthesis. We describe two patients with prolidase deficiency and review the different clinical manifestations suggesting the pathogenetic mechanism through few hypotheses.

Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.

Psoriasis impacts the quality of life (QoL) by disrupting overall health and social life. Thus, the use of a QoL evaluation item is crucial in assessing a therapeutic regimen. Also, faster improvements in QoL lead to better patient compliance, but very few studies compare psoriasis traditional and biologic therapies timing. To evaluate how much different systemic therapies improve disease severity and QoL, a retrospective analysis was performed on 56 patients. Subjects were administered different drugs and their vital statistics, psoriasis area severity index (PASI) and PSOdisk were collected at baseline and after 30 days. We found a moderate correlation between PASI and PSOdisk score with (r): .62. In terms of clinical scores improvement after 30 days, Ustekinumab turned out to be the fastest therapy available, while cyclosporine, among the systemic therapies available, appeared as highly competitive if not better than other biologic therapies., (© 2019 Wiley Periodicals, Inc.)

Spitz nevi, atypical Spitz tumors and Spitzoid melanoma, the three clinicopathologic forms that constitute the spectrum of the Spitz-type melanocytic lesions, share a histologic picture characterized by large spindle and/or epithelioid ganglion-like cells, with various admixtures of multinucleate bizarre cells. This remarkable cytology has always been interpreted as an unusual, as well as unexplained form of atypia. We report a case of atypical Spitz tumor with Homer Wright-like rosettes, a feature characteristic of ganglioneuroblastic proliferation. Furthermore, the ganglion-like cells of the tumor showed basophilic punctuation in the cytoplasm, reminiscent of Nissl substance, and a few cells, whether spindled or epithelioid, were positive to neuron-specific enolase and glial fibrillary acid protein. Based on our findings, we hypothesize that the outstanding similarity of the ganglion-like cells of Spitz tumors to the normal parasympathetic ganglion cells and to the cells of ganglioneuroma and ganglioneuroblastoma may not be fortuitous. Instead, it may represent the expression of a specific pattern of melanocytic differentiation, analogous to the neurotization of common and cellular blue nevi, although in this case, it would privilege the parasympathetic lineage over the Schwannian, perineural, or endoneural pathway. Our hypothesis is supported by the literature reports of rosette formation and frank ganglioneuroblastic differentiation in Spitz tumors and melanoma and by the demonstration that parasympathetic neurons take origin from the same tracts of the neural crest as other neural and melanocytic cells.

Targetoid hemosiderotic hemangioma represents an uncommon, distinctive, benign lympho-vascular lesion, with a variable clinical appearance, typically occurs in the lower limbs and trunk. Most patients are in their 20's or 30's. We describe three dermoscopic cases followed by the review of the literature. Dermoscopic images have been collected and have been evaluated for the presence of dermoscopic features. Concerning the review, we researched on pubmed and records were reviewed noting patient age of onset, sex, location, overall size, dermoscopic appearance. The harmonic mean age of patients was 31 years; the female-to-male ratio was 1:1, and the most common locations were lower extremities (47%) and the trunk (29%). In the most recent years several pediatric cases were described, lowering the mean age of the patients in the literature. Most targetoid hemosiderotic hemangioma appear clinically as a small, solitary, reddish-violaceous vascular lesion with a targetoid appearance. The most typical dermoscopic findings are a homogeneous central area, red lacunae, dark lacunae, peripheric red-violaceous ring, whitish structures, peripheric vascular structures, yellowish intermediate areas, and a peripheral pigment network. Histologically, more superficially, in the papillary dermis there are dilated thin blood vessels lined by hobnail-appearing endothelial cells. In the deeper dermis there are typically slit-like capillaries that ramify in the dermis and dissect through collagen bundles. We wanted to evaluate the features of a large series of targetoid hemosiderotic hemangiomas for a better awareness of the entity, to improve its clinical and dermoscopic diagnostic accuracy, to focus attention on nontargetoid patterns, which often mimic other lesions, including melanoma.

Background: Catalase gene (CAT) polymorphisms were analyzed as responsible for the deficiency of catalase enzyme activity and concomitant accumulation of excessive hydrogen peroxide in vitiligo patients. Catalase is a well-known oxidative stress regulator that could play an important role in the pathogenesis of vitiligo. This study was conducted to evaluate three CAT gene polymorphisms (-89A/T, 389C/T, 419C/T) and their association with vitiligo susceptibility in Sicilian population., Methods: Sixty out of 73 Sicilian patients with vitiligo were enrolled and submitted to CAT gene analysis., Results: Contrary to the Northern part of Europe but likewise to the Mediterranean area, the frequency of the CAT genotypes in Sicily is equally distributed. Out of all CAT genotypes, only CAT-89 T/T frequency was found to be significantly higher amongst vitiligo patients than controls., Conclusions: Despite the involvement of the CAT enzyme in the pathogenesis of vitiligo, the biological significance of CAT gene polymorphisms is still controversial. With the only exception for CAT variant -89A/T, the other studied CAT gene polymorphisms (389C/T and 419C/T) might not to be associated with vitiligo in Sicilian population.

Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the population in the world. The scalp is the most common, and frequently the first site of disease involvement. Occasionally it may be the only localization of psoriasis. Treatment of scalp psoriasis is often unsatisfactory, due to limited available topical therapy and reduced efficacy of some systemic drugs. Biologic therapies are recommended for severe psoriasis, resistant to topical treatment, but evidence from randomized, controlled studies is lacking regarding effectiveness on scalp-localized lesions. Several clinical studies have shown the efficacy of secukinumab on plaque psoriasis, and some encouraging experience suggest the use in difficult sites such as the scalp; this article reports effective treatment with secukinumab of a series of patients with plaque and scalp psoriasis.

Nail involvement is frequent in patients with psoriasis, especially those with psoriatic arthritis (PsA), and can significantly impair quality of life (QoL). It is typically difficult to treat compared with skin lesions, although several conventional treatment options are available. The aim of this article is to describe our experience in the treatment of nail psoriasis with secukinumab in a case series. Fifteen patients (11 males and 4 females), with moderate-severe plaque psoriasis and nail psoriasis, eligible for systemic therapy, and received secukinumab. The Psoriasis Area and Severity Index (PASI) and body surface area (BSA) assessed cutaneous severity. Nail Psoriasis Severity Index (NAPSI) was used to evaluate nail involvement. Starting from 6 weeks after initiation of treatment with secukinumab 300 mg, a clinically significant response was observed, with progressive reduction of both skin and nail disease indexes. Average reduction of PASI was 75%, of BSA 70%, and of NAPSI 50%, at week 6. At week 12, NAPSI reduction was by 80%, of PASI 90%, and of BSA 97%. Effective treatment of both skin and nail psoriasis was obtained with secukinumab, a new approach to psoriatic patients resistant to topical therapy.

Background: Leishmaniasis is a widespread infectious disease, but there is not much information about its prevalence in high risk occupational categories., Objectives: The aim of this study is to assess the prevalence of Leishmania immunological positivity in human skin tissues collected from subjects living in Western Sicily, with suspected cutaneous Leishmania infection, in order to explore the risk possibly related to occupation., Methods: 318 consecutive subjects (M/F ratio=1.0, mean age=40±25.4 years), attending the Dermatology Department of the University of Palermo Hospital from 2013 to 2015, without any previous history of Leishmania infection and performing various occupations, were included. Parasite isolation and PCR-RT test on skin scrapings were performed to evaluate the immunological status; all data were analyzed by the chi square test, comparing all positive results from the different provinces., Results: 81 (50.9%) out of 159 females and 79 (49.7%) out of 159 males were found PCR-RT positive to Leishmania infantum, with a higher risk in the Agrigento district (p<0.001) and in subjects living in rural areas (p=0.0038), regardless of the type of work performed. The observed animal leishmaniasis prevalence in the same areas shows the endemic status of the disease in Sicily., Conclusions: Although based on a relatively small sample, our study shows that cutaneous leishmaniasis represents a health care problem with a medical and social impact in Western Sicily. An active surveillance system and the establishment of diagnosis and treatment centres could be useful in controlling this public health problem.

Background: Avian mite dermatitis is a skin disease caused in mammals by the incidental bites of blood-sucking mites which customarily parasitize wild and domestic birds. It manifests in the form of pruritic, erythematous, or urticarial papules, with a central sting mark, in skin regions normally covered by clothing. The species mainly implicated in human bite cases are Dermanyssus gallinae, Ornithonyssus sylviarum and, less frequently, Ornithonyssus bursa. The latter is mainly a tropical and subtropical mite and its - presumably transitory - presence has been recorded only once in Europe, in migratory birds., Case Report: We report a case of avian mite dermatitis in a 70-year-old man, an owner of chickens, who lived in Sicily, an island in southern Italy. He presented with an itching, erythematous, papular eruption. Numerous mites were seen racing across his skin. The precise identification of O. bursa was based on the morphology of its plates and chelicerae and on the arrangement of its setae., Conclusions: Not only does this paper report the first European case of human infestation with O. bursa, it provides evidence that this alien species has settled and spread in the Old Continent. It may have been flown in from a small focus reported in Danish migratory birds in the 1980s or may have been accidentally introduced into Italy through the importation of infested poultry from South America. Such occurrences may have unpredictable epidemiological and ecological consequences. More comprehensive veterinary inspection of imported birds is desirable., (© 2015 The International Society of Dermatology.)

Unlabelled: What is known and objective: Pemphigus is a severe, potentially life-threatening autoimmune blistering disease. The use of corticosteroids has dramatically improved the prognosis and changed its course. However, current morbidity of pemphigus is largely iatrogenic, caused by side effects of the long-term, high-dose corticosteroid therapy that is necessary to sustain disease control. In order to minimize side effects, a range of corticosteroid-sparing immunosuppressive agents have been introduced, including mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). A systematic review was performed to evaluate the effectiveness of MMF and EC-MPS in the treatment of pemphigus vulgaris and pemphigus foliaceus., Methods: A retrospective literature search was conducted through multiple electronic databases (PubMed, Medline, The Cochrane database of systematic reviews) for reports on the use of mycophenolic acid (MPA) in the treatment of pemphigus vulgaris and pemphigus foliaceus., Results: Sixteen studies with a total of 239 patients have evaluated the treatment of pemphigus vulgaris and pemphigus foliac;eus with MPA. The majority of patients had refractory disease treated with corticosteroids as monotherapy or associated to adjuvant agents., Discussion: The results of this review suggest that MPA, as MMF or EC-MPS, may be a promising adjuvant or alternative therapy for the treatment of pemphigus vulgaris and pemphigus foliaceus. It appears safe, at least in the medium term and its adverse events seem to be dose dependent., What Is New and Conclusion: The use of mycophenolate is first-line adjuvant therapy in the treatment of pemphigus vulgaris and pemphigus foliaceus.

Purpose: The purpose of this study was to show that gender also plays an important role in pharmacokinetics, pharmacodynamics, and drug toxicity. It is only fair to take into account the so-called "gender-based medicine.", Methods: We again selected admission for cutaneous adverse drug reaction (CADRs), from January 2012 to July 2012, in order to detect and verify, in an analytical way, the substantial gender differences in adverse drug reactions in term incidence, clinical manifestations, severity and drugs involved., Results: In the period January-July 2012, at the Department of Dermatology and Sexually Transmitted Disease of A.O.U.P. "Paolo Giaccone" Palermo, 384 patients were admitted, of which 192 were females (50%) and 192 males (50%). Out of a total of 384 patients, 34 cases of CADRs (8.9%) were identified including 24 females (71%) and 10 males (29%)., Conclusions: The female gender is an important predisposing factor for the RAF: a large case series showed that in the RAF female/male ratio is 1.7:1.

Background: Psoriatic arthropathy is a progressive and debilitating disease involving reduction of functional activity of the articulations with consequent deterioration of the patient's quality of life. The entheses represent the initial site of articular inflammation and the enthesis of the Achilles tendon is the first to be affected. In some patients with psoriasis, enthesitis may not be diagnosed because it is still asymptomatic., Objectives: To evaluate whether ultrasonography allows early diagnosis in a larger population and to identify significant alterations of enthesitis beyond increased thickness of the Achilles tendon., Materials and Methods: The study was undertaken on 59 patients (16 women, 43 men), with chronic plaque psoriasis and 59 patients with other dermopathies. The patients underwent echographic evaluation of the Achilles heel using a Voluson imaging system. The severity of the psoriasis was evaluated by the Psoriasis Area Severity Index and the enthesitis by the Glasgow Ultrasound Enthesitis Scoring System (GUESS)., Results: The GUESS score was higher in those patients with psoriasis compared with patients with other dermopathies. Among psoriatic patients, 22% (13 of 59) presented tendon thickness over 5·29 mm and irregular tendon structure. Other abnormalities affected the tendon in 12 patients. In seven patients (12%) bursitis was also revealed., Conclusions: Our data confirm that ultrasonography is a sensitive technique which reveals enthesitis more frequently than clinical examination in patients affected by psoriasis. We suggest the use of ultrasonography of the Achilles tendon in early diagnosis of psoriatic arthropathy with the objective of preventing progression of the pathology., (© 2014 British Association of Dermatologists.)