Chronic Nodular Prurigo: An Update on the Pathogenesis and Treatment.

Chronic nodular prurigo (CNPG) is a recalcitrant chronic itchy disorder that affects the quality of life. It can be triggered by multiple etiologies, such as atopic dermatitis, diabetes, and chronic renal diseases. The mechanisms of CNPG are complicated and involved the interaction of the cutaneous, immune, and nervous systems. Diverse immune cells, including eosinophils, neutrophils, T cells, macrophages, and mast cells infiltrated the lesional skin of CNPG, which initiated the inflammatory cytokines and pruritogens release. In addition, the interaction between the immune cells and activated peripheral sensory nerve fibers by neurotransmitters caused neuroinflammation in the skin and intractable itch. This itch-scratch vicious cycle of CNPG results in disease exacerbation. CNPG is difficult to treat with traditional therapies. Recently, great advances have been made in the pathophysiology of both inflammation and pruritus transmission in CNPG. In this review, we summarize the updated mechanisms and novel therapies for CNPG.

Increased Epidermal Nerve Growth Factor without Small-Fiber Neuropathy in Dermatomyositis.

Small-fiber neuropathy (SFN) is suggested to be involved in the pathogenesis of some types of autoimmune connective tissue diseases. SFN with a reduction in epidermal nerve fibers might affect sensory fibers and cause neuropathic symptoms, such as pruritus and pain, which are common in both dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). Nerve growth factor (NGF) has been recognized as important in nociception by regulating epidermal nerve fiber density and sensitizing the peripheral nervous system. The present study aimed to investigate whether SFN was associated with the cutaneous manifestations of DM and CLE. We also investigated the relationship between SFN and axon guidance molecules, such as NGF, amphiregulin (AREG), and semaphorin (Sema3A) in DM and CLE. To explore the molecular signaling, interleukin (IL)-18 and IL-31, which have been implicated in the cutaneous manifestation and neuropathic symptoms in DM, were examined in keratinocytes. Our results revealed that intraepidermal nerve fiber density (IENFD) was unchanged in patients with DM, but significantly reduced in IENFD in patients with CLE compared with healthy control. Increased epidermal expression of NGF and decreased expression of Sema3A were demonstrated in patients with DM. Furthermore, IL-18 and IL-31 both induced the production of NGF from keratinocytes. Taken together, IL-18 and IL-31 mediated epidermal NGF expression might contribute to the cutaneous neuropathic symptoms in DM, while SFN might be important for CLE.

Autoimmune Connective Tissue Diseases-Related Pruritus: Proper Diagnosis and Possible Mechanisms.

Pruritus is a well-known bothersome symptom among skin disorders, especially inflammatory skin disorders. Lately, a high prevalence of pruritus in patients with autoimmune connective tissue diseases (ACTDs) has been revealed. Patients with ACTDs may suffer from varying degrees of pruritus, which affect their quality of life. However, it is rarely recognized both by patients and physicians. Meanwhile, pruritus is not only a symptom but is also related to the disease severity of some ACTDs. The pathophysiology of ACTD related pruritus is ambiguous. This review summarizes the features and possible mechanisms of ACTD-related pruritus, which might lead to proper diagnosis and treatment.

Uremic Pruritus: From Diagnosis to Treatment.

Uremic pruritus, or chronic kidney disease-associated pruritus, is common, bothersome, and sometimes debilitating in patients with chronic kidney disease or end-stage renal disease. Due to its variable clinical manifestations, the diagnosis of uremic pruritus requires exquisite evaluation. Excluding itch resulting from other dermatological causes as well as other systemic conditions is essential for a proper diagnosis. The pathophysiology of uremic pruritus remains uncertain. Hypotheses including toxin deposition, immune system dysregulation, peripheral neuropathy, and opioid imbalance are supposed. This review summarizes the way to accurately diagnose uremic pruritus and describes the latest treatment options.

Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy.

The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis.

Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.

Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity.

BACKGROUND: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.

Taiwanese Dermatological Association consensus for the management of atopic dermatitis: A 2020 update.

BACKGROUND/PURPOSE: Atopic dermatitis (AD) is a chronic inflammatory disease commonly seen in children and increasingly recognized in adults. With recent advances in the therapeutic development for AD, the Taiwanese Dermatological Association (TDA) established a committee to update the consensus for AD management in Taiwan. This report describes the 2020 updated consensus for the management of AD. METHODS: A panel of 11 core members was convened to review and discuss aspects of AD management and draft recommendation during the first two meetings. The 2015 TDA consensus and the 2017 European guideline, along with recent peer-reviewed articles, serve as the foundation for the update. In the third meeting, AD expert dermatologists selected on a national scale were invited to vote on the final statements. A total of 27 dermatologists attended the final meeting. The consensus was achieved when ratings of 7-9 (out of a total score of 9) accounted for ≥ 75% of the total votes. RESULTS: Consensus was achieved on the therapeutic options for AD by lines of treatment. A treatment algorithm was presented to illustrate the place of each modality in terms of basic care, acute disease control, and maintenance therapy. Special considerations for the pediatric population, as well as for women during pregnancy and lactation, are discussed. CONCLUSION: Topical corticosteroids with long-term emollient-based therapies remain the cornerstone of AD treatment. Systemic treatments are indicated when topical therapies and phototherapy fail to control the disease. The recent approval of dupilumab and emerging targeted therapies are expected to bring significant clinical benefit for patients whose disease is inadequately managed by existing options.

The addition of pretreatment plasma Epstein-Barr virus DNA into the eighth edition of nasopharyngeal cancer TNM stage classification.

The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity-modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein-Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five-year progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA-I (T1-T4 N0-N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA-II (T1-T4 N0-N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA-III (T1-T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA-IVA (T3-T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1-T2 N0-N2; II: T3-T4 N0-N2 or T1-T2 N3 and III: T3-T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA-based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups.

BQ323636.1, a Novel Splice Variant to NCOR2, as a Predictor for Tamoxifen-Resistant Breast Cancer.

Purpose: Adjuvant tamoxifen treatment revolutionized the management of estrogen receptor (ER)-positive breast cancers to prevent cancer recurrence; however, drug resistance compromises its clinical efficacy. The mechanisms underlying tamoxifen resistance are not fully understood, and no robust biomarker is available to reliably predict those who will be resistant. Here, we study BQ323636.1, a novel splice variant of the NCOR2 gene, and evaluate its efficacy in predicting tamoxifen resistance in patients with breast cancer.Experimental Design: A monoclonal anti-BQ323636.1 antibody that specifically recognizes the unique epitope of this splice variant was generated for in vitro mechanistic studies and for in vivo analysis by immunohistochemistry on tissue microarrays of two independent cohorts of 358 patients with more than 10 years clinical follow-up data, who had ER-positive primary breast cancer and received adjuvant tamoxifen treatment. An orthotopic mouse model was also used.Results: Overexpression of BQ323636.1 conferred resistance to tamoxifen in both in vitro and in an orthotopic mouse model. Mechanistically, coimmunoprecipitation showed BQ323636.1 could bind to NCOR2 and inhibit the formation of corepressor complex for the suppression of ER signaling. Nuclear BQ3232636.1 overexpression in patients samples was significantly associated with tamoxifen resistance (P = 1.79 × 10-6, sensitivity 52.9%, specificity 72.0%). In tamoxifen-treated patients, nuclear BQ323636.1 overexpression was significantly correlated with cancer metastasis and disease relapse. Nuclear BQ323636.1 was also significantly associated with poorer overall survival (P = 1.13 × 10-4) and disease-specific survival (P = 4.02 × 10-5).Conclusions: These findings demonstrate that BQ323636.1 can be a reliable biomarker to predict tamoxifen resistance in patients with ER-positive breast cancer. Clin Cancer Res; 24(15); 3681-91. ©2018 AACRSee related commentary by Jordan, p. 3480.

Decrease of superficial serine and lactate in the stratum corneum due to repetitive frictional trauma.

BACKGROUND: Repetitive frictional trauma can be induced in daily and occupational activities, such as daily ablutions with washcloths. The influence of frictional trauma on the skin barrier function, especially in the perspective of the components of stratum corneum (SC), has not yet been studied in detail. Raman spectroscopy is a noninvasive optical technique based on inelastic light scattering that is capable of measuring several components in the skin. In this study, we used Raman spectroscopy to investigate the change in natural moisturizing factor (NMF) components in the SC following repetitive physical friction. METHODS: Six healthy volunteers, who were included in the study after obtaining an informed consent, performed repetitive washing with soap using nylon towels on the forearm twice a day for 2 weeks and used Raman spectroscopy to investigate the change in NMF components in the SC. RESULTS: Compared with the control, which was washed with soap at the same frequency on the opposite forearm, a significant increase in the transepidermal water loss (TEWL) and a decrease in NMF, serine, and total lactate, responsible for maintenance the SC hydration and structuring and maintaining the epidermal barrier function, in the SC were found. CONCLUSIONS: Increased TEWL and decreased NMF are considered as an etiology of atopic dermatitis (AD); therefore, our findings provide evidence that daily activities with repetitive frictional trauma may be related to the predisposition of AD.

Inflammatory and Noninflammatory Itch: Implications in Pathophysiology-Directed Treatments.

Itch is the main chief complaint in patients visiting dermatologic clinics and has the ability to deeply impair life quality. Itch results from activation of cutaneous nerve endings by noxious stimuli such as inflammatory mediators, neurotransmitters and neuropeptides, causing itch signal transduction from peripheral skin, through the spinal cord and thalamus, to the brain cortex. Primarily noninflammatory diseases, such as uremic pruritus, cause itch through certain pruritogens in the skin. In inflammatory skin diseases, atopic dermatitis (AD) is the prototypic disease causing intensive itch by aberrant skin inflammation and epidermal barrier disruption. Recent understanding of disease susceptibility, severity markers, and mechanisms have helped to develop targeted therapy for itch in AD, including monoclonal antibodies against IL-4, IL-13, thymic stromal lymphopoietin (TSLP), IgE and IL-31. Promising effects have been observed in some of them. In this review, we summarized targeted therapies for inflammatory itch in AD and for managing abnormal itch transductions in other common itching skin diseases.

Metronomic oral cyclosphosphamide as third-line systemic treatment or beyond in patients with inoperable locoregionally advanced recurrent or metastatic nasopharyngeal carcinoma.

There is no standard third-line or further systemic treatment for patients with inoperable locoregionally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC). Metronomic oral cyclophosphamide provides an acceptable and cheap option for these heavily pretreated patients who had limited choices. We conducted a prospective phase II single-arm open-label study of metronomic oral cyclophosphamide. Patients with locoregionally advanced recurrent inoperable (rT3/T4, rN2-N3b) or metastatic (rM1) NPC who had Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0-2) and had progressed after at least 2 lines of palliative systemic chemotherapy were eligible. They received oral cyclophosphamide between 50 and 150 mg once daily until progressive disease or unacceptable toxicity. Objective response rate (ORR), disease control rate (DCR), biochemical response (two consecutive declines of plasma EBV DNA after treatment), progression-free survival (PFS), overall survival (OS), and safety profiles were evaluated. A total of 56 patients were recruited. Thirty-three, 13, 6, 3, and 1 patients received cyclophosphamide as 3rd, 4th, 5th, 6th, and 7th line of therapy respectively. After a median follow-up of 9.95 months (range 1.76-59.51 months), the ORR was 8.9% and the DCR was 57.1%. The median PFS and OS were 4.47 and 9.20 months, respectively. Those with PS 1 had longer median PFS (5.49 months) compared to those with PS 2 (3.75 months, P = .011). Besides, those who had locoregionally recurrent disease had better PFS (8.97 months, 95% CI, 0.53-17.41 months) compared to those who had distant metastases (4.14 months, 95% CI, 2.53-5.75 months, P = .020). Multivariable analysis revealed that PS 1 (vs 2) (P = .020) and locoregional recurrence (vs metastasis) (P = .029) were the only significant independent prognostic factors of PFS. Around 16 (28.6%) patients developed grade ≥3 adverse events, including malaise (5.4%), hematological (8.9%), gastrointestinal (3.6%), feverish (3.6%), and hemorrhagic (1.8%) events. The median cost of the whole drug treatment was 51.65 US dollars (USD) (range 4.15-142.75 USD) (1 USD = 7.8 HK dollars [HKD]). Metronomic oral cyclophosphamide is an acceptable third-line or beyond systemic therapy for locoregionally advanced recurrent or metastatic NPC with acceptable toxicity and limited financial burden.