Taxane-Induced Cutaneous Toxic Effects.

This case report describes dusky red to violaceous lesions with desquamation on the wrists and dorsal surface of both hands and near the Achilles tendon that occurred after intravenous paclitaxel treatment for invasive ductal carcinoma of the breast.

Dermoscopic features of pigmented basal cell carcinoma according to size.

BACKGROUND: Basal cell carcinoma (BCC), the most common skin cancer in humans, requires early detection. Dermoscopy enhances diagnostic accuracy through a noninvasive approach. Pigmented BCC (pBCC) is characterized by distinctive dermoscopic features, including the presence of pigmented globules or nests. While dermoscopic features of large pBCC (size >6 mm) have been extensively studied, limited data are available on small pBCC (size ≤6 mm) and its relationship with tumor progression. METHODS: Dermoscopic images of histologically proven pBCCs were collected between 2014 and 2022 at Hualien Tzu Chi Hospital. Each image was analyzed for patterns of pigmentation, vasculature, and epidermal and dermal structures. Statistical analysis was performed to compare the differences according to the size and the trend during tumor progression. RESULTS: In total, 135 pBCCs (48 small and 87 large) were included. Pigment structures were present in all cases. Short fine telangiectasia and small erosions constituted over 85% of the cases, showing no significant distinction between small and large pBCCs, nor any specific pattern correlating with tumor enlargement. The number of arborizing vessels, ulcerations, and shiny white structures showed an increasing trend associated with size progression. Arborizing vessels appeared when tumor size exceeded 6 mm. CONCLUSIONS: This study provides a dynamic interpretation of the dermoscopic features of pBCC according to size enlargement. Short fine telangiectasia and small erosions are highly important features for the early diagnosis of small pBCCs. Arborizing vessels, ulceration, and shiny white structures are more frequent in large pBCCs, and they increase in association with tumor progression.

Diagnosis and treatment of female alopecia: Focusing on the iron deficiency-related alopecia.

Objectives: Alopecia is a soft but meaningful complaint affecting women's physical and psychological health. Female alopecia (FA) has diverse etiologies. Nonetheless, FA is stereotyped as female pattern hair loss, also known as female androgenetic alopecia, and has not been thoroughly investigated. This study aimed to identify the etiologies of FA at a tertiary medical center in Eastern Taiwan. Materials and Methods: This retrospective study enrolled female patients with hair loss who visited the dermatology department of (blinded information). A complete history taking was obtained, including the onset and duration of alopecia, menstruation, gynecologic diseases, psychological stress, underlying diseases, vaccination, and dietary habits, etc., Blood tests were performed, including hemoglobin (Hb), ferritin, Zn, autoimmune and thyroid profiles, etc., Iron deficiency (ID) was defined as serum ferritin level <60 ng/mL. The hair condition, ferritin, and Hb levels were monitored every 3 months after supplementation. Results: A total of 155 patients were recruited. The etiologies of FA were diverse; the top five etiologies were nutrient deficiencies (83.9%), autoimmune (14.8%) and thyroid (7.7%) diseases, psychological stress (12.3%), and coronavirus disease 2019 (COVID-19) vaccination (6.5%). ID accounted for 70.3% of cases. The disease duration was an important prognostic factor for the improvement of serum ferritin. Patients with subjective improvement of hair regrowth also had more increase of ferritin levels after iron supplementation. The corresponding ferritin level for female anemia (Hb: 12.0 g/dL) was 5.1 ng/mL, lower than the adequate level for hair growth (40-60 ng/mL), the corresponding Hb level of which was 13.1-13.8 g/dL. Conclusion: The causes of FA varied, including nutrient deficiencies, autoimmune diseases, psychological stress, thyroid diseases, and COVID-19 vaccination, etc., Therefore, a complete survey before treatment is essential. Seventy percentage of FA cases were ID-FA. We suggest to redefine the serum ferritin level ≥60 ng/mL, with the corresponding Hb ≥13.0 g/dL as the normal range for early diagnosis. Initiation of iron supplementation within 6 months would result in a better prognosis.

Disseminated Herpes Zoster Following Protein Subunit and mRNA COVID-19 Vaccination in Immunocompetent Patients: Report of Two Cases and Literature Review.

Disseminated herpes zoster (DHZ), resulting from the reactivation of the varicella-zoster virus (VZV), typically occurs in immunocompromised persons. To date, only four cases of DHZ following mRNA, viral vector, or inactivated COVID-19 vaccinations have been reported in immunocompetent patients. Herein, we present the first case of DHZ following the protein subunit COVID-19 vaccination (case 1, 64 years old) and a case of DHZ following mRNA COVID-19 vaccination (case 2, 67 years old) in elderly, immunocompetent male patients. Both cases were generally healthy, without a remarkable underlying disease and without a history of immunosuppressant use. Case 1 developed DHZ (left C3-5 predominant) 1 month after receiving the third dose of the SARS-CoV-2 spike protein vaccine (MVC-COV1901). Case 2 developed DHZ (right V1-3 predominant) 7 days after receiving the second dose of the mRNA-1273 SARS-CoV-2 vaccine. Through skin examination, Tzanck smears, and dermoscopy, the diagnosis of COVID-19 vaccination-related DHZ was established in both cases. Oral famciclovir (250 mg, three times/day for 7 days) was administered, and both cases achieved total remission of skin lesions without visceral involvement or severe post-herpetic neuralgia. Our cases demonstrate that DHZ, as a rare cutaneous adverse event in immunocompetent patients, can be secondary not only to mRNA COVID-19 vaccination but also to the protein subunit COVID-19 vaccination. It is speculated that the spike protein of SARS-CoV-2 could be the common trigger for the reactivation of VZV among different types of vaccinations.

Case Report: Ribociclib-induced phototoxicity presented as dyschromia with subsequent bullae formation.

Ribociclib, a cyclin-dependent kinase 4/6 inhibitor, is a novel targeted therapy for advanced-stage breast cancer. Although ribociclib-induced cutaneous side effects have been previously noted, they have not been well documented. Herein, we present a case of ribociclib-induced phototoxicity, which manifested as dyschromia over sun-exposed forearms and neck initially and as bullae formation subsequently. A 71-year-old woman with metastatic breast cancer developed dyschromia after daily treatment with ribociclib (600 mg) for 7 months. Skin biopsy of the pigmented lesion revealed interface dermatitis with melanin incontinence and dyskeratotic cells and ballooning keratinocytes with loss of melanocytes in the basal layer. Further, clefting at the basal layer of epidermis was noted in a more hyperpigmented field. Fontana-Masson staining revealed melanophages in the dermis. Human Melanoma Black-45 staining revealed decreased melanocyte numbers in the epidermis above the cleft. Immunohistochemical analyses revealed activated CD1a+ epidermal Langerhans cells and infiltrating CD4+ and CD8+ T cells in the epidermis and dermis, thereby indicating type IV hypersensitivity that was associated with damage to keratinocytes and melanocytes. To prevent progression of bullous dermatitis, we advised the patient to discontinue ribociclib and prescribed oral and topical prednisolone. Due to the risk of phototoxicity, we educated the patient on sun-protection strategies. The patient's skin lesions subsided during the 2 months of treatment. Phototoxicity with dyschromia is a rare but significant ribociclib-induced cutaneous side effect. Early diagnosis, rapid ribociclib withdrawal, protection from sunlight, and prompt treatment are critical for preventing subsequent severe bullous dermatosis.

Orthopedic implant hypersensitivity: Characterization of clinical presentation and effects of photobiomodulation therapy.

Objectives: Orthopedic implants have improved the quality of life in aging society but also induces several kinds of tissue reactions, referred to as orthopedic implant hypersensitivity (OIH). The aim of our study is to report the clinical characteristics of OIH and the effects of photobiomodulation therapy (PBMT) on these groups of patients. Materials and Methods: We collected cases that complained of skin rashes with pruritus after orthopedic implants from January 2017 to June 2022 at the Dermatology clinic in Hualien Tzu Chi Hospital. We recorded the sites and material of orthopedic implants, skin lesions onset time, symptoms, location after implantation, and the disease duration. Laboratory tests were measured, including complete blood count, differential count, serum immunoglobulin E (IgE) level, as well as inflammatory and autoimmune markers. PBMT, including UVB311 nm or low-level laser therapy 808 nm, was performed. Dose, duration, and response were documented. Results: Fourteen patients were diagnosed with OIH; twelve presented with localized eczema at the implant sites, and two with generalized eczema. Eleven patients (78.6%) had either elevated eosinophils percentage (>6%) or IgE level (>200 U/mL) or both. Seven patients (50%) had favorable outcome after PBMT and successfully withdrew from systemic steroid. Conclusion: In our case series, localized eczema at implant sites was a common cutaneous presentation in OIH. Hence, a surgical scar at the eczema site or long-term waxing and waning generalized eczema should prompt physicians on the possibility of OIH. Blood eosinophils percentage and serum IgE level can be reference biomarkers for OIH. PBMT provides a noninvasive and effective treatment strategy for immune regulation and tissue regeneration.

Successful treatment of extremely large Bowen's disease lesion by topical photodynamic therapy and imiquimod: Using optical coherence tomography to detect early recurrence loci and validate the cure.

Bowen's disease, a form of skin cancer, is an intraepithelial carcinoma involving keratinocytes. It is associated with a risk of developing invasive squamous cell carcinoma in 3-5% of cases. Ultraviolet exposure, arsenic, human papillomavirus infection, immunosuppression, and genetic factors have been reported to be the causes. Clinically, it presents as symptomless and slowly growing, well-demarcated, irregular erythematous patches or plaques with scaly or crusted surfaces. Surgical excision remains common; however, for large (>20 mm) or multiple Bowen's disease lesions, alternative therapies need to be considered. Here, we present a case of extremely large Bowen's disease lesions in the lower extremities successfully treated with combination therapy using topical aminolevulinic acid-based photodynamic therapy followed by topical 5% imiquimod cream. Optical coherence tomography revealed disorganized and uneven nuclei of keratinocytes in the recurrent lesions, which became relatively small and uniform upon resolution. We demonstrated that photodynamic therapy provides a generally safe and effective strategy for treating large Bowen's disease lesions and optical coherence tomography provides a useful and noninvasive diagnosis of early Bowen's disease recurrence.

Nevi, dysplastic nevi, and melanoma: Molecular and immune mechanisms involving the progression.

Melanocytic nevi, dysplastic nevi, and melanoma are all derived from the pigment-producing cells, namely melanocytes. Concerning the clinical spectrum, cutaneous melanoma is the most aggressive skin cancer with a low survival rate, while nevi are the most common benign lesions in the general population, and dysplastic nevi place in between nevi and melanoma. Ultraviolet (UV) radiation is a well-recognized extrinsic risk factor for all three. BRAFV600E is a well-recognized driver mutation that activates the RAS-BRAF-mitogen-activated protein kinase (MAPK) signaling pathway among 40%-60% of melanoma cases. Interestingly, BRAFV600E mutation is detected even more in acquired nevi, approximately 80%. However, in nevi, several tumor suppressors such as p53 and phosphatase and tensin homolog (PTEN) are intact, and senescence factors, including p15INK4b, p16INK4a, p19, and senescence-associated acidic ß-galactosidase, are expressed, leading to cell senescence and cell cycle arrest. Although loss of p53 function is rarely found in melanoma, decreased or loss of PTEN with an activated PI3k/Akt signaling pathway is common in nevi, which may abolish senescence status and allow further progression into dysplastic nevi or melanoma. At present, mouse models closely resembling human nevi are used for investigating these phenomena. Melanocortin 1 receptor deficiency, an intrinsic risk factor for melanomagenesis, is related to the production of procarcinogenic pheomelanin and the inhibition of PTEN function. Immune response escape via programmed cell death-1/programmed cell death ligand-1 interaction plays further roles in monitoring the spectrum. Here, we review the current literature on the molecular and immune mechanisms involving the transition from benign nevi to malignant melanoma.

In Vivo Longitudinal Tracking of Lymphangiogenesis and Angiogenesis in Cutaneous Melanoma Mouse Model Using Multifunctional Optical Coherence Tomography.

Melanoma is a high-risk skin cancer because it tends to metastasize early and ultimately leads to death. In this study, we introduced a noninvasive multifunctional optical coherence tomography (MFOCT) for the early detection of premetastatic pathogenesis in cutaneous melanoma by label-free imaging of microstructures (i.e., providing the thickness and the scattering information) and microcirculation (i.e., providing depth-resolved angiography and lymphangiography). Using MFOCT-based approaches, we presented an in vivo longitudinal observation of the tumor microenvironment in Braf V600E/V600E ;Pten -/- mice with inducible melanoma monitored for 42 days. Quantitative analysis of MFOCT images identified an increased number of lymphatic and vascular vessels during tumor progression and faster lymphangiogenesis (beginning on day 21) than angiogenesis (beginning on day 28) in the melanoma microenvironment. We further observed lymphatic vessel enlargement from the first week of melanoma development, implying tumor cells interacting with the vessels and increased likelihood of metastasis. MFOCT identified cutaneous melanoma‒associated angiogenesis and lymphangiogenesis before the possible visual perception of the tumor (≥42 days) and before metastasis could be diagnosed using micropositron emission tomography (35 days). Thus, the proposed quantitative analysis using MFOCT has the potential for early detection of cutaneous melanoma progression or prediction of metastatic melanoma in a mouse model. However, retrospective and extensive experiments still need to be performed in the future to confirm the value of MFOCT in clinical application.

Risk of chronic spontaneous urticaria in reproductive-aged women with abnormal uterine bleeding: A population-based cohort study.

Women with abnormal uterine bleeding (AUB) have been reported to develop chronic spontaneous urticaria (CSU). Nevertheless, whether or not AUB women have an increased risk of CSU has not been examined in large-scale epidemiologic studies. This study aimed to investigate the risk of CSU among reproductive-aged women with AUB. A total of 79 595 patients and 79 107 propensity-score matched controls were recruited from Taiwan's National Health Insurance Research Database to conduct a nationwide cohort study. The Cox proportional-hazard regression model was applied to examine the adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for CSU in relation to AUB. We found that women with AUB had a higher risk for CSU (aHR = 1.83; 95% CI, 1.76-1.90) than women without AUB. Subgroup analyses revealed that AUB with an abnormal bleeding frequency (aHR = 1.70; 95% CI, 1.60-1.79), irregular bleeding (aHR = 1.80; 95% CI, 1.71-1.89), and intermenstrual bleeding (aHR = 1.65; 95% CI, 1.49-1.83) were associated with an increased risk of CSU compared with those without abnormalities. The Kaplan-Meier analysis revealed that the cumulative incidence of developing CSU was consistently higher in the AUB cohort than in the non-AUB cohort during the entire follow-up period (log-rank test, p < 0.001). In conclusion, reproductive-aged women with AUB were found to have a higher risk of developing CSU. This study emphasizes the importance of enquiring CSU patients about menstrual problems in clinical practice. Further consultation with obstetrician-gynecologists may be beneficial.

Combined methyl aminolevulinate-based photodynamic therapy and imiquimod in a patient with perianal extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare form of intraepithelial adenocarcinoma. Complete surgical removal of localized disease is the standard treatment for EMPD but carries anaesthesia-related risks and possible postoperative functional deficits. Herein, we present a case of perianal EMPD successfully treated with topical methyl aminolevulinate-based photodynamic therapy (MAL-PDT), followed by topical imiquimod. Immunohistochemical analysis after PDT revealed high expression of Toll-like receptor 7 on keratinocytes, Paget's cells, and dermal inflammatory cells, as well as increased expression of intraepidermal Langerhans cells, dermal macrophages, and T cells. We propose that MAL-PDT may prime the enhancing effects of topical imiquimod. Combined local treatment with PDT and imiquimod may provide an alternative and non-invasive strategy for perianal EMPD.

Lymphatic vessel segmentation in optical coherence tomography by adding U-Net-based CNN for artifact minimization.

The lymphatic system branches throughout the body to transport bodily fluid and plays a key immune-response role. Optical coherence tomography (OCT) is an emerging technique for the noninvasive and label-free imaging of lymphatic capillaries utilizing low scattering features of the lymph fluid. Here, the proposed lymphatic segmentation method combines U-Net-based CNN, a Hessian vesselness filter, and a modified intensity-thresholding to search the nearby pixels based on the binarized Hessian mask. Compared to previous approaches, the method can extract shapes more precisely, and the segmented result contains minimal artifacts, achieves the dice coefficient of 0.83, precision of 0.859, and recall of 0.803.

Efficacy and safety of topical SR-T100 gel in treating actinic keratosis in Taiwan: A Phase III randomized double-blind vehicle-controlled parallel trial.

BACKGROUND: Currently available topical treatments for actinic keratosis (AK) are associated with substantial side-effects. OBJECTIVES: To evaluate the efficacy and safety of topical SR-T100 gel in treating AK. METHODS: A multicenter, randomized, double-blinded phase III trial was conducted. Patients with at least two clinically visible AK were enrolled and a punch biopsy was performed on one of the AK to confirm the diagnosis. This study consisted of up to 16-week treatment and 8-week post-treatment periods. Medication was applied daily with occlusive dressing. RESULTS: 123 subjects were recruited and 113 were randomized. 76 subjects were in the SR-T100 and 37 in the vehicle arms. In SR-T100 and vehicle groups, 32.39% and 17.14% of subjects achieved complete clearance, respectively. For 75% partial clearance of lesions, 71.83% and 37.1% of subjects achieved this goal in SR-T100 and vehicle group, respectively. When comparing SR-T100 to vehicle, the odds ratio of complete clearance was 2.14 (p = 0.111), and odds ratio of partial clearance was 4.36 (p < 0.001). Severe local reactions were reported by only one subject using SR-T100. CONCLUSION: The imitation of the study was that not all the treated AK lesions were confirmed by histopathology. The diagnostic uncertainty may contribute to the high partial clearance rate in the vehicle group since the clinical-diagnosed AK showed higher clearance rate compared to histopathology-confirmed AK. The use of occlusive dressing was another possible explanation for high placebo effects. The results suggested that topical SR-T100 gel may be an effective and safe treatment for field therapy of AK.

Involvement of M1 Macrophage Polarization in Endosomal Toll-Like Receptors Activated Psoriatic Inflammation.

Psoriasis is a chronic inflammatory skin disorder that affects ~2%-3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7-9) at the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7-9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7-9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7-9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7-9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.

CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation.

Casein kinase 1α (CK1α), a component of the ß-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded by Csnk1a1) in skin physiology, we crossed mice harboring floxed Csnk1a1 with mice expressing K14-Cre-ERT2 to generate mice in which tamoxifen induces the deletion of Csnk1a1 exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by ß-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after Csnk1a1 ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14-Cre-ERT2 CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte-stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.