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.

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.

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.

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7-9.

Activation of TLR7-9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7-9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7-9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7-9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7-9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7-9.

GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation.

GSK3ß binding of GSKIP affects neurite outgrowth, but the physiological significance of PKA binding to GSKIP remains to be determined. We hypothesized that GSKIP and GSK3ß mediate cAMP/PKA/Drp1 axis signaling and modulate mitochondrial morphology by forming a working complex comprising PKA/GSKIP/GSK3ß/Drp1. We demonstrated that GSKIP wild-type overexpression increased phosphorylation of Drp1 S637 by 7-8-fold compared to PKA kinase-inactive mutants (V41/L45) and a GSK3ß binding-defective mutant (L130) under H2O2 and forskolin challenge in HEK293 cells, indicating that not only V41/L45, but also L130 may be involved in Drp1-associated protection of GSKIP. Interestingly, silencing either GSKIP or GSK3ß but not GSK3α resulted in a dramatic decrease in Drp1 S637 phosphorylation, revealing that both GSKIP and GSK3ß are required in this novel PKA/GSKIP/GSK3ß/Drp1 complex. Moreover, overexpressed kinase-dead GSK3ß-K85R, which retains the capacity to bind GSKIP, but not K85M which shows total loss of GSKIP-binding, has a higher Drp1 S637 phosphorylation similar to the GSKIP wt overexpression group, indicating that GSK3ß recruits Drp1 by anchoring rather than in a kinase role. With further overexpression of either V41/L45P or the L130P GSKIP mutant, the elongated mitochondrial phenotype was lost; however, ectopically expressed Drp1 S637D, a phosphomimetic mutant, but not S637A, a non-phosphorylated mutant, restored the elongated mitochondrial morphology, indicating that Drp1 is a downstream effector of direct PKA signaling and possibly has an indirect GSKIP function involved in the cAMP/PKA/Drp1 signaling axis. Collectively, our data revealed that both GSKIP and GSK3ß function as anchoring proteins in the cAMP/PKA/Drp1 signaling axis modulating Drp1 phosphorylation.

Autocrine protective mechanisms of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells after optic nerve crush.

This study investigated the role of autocrine mechanisms in the anti-apoptotic effects of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells (RGCs) after optic nerve (ON) crush. We observed that both G-CSF and G-CSF receptor (G-CSFR) are expressed in normal rat retina. Further dual immunofluorescence staining showed G-CSFR immunoreactive cells were colocalized with RGCs, Müller cells, horizontal and amacrine cells. These results confirm that G-CSF is an endogenous ligand in the retina. The semi-quantitative RT-PCR finding demonstrated the transcription levels of G-CSF and G-CSFR were up-regulated after ON crush injury. G-CSF treatment further increased and prolonged the expression level of G-CSFR in the retina. G-CSF has been shown to enhance transdifferentiation of the mobilized hematopoietic stem cells into tissue to repair central nervous system injury. We test the hypothesis that the hematopoietic stem cells recruited by G-CSF treatment can transdifferentiate into RGCs after ON crush by performing sublethal irradiation of the rats 5 days before ON crush. The flow cytometric analysis showed the number of CD34 positive cells in the peripheral blood is significantly lower in the irradiated, crushed and G-CSF-treated group than the sham control group or crush and G-CSF treated group. Nevertheless, the G-CSF treatment enhances the RGC survival after sublethal irradiation and ON crush injury. These data indicate that G-CSF seems unlikely to induce hematopoietic stem cell transdifferentiation into RGCs after ON crush injury. In conclusion, G-CSF may serve an endogenous protective signaling in the retina through direct activation of intrinsic G-CSF receptors and downstream signaling pathways to rescue RGCs after ON crush injury, exogenous G-CSF administration can enhance the anti-apoptotic effects on RGCs.

Concomitant induction of apoptosis and autophagy by prostate apoptosis response-4 in hypopharyngeal carcinoma cells.

The tumor-suppressive activity of prostate apoptosis response-4 (Par-4) has been demonstrated in a variety of human cancers. In this study, for the first time to our knowledge, we demonstrated that a higher intensity of Par-4 was significantly correlated with a better response in patients with hypopharyngeal carcinoma undergoing radiotherapy alone or concurrent chemoradiotherapy. Mechanistically, an elevated expression of Par-4 induced apoptosis of hypopharyngeal carcinoma cells and sensitized cells toward chemotherapeutic agents or X-ray irradiation. Along with apoptotic incitation, intriguingly, autophagic flux also increased on Par-4 stimulation and contributed to cell death. Moreover, the expressions of multiple common regulators involved in apoptosis and autophagy were regulated by Par-4. Taken together, our results suggested a prognostic role of Par-4 in hypopharyngeal carcinoma and showed novel activity of Par-4 in apoptosis and autophagy induction.

Leptin of dermal adipose tissue is differentially expressed during the hair cycle and contributes to adipocyte-mediated growth inhibition of anagen-phase vibrissa hair.

Adipose tissue encircles the lower portion of anagen hair follicles and may regulate hair cycle progression. As leptin is a major adipokine, its level of expression from the dermal white adipose tissue during hair cycle progression was studied. The result shows that leptin level is differentially expressed during hair cycle, the lowest in early anagen phase, upregulated in late anagen phase and the highest in the telogen phase. On the other hand, leptin receptor is detected in keratin 15-positive hair bulge epithelium of both anagen- and telogen-phase hair follicles of mice pelage and vibrissa hair, and hair from human scalp. Leptin contributes to adipocyte-mediated growth inhibition of anagen-phase vibrissa hair as demonstrated in organ culture and coculture system. Our data suggest that leptin of dermal white adipose tissue might regulate hair growth and, therefore, hair cycle progression via leptin receptor on the hair follicle epithelium.

Protective effects of systemic treatment with methylprednisolone in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION).

This study investigated the protective effects of the administration of steroids on optic nerves (ON) and retinal ganglion cells (RGCs) in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION). We induced rAION using rose bengal and argon laser irradiation in a photodynamic procedure on the optic discs of rats. The treated groups received methylprednisolone (MP) via peritoneal injection for 2 weeks. The control group received intraperitoneal injections of phosphate-buffered saline (PBS) post-rAION. At the 4th week post-infarct, MP treatments significantly rescued the RGCs (mm(2)) in the central retinas (1920 ± 210, p < 0.001) and mid-peripheral retinas (950 ± 240, respectively, p = 0.018) compared with those of the PBS-treated rats (central: 900 ± 210 and mid-peripheral: 440 ± 180). Functional assessment with flash visual-evoked potentials demonstrated that P1 latency (ms) was shortened in the MP group compared to the PBS group (108 ± 14 and 147 ± 9, respectively, p < 0.001). In addition, the P1 amplitude (uV) was enhanced in the MP group compared to the PBS group (55 ± 12 and 41 ± 13, respectively, p < 0.05). TUNEL assays showed a decrease in the number of apoptotic cells in the RGC layers of MP-treated retinas compared to the PBS-treated group (p < 0.05). ED1 positive cells (/HPF) were significantly decreased in the ONs of the MP group compared to the PBS group (p < 0.001). In conclusion, systemic administration of MP had neuroprotective effects on RGC survival and ON function in the rAION animal model.

Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in a rat model of anterior ischemic optic neuropathy (rAION).

The purpose of this study was to investigate the neuroprotective effects of recombinant human granulocyte colony stimulating factor (G-CSF), as administered in a rat model of anterior ischemic optic neuropathy (rAION). Using laser-induced photoactivation of intravenously administered Rose Bengal in the optic nerve head of 60 adult male Wistar rats, an anterior ischemic optic neuropathy (rAION) was inducted. Rats either immediately received G-CSF (subcutaneous injections) or phosphate buffered saline (PBS) for 5 consecutive days. Rats were euthanized at 4 weeks post infarct. Density of retinal ganglion cells (RGCs) was counted using retrograde labeling of Fluoro-gold. Visual function was assessed by flash visual-evoked potentials (FVEP) at 4 weeks. TUNEL assay in the retinal sections and immunohistochemical staining of ED1 (marker of macrophage/microglia) were investigated in the optic nerve (ON) specimens. The RGC densities in the central and mid-peripheral retinas in the G-CSF treated rats were significantly higher than those of the PBS-treated rats (survival rate was 71.4% vs. 33.2% in the central retina; 61.8% vs. 22.7% in the mid-peripheral retina, respectively; both p < 0.05). FVEP measurements showed a significantly better preserved latency and amplitude of the p1 wave in the G-CSF-treated rats than that of the PBS-treated rats (latency120 ± 11 ms vs. 142 ± 12 ms, p = 0.03; amplitude 50 ± 11 µv vs. 31 ± 13 µv, p = 0.04). TUNEL assays showed fewer apoptotic cells in the retinal ganglion cell layers of G-CSF treated rats [2.1 ± 1.0 cells/high power field (HPF) vs. 8.0 ± 1.5/HPF; p = 0.0001]. In addition, the number of ED1 positive cells was attenuated at the optic nerve sections of G-CSF-treated rats (16 ± 6/HPF vs. 35 ± 10/HPF; p = 0.016). In conclusion, administration of G-CSF is neuroprotective in the rat model of anterior ischemic optic neuropathy, as demonstrated both structurally by RGC density and functionally by FVEP. G-CSF may work via the dual actions of anti-apoptosis for RGC surviving as well as anti-inflammation in the optic nerves as evidenced by less infiltration of ED1-povitive cells.

Factors influencing the retrograde labeling of retinal ganglion cells with fluorogold in an animal optic nerve crush model.

PURPOSE: To investigate whether different crush durations or a different fluorogold (FG) injection timing can affect the efficiency of FG retrograde labeling of retinal ganglion cells (RGCs) in the optic nerve (ON) crush model. METHODS: We performed the ON crush in rats with a clip at different durations or a jewel forceps to compare the effects of different crush methods with FG staining. RGC density was compared between the FG injection 1 week before the sacrifice of the animals (group A) and the injection before the crush experiment (group B). Double staining with CD11b and FG in the retinal sections was conducted to investigate the relationship between the overcounting of RGCs and microglia. RESULTS: The FG-stained particles were significantly decreased at the distal part of the crush site compared to the proximal site of the ON with a crush duration of over 30 s or when crushed with the jewel forceps. Two weeks after ON crush, the RGC count was higher both in the central and mid-peripheral retinas in group B. The percentage of CD11b-stained cells among the FG-stained cells in the RGC layer of retinas in group B was higher than that of group A (34% in group B vs. 4% in group A, p = 0.0001). Overcounting of RGC density in group B was due to additional microglia with FG engulfing. CONCLUSIONS: Our results suggest that each laboratory should test its setting conditions to avoid factors influencing the RGC density measurement before conducting ON crush experiments.

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.

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.

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.

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.

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.

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.