Neoadjuvant Photodynamic Therapy: An Updated Therapeutic Approach for Non-Melanoma Skin Cancers.

OPINION STATEMENT: Non-melanoma skin cancers (NMSCs) are the most common malignancy and surgical excision is considered treatment of choice for the majority of cases. However, surgery can be very extensive in cases of large, multiple, or cosmetic-sensitive tumors located on areas such as scalp and face or genital region, leading to significant functional and cosmetic deficit. Aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a widely used approach in a variety of skin diseases, demonstrating remarkable efficacy in treatment of actinic keratosis, Bowen disease and basal cell carcinoma. Besides, when employed as a preoperative intervention, ALA-PDT effectively reduces tumor size and minimizes subsequent local surgical morbidity. With its minimally invasive nature and proven effectiveness, ALA-PDT holds significant promise as a neoadjuvant treatment option for NMSCs. In cases where the tumor is large, invasive, multiple, or located in cosmetically and functionally sensitive areas, or when considering patient factors such as age, comorbidity, willingness to undergo surgery, and post-operative quality-of-life, surgical intervention or radiotherapy alone may be impracticable or unacceptable. In such scenarios, neoadjuvant ALA-PDT can offer remarkable outcomes. In order to further ensure the maximum benefit of patients from neoadjuvant PDT, collaboration with multidisciplinary teams and whole-process management may be in need.

Real-world data of 5-aminolevulinic acid-mediated photodynamic therapy for Bowen's disease: A 10-year retrospective study in the skin of color patients (2011-2021).

BACKGROUND: Photodynamic therapy (PDT) has been strongly recommended as an excellent alternative treatment for Bowen's disease (BD). However, reported data on 5-aminolevulinic acid-mediated PDT (ALA-PDT) with red light irradiation are limited and the long-term effectiveness remains to be determined, especially in dark-skinned populations. METHODS: Medical records of BD patients who received ALA-PDT with red light irradiation between February 2011 and June 2021 were reviewed and summarized. Univariate and multivariate analyses of clinically relevant variables that may affect treatment outcomes were performed to identify risk predictors. RESULTS: The overall clearance rate of 122 BD lesions was 89.3% with a median follow-up time of 36 months. The correlation between the effectiveness and fluorescence intensity of pre-PDT or PDT sessions was statistically significant after eliminating the interference of confounding factors. All recurrences occurred in the first two years following ALA-PDT. CONCLUSION: ALA-PDT is an effective treatment for BD in the skin of color patients. Well-executed operation and effective pre-treatment are the determinants of effectiveness. Fluorescence intensity of pre-PDT appeared to be a significant predictor of final effectiveness. In addition, two years of follow-up is necessary following ALA-PDT.

Curcumin-mediated photodynamic therapy for mild to moderate Acne: A self-controlled split-face randomized study.

OBJECTIVE: To evaluate the effectiveness and safety of Curcumin-mediated Photodynamic Therapy (Curcumin-PDT) in the treatment of mild to moderate acne. METHODS: In this randomized split-face controlled study, 11 patients with mild to moderate acne were randomly divided into two groups. One side received a single 445 nm LED light exposure of 36 J/cm2, while the other side received Curcumin-PDT. The process of Curcumin-PDT involves the application of a mask containing 1 % curcumin for 20 min, followed by exposure to 445 nm LED light at 36 J/cm². The treatment consists of sessions spaced every 3 days, with a total of 2 treatments per week, administered continuously for 2 weeks. Efficacy assessment and comparison were conducted on both groups of patients before treatment and 2 weeks after the last treatment, and adverse reactions were observed and recorded. RESULTS: At the 2-week follow-up after the last treatment, the total lesion clearance rates for Curcumin-PDT and monotherapy light were 54.7 ± 21.5 % and 28.1 ± 19.9 %, respectively (P = 0.001). The clearance rates for non-inflammatory lesions were 32.3 ± 25.7 % and 21.9 ± 14.0 % for Curcumin-PDT and monotherapy light sides (P = 0.252), while for inflammatory lesions, the clearance rates were 59.3 ± 28.2 % and 36.5 ± 21.6 % (P = 0.013). Both groups experienced mild erythema after treatment, which subsided within 1-2 h. Two patients developed mild localized pigmentation, which self-resolved after 1 month of follow-up. Both groups did not exhibit edema, crust formation, scaling, pigment reduction, or scarring. CONCLUSION: Curcumin-PDT can be considered a safe and effective method for the treatment of mild to moderate acne.

miR-219-5p attenuates cisplatin resistance of ovarian cancer by inactivating Wnt/ß-catenin signaling and autophagy via targeting HMGA2.

Our previous study confirmed that miR-219-5p inhibits the progression of ovarian cancer (OC) by targeting high mobility group AT-hook 2 (HMGA2), while the role of miR-219-5p on the chemoresistance of OC is unclear. HMGA2 and miR-219-5p expression in OC tumors and various types of OC cells were determined by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. The miRNA profiles in A2780 and cisplatin-resistant A2780 cells were investigated via bulk miRNA sequencing, and the interactions of miR-219-5p and HMGA2 were determined by luciferase reporter activity assay. Cell function was verified through Cell Counting Kit-8, invasion assay, wound-healing, and TUNEL assays. HMGA2 level is highly expressed in cisplatin-resistant OC cell lines compared to normal OC cells, while the expression trend of miR-219-5p is the opposite. In addition, we found that miR-219-5p is one of the miRNAs that have the most significant reduction in levels in the cisplatin-resistant A2780/DDP cell line compared to A2780 cells. Then, we reveal that miR-219-5p directly targets HMGA2 in cisplatin-resistant OC cells, and upregulation of miR-219-5p significantly reduces the resistance of OC cells to cisplatin both in vitro and in vivo. Finally, our results suggest that Wnt/ß-catenin signaling and autophagy pathway is involved in the role of miR-219-5p/HMGA2 on resistance of OC cells to cisplatin via gain-of-function experiments. Collectively, the present study shows that miR-219-5p decreases the resistance of OC cells to cisplatin via Wnt/ß-catenin signaling and autophagy by regulating HMGA2, which provides a feasible solution for the resistance of OC to chemotherapy.

Local narrow margin excision sequential with modified ALA-PDT for successful treatment of an 86-year-old patient with malignant proliferating trichilemmal tumor.

Malignant proliferating trichilemmal tumor (MPTT) is thought to represent the malignant counterpart of benign proliferative pilar cyst, a lesion originating from the outer hair root sheath. We report a case of an 86-year-old woman with an exophytic nodule containing an ulcerated surface in the temporal region. Histopathologically confirmed MPTT without metastasis, and considering the risk of metastasis and recurrence, we used single local narrow margin excision combined with modified 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT). No recurrence of skin lesions was found in the 2-year follow-up after combined therapy. In conclusion, local narrow margin excision sequential with modified ALA-PDT may be a particularly promising and effective treatment option for MPTT.

Successful treatment of hidradenocarcinoma using ALA-PDT combined with local narrow margin excision.

Hidradenocarcinoma is a rare malignancy of sweat gland differentiation. It is known for its high rate of recurrence and metastasis, which has a serious impact on human health and aesthetics. However, the treatment options for this disease are limited, making prompt and appropriate treatment is a daunting challenge. In this report, we present the first successful cure of hidradenocarcinoma using 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with local narrow margin excision on the left side of the forehead in an elderly woman. No recurrence during one year of follow-up after the combined therapy. This case will provide a valuable reference for more efficient management of similar cases in clinic.

Single cell transcriptome profiling reveals cutaneous immune microenvironment remodeling by photodynamic therapy in photoaged skin.

Background: The immune microenvironment plays a critical role in maintaining skin homeostasis, which is closely related to the dysfunction in photoaged skin such as autoimmunity and tumorigenesis. Several recent studies have demonstrated the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in alleviating photoaging and skin cancer. However, the underlying immune mechanisms and the immune microenvironment change by ALA-PDT remain largely unknown. Methods: To illustrate the effects of ALA-PDT on immune microenvironment in photoaged skin, single cell RNA sequencing (scRNA-seq) analysis of photoaged skin on the extensor side of the human forearm before and after ALA-PDT was performed. R-packages of Seurat, clusterProfiler, Monocle, CellChat were used for cell clustering, differentially expressed genes analysis, functional annotation, pseudotime analysis and cell-cell communication analysis. The gene sets related to specific functions were extracted from the MSigDB database, which were used to score the functions of immune cells in different states. We also compared our result with published scRNA-seq data of photoaged skin of the eyelids. Results: The increase score of cellular senescence, hypoxia and reactive oxygen species pathway in immune cells and the decrease of immune receptor activity function and proportion of naive T cells were found in skin photoaging. Moreover, the function of T cell ribosomal synthesis was also impaired or down regulated and function of G2M checkpoint was up regulated. However, ALA-PDT showed promising results in reversing these effects, as it improved the above functions of T cells. The ratio of M1/M2 and percentage of Langerhans cells also decreased with photoaging and increased after ALA-PDT. Additionally, ALA-PDT restored the antigen presentation and migration function of dendritic cells and enhanced cell-cell communication among immune cells. These effects were observed to last for 6 months. Conclusion: ALA-PDT has potential to rejuvenate immune cells, partially reversed immunosenescence and improved the immunosuppressive state, ultimately remodelling the immune microenvironment in photoaged skin. These results provide an important immunological basis for further exploring strategies to reverse skin photoaging, chronological aging and potentially systemic aging.

ALA-iPDT for follicular occlusion tetrad concomitant with pachyonychia congenital type â ¡ and ankylosing spondylitis.

The follicular occlusion tetrad is a complex dermatologic syndrome which can concomitant with other diseases. The case reported a young male patient suffer from follicular occlusion tetrad (acne conglobata, hidradenitis suppurativa, dissecting cellulitis of the scalp, and pilonidal sinuses) concomitant with pachyonychia congenital type Ⅱ (thickened nails, palmoplantar keratoderma, multiple cysts) and ankylosing spondylitis (lumbago, human leukocyte antigen-B27 positive). The genetic analysis showed the KRT17 gene mutation on exon 1 (c.T284C) supports the diagnosis. Whereupon, a comprehensive therapy scheme of 5-aminolevulinic acid-mediated interstitial photodynamic therapy (ALA-iPDT) combined with surgery offered excellent response. This case reports a rare condition and proposes a therapeutic option that may work.

Bimodal photodynamic therapy for treatment of a 91-year-old patient with locally advanced cutaneous basal cell carcinoma and postoperative scar management.

Locally advanced basal cell carcinoma (laBCC) is an uncommon cutaneous malignant tumor characterized by direct spread and extensive tissue destruction. The optimal therapy for laBCC remains a challenge, especially for elderly patients. Photodynamic therapy (PDT) has its advantage of better tumor selectivity, providing focal treatment for various non-melanoma carcinomas. We report that a new combination treatment of HiPorfin-photodynamic therapy (HiPorfin-PDT) and modified topical 5-aminolevulinic acid-photodynamic therapy (ALA-PDT), named bimodal PDT was successful to treat a 91-year-old patient with laBCC. As for side effects, hypertrophic scar and pain were observed. The symptoms were relieved after intralesional corticosteroid, 980 nm laser and 595 nm pulsed dye laser treatment in 3 months.

Combination curettage and modified ALA-PDT for multiple basal cell carcinomas of the face and head.

Basal cell carcinoma (BCC) is a common non-melanoma skin malignancy arising in sun exposure area. Patients with multiple BCCs have a high-risk factor for recurrence and are very difficult to  treat with current methods. 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT) treat superficial type of BCCs with superior efficacy and an excellent cosmetic result, but deep tumor success is limited. Herein, a case of numerous nodular BCCs scattered on the face and head, which was treated with the combination of topical curettage and modified ALA-PDT is reported. Curettage was to rapidly scalp away nodular tumors and contributed to ALA transdermal depth to the tumor base. Modified ALA-PDT as an advanced treatment was nearly painless and can cure multiple BCCs of face and head combing curettage.

Single-cell transcriptomic analysis reveals the critical molecular pattern of UV-induced cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer characterized by high invasiveness, heterogeneity, and mainly occurs in the ultraviolet (UV)-exposed regions of the skin, but its pathogenesis is still unclear. Here, we generated single-cell transcriptome profiles for 350 cells from six primary UV-induced cSCCs, together with matched adjacent skin samples, and three healthy control skin tissues by single-cell RNA-sequencing technology based on Smart-seq2 strategy. A series of bioinformatics analyses and in vitro experiments were used to decipher and validate the critical molecular pattern of cSCC. Results showed that cSCC cells and normal keratinocytes were significantly distinct in gene expression and chromosomal copy number variation. Furthermore, cSCC cells exhibited 18 hallmark pathways of cancer by gene set enrichment analysis. Differential expression analysis demonstrated that many members belonging to S100 gene family, SPRR gene family, and FABP5 were significantly upregulated in cSCC cells. Further experiments confirmed their upregulation and showed that S100A9 or FABP5 knockdown in cSCC cells inhibited their proliferation and migration through NF-κB pathway. Taken together, our data provide a valuable resource for deciphering the molecular pattern in UV-induced cSCC at a single-cell level and suggest that S100A9 and FABP5 may provide novel targets for therapeutic intervention of cSCC in the future.

Advanced application of holmium: YAG laser combined ALA-PDT for the treatment of refractory condylomata acuminata in anal canal.

BACKGROUND: Anal canal condylomata acuminata is a disease caused by the human papilloma virus. Conventional cauterizing laser treatment cannot achieve a satisfactory result owing to a high recurrence rate, and the application of 5-aminolaevulinic acid-photodynamic therapy (ALA-PDT) also has limitations in the anal canal. Holmium yttrium aluminum garnet (Ho: YAG) laser with fiber is found to be effective at removing canal lesions, and may create suitable conditions for ALA-PDT. We aim to investigate the feasibility of Ho: YAG laser combined with ALA-PDT and to explore a more optimal therapy in refractory anal canal condylomata. METHODS: Data of 37 patients with anal canal condylomata (number of warts≥ 10 lesions) from May 2017 to March 2019 were reviewed. In total 17 cases were treated with Ho: YAG laser plus ALA-PDT, and 20 patients treated with CO2 laser plus ALA-PDT were selected as control. Wart clearance and recurrence rates were evaluated as well as laser complications. RESULTS: Most warts (88.23 %) were removed after a session of Ho: YAG laser pretreatment. The average number of laser sessions required to clear all warts was 1.94 in the Ho: YAG laser plus ALA-PDT group. Meanwhile, no wound infections or defecation disfunctions were found. Ho: YAG laser with ALA-PDT could significantly reduce wart recurrence rates (17.6 %) in comparison with CO2 laser with ALA-PDT (55 %). CONCLUSIONS: Ho: YAG laser combined with ALA-PDT raised the cure rate of refractory anal canal condylomata and has important guidance implications for clinical application.

In Vitro and In Vivo Osteogenesis of Human Orbicularis Oculi Muscle-Derived Stem Cells.

BACKGROUND: Cell-based therapies for treating bone defects require a source of stem cells with osteogenic potential. There is evidence from pathologic ossification within muscles that human skeletal muscles contain osteogenic progenitor cells. However, muscle samples are usually acquired through a traumatic biopsy procedure which causes pain and morbidity to the donor. Herein, we identified a new alternative source of skeletal muscle stem cells (SMSCs) without conferring morbidity to donors. METHODS: Adherent cells isolated from human orbicularis oculi muscle (OOM) fragments, which are currently discarded during ophthalmic cosmetic surgeries, were obtained using a two-step plating method. The cell growth kinetics, immunophenotype and capabilities of in vitro multilineage differentiation were evaluated respectively. Moreover, the osteogenically-induced cells were transduced with GFP gene, loaded onto the porous ß-tricalcium phosphate (ß-TCP) bioceramics, and transplanted into the subcutaneous site of athymic mice. Ectopic bone formation was assessed and the cell fate in vivo was detected. RESULTS: OOM-derived cells were fibroblastic in shape, clonogenic in growth, and displayed phenotypic and behavioral characteristics similar to SMSCs. In particular, these cells could be induced into osteoblasts in vitro evidenced by the extracellular matrix calcification and enhanced alkaline phosphatase (ALP) activity and osteocalcin (OCN) production. New bone formation was found in the cell-loaded bioceramics 6 weeks after implantation. By using the GFP-labeling technique, these muscle cells were detected to participate in the process of ectopic osteogenesis in vivo. CONCLUSION: Our data suggest that human OOM tissue is a valuable and noninvasive resource for osteoprogenitor cells to be used in bone repair and regeneration.

Identification and Characterization of Skeletal Muscle Stem Cells from Human Orbicularis Oculi Muscle.

Skeletal muscle stem cell (SMSC) transplantation has shown great therapeutical potential in repairing muscle loss and dysfunction, but the muscle acquisition is usually a traumatic procedure causing pain and morbidity to the donor. In this study, we investigated the feasibility of isolating SMSCs from human orbicularis oculi muscle (OOM), which is routinely removed and discarded during ophthalmic cosmetic surgeries. OOM fragments were harvested from 18 female healthy donors undergoing upper eyelid plasties. Plastic-adherent cells were isolated from the muscles using a two-step plating method combined with collagenase digestion. A total of 15 cell cultures were successfully established from the muscle samples. These adherent cells were positive for the specific markers of SMSCs and could be directed toward the osteogenic, adipogenic, chondrogenic, and myogenic phenotypes in the presence of lineage-specific inductive media. Moreover, after cultured in the myogenic inductive medium for 3 weeks, the muscle cells were injected into the tibialis anterior muscles of nude mice and the cell fate was detected using a DiI-labeling technique. In vivo myogenesis was evidenced by the expression of DiI fluorescence after cell transplantation. The donor cells could be found in the satellite cell position and incorporated into the host myofibers. Our results demonstrated that human OOM represents a novel source of myogenic precursors with stem cell-like properties, which may provide a foundation for the SMSC-based therapeutics of skeletal muscle diseases.

Age-Related Changes in the Regenerative Potential of Adipose-Derived Stem Cells Isolated from the Prominent Fat Pads in Human Lower Eyelids.

The existence of multipotent adipose-derived stem cells isolated from human orbital fat (OF) tissue has shown great therapeutic potential in tissue engineering and regenerative medicine. But the use of stem cells for therapeutic applications is influenced by their proliferative and differentiation potentials, which may be affected by the age of the donor. So far there is little knowledge about the effects of donor age on the biological properties of human orbital adipose-derived stem cells (OASCs). The intraorbital fat protrusion in the lower eyelids occurs as an aging process, and the protruded fat is routinely removed during aesthetic surgeries. Based on the ease of OF harvest and the availability of OASCs, we investigated in this study the relationship between age and the differentiation and proliferation potentials of human OASCs. Human orbital adipose samples were harvested from young (with normal lower eyelid appearance) and old donors (having protruded fat pads in the lower eyelids). The morphological properties of orbital adipocytes were assessed and the fat cell size displayed a decreasing trend with advancing age. OASCs were isolated from the fat samples, expanded in vitro and cultured under appropriate inducive conditions. Compared to the young cells, although no difference was found in the cell yield and phenotype expression, aged OASCs showed fewer progenitor cell numbers, reduced proliferative rates, increased senescent features and decreased differentiation potentials towards adipogenic, osteogenic and chondrogenic lineages. Our data suggested that using autologous OASCs from elderly patients for potential therapeutic purposes might be restricted.