The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

(N-NITROSO) PROPAFENONE INDUCED ADVANCED NODULAR MELANOMA-FIRST REPORTED CASE IN THE WORLD LITERATURE: THE INEXTRICABLE LINKS BETWEEN THE PHOTOCARCINOGENESIS, DRUG RELATED NITROSOGENESIS AND PHARMACO-ONCOGENESIS.

Onco-pharmacogenesis or pharmaco-oncogenesis of skin cancer is a concept , which could also be considered as an "end product" of drug-mediated Nitrosogenesis or of the permissive regime for carcinogens to be (un)controlled released in drugs. Their controlled distribution remains until 2025 as a forced and non-alternative and there is no indication of any possibility to introduce a full elimination regime against the already mentioned carcinogenic availability. There are three main worrying facts that determine the need for these elimination regimes: 1) the clinicopathological correlations concerning the intake of a heterogeneous class of drugs and the subsequent development of relatively homogeneous tumours/ such as melanoma, 2) the recently proven mutagenic/ carcinogenic action of certain nitrosamines, but this time directly on human DNA, and 3) the fact that some of the nitrosamines are potent photocarcinogens that exert their genotoxic effects only after irradiation with UVA/ also recently proven/. In addition to the rhetoric mentioned above, there is also an overlap in mutational patterns between the genes previously generally accepted to affect melanomas - p53 / RAS oncogenes , with those identified as target genes, but being affected "mutationally", by certain nitrosamines. The processes of photocarcinogenesis, nitrosogenesis and oncopharmacogenesis of skin cancer are inextricably linked and should not be considered and analysed unilaterally or in a semi-invasive manner. Cataloguing the type of nitrosamines and their precise concentration on drug leaflets and prescription/official websites with permanent access to clinicians and end-users remains the only safe and effective weapon in the fight against (un)controlled contamination. The pharmaceutical industry and regulators remain the creators, the 'parents' of onco-pharmacogenesis, nitrosogenesis, and therefore the processes involved in the generation and progression of skin cancer. The impossibility of establishing elimination regimes for certain mutagens and/or carcinogens already proven to be present in medicines remains a mystery. In practice, end consumers find themselves in a state of enforced tolerance of certain genotoxic substances that are not even declared as available. Clinicians in the face of dermatologists/ dermatological surgeons remain the analysers and identifiers of these globalization processes. Once again, we present a patient who took the antiarrhythmic (nitroso-) drug propafenone and developed a relatively short-term nodular melanoma with a subsequent fatal outcome. We comment on the role of drug-mediated nitrosogenesis and its relationship to photocarcinogenesis and onco-pharmacogenesis.

Efficacy of Cemiplimab as Adjuvant or Neoadjuvant Therapy in the Treatment of Cutaneous Squamous Cell Carcinoma.

INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer in the White population. Unfortunately, the prognosis of advanced cSCC is poor, and management can be challenging. Until recently, the choice of systemic medications was limited, and those that were available had modest efficacy. Cemiplimab is an anti-programmed cell-death protein 1 inhibitor and the first immunotherapeutic agent approved for the treatment of metastatic or locally advanced cSCC. The purpose of this study was to evaluate the efficacy of cemiplimab when used as adjuvant or neoadjuvant therapy in patients treated at our institution. METHODS: A retrospective review of patients with locally advanced or metastatic cSCC who were treated with cemiplimab as adjuvant or neoadjuvant therapy at a single institution between February 2019 and November 2022 was performed. Response to treatment was objectively assessed based on Response Evaluation Criteria in Solid Tumors, version 1.1, criteria. The primary end point was objective response rate. Secondary endpoints included time to observed response, disease-control rate, progression-free survival, overall survival, and adverse effects of therapy. RESULTS: A total of 6 patients were identified with a median age of 79 years (range, 51-90 years). Four patients had locally advanced cSCC, and 2 had distant metastasis. Cemiplimab was used as adjuvant therapy in 3 patients and neoadjuvant therapy in 2 patients. There was 1 patient in which it was used for limb salvage, who would have otherwise required an amputation. Objective response rate, complete response, and partial response were 66% (4 of 6), 33% (2 of 6), and 33% (2 pf 6), respectively. Average time to observed response was 2.9 months. Disease-control rate was 83% (5 of 6), and average progression-free survival was 10 months. Toxicity was reported in 2 patients, both of which were grade 1 severity. CONCLUSIONS: Cemiplimab has established its utility in the treatment of advanced cSCC, demonstrating clinical efficacy while generally having a tolerable adverse effect profile. Our preliminary results suggest that cemiplimab has potential as an adjuvant or neoadjuvant therapy in combination with surgery for treatment of cSCC.

Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study.

PURPOSE: Immune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy. METHODS: A national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent. RESULTS: Of 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63-3.70; p < 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50-1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52-2.12, p = 0.891). CONCLUSIONS: IrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.

T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.

Cold atmospheric plasma attenuates skin cancer via ROS induced apoptosis.

BACKGROUND: Cold atmospheric plasma (CAP) has been widely used in biomedical research, especially in vitro cancer therapy. Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor originating from epidermal keratinocytes. However, the mechanism of CAP therapy on CSCC remains unclear. METHODS AND RESULTS: The animal models of CSCC induced by 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) were constructed. For the CAP treatment group, after each TPA application, CAP was administered for 3 min twice weekly after drying. HE staining were used to detect the pathological status of tumor tissue in each group. The levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 were evaluated by western blot and qPCR. TUNEL staining were used to detect apoptosis in tumor tissues. In vivo, serum samples were used for ELISA of total ROS. MTT assay was used to detect the viability of A431 cells. Western blot and qPCR were used to detect the levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 in A431 cells. A431 cell proliferation was examined by colony formation assay. The proportions of apoptosis of A431 cells were detected by flow cytometry. Transwell assessed the ability of A431 cells migration and proliferation. We found that CAP could induce skin cancer cells apoptosis and inhibit the progress of skin cancer. Through experiments in vitro, reactive oxygen species (ROS) generated by N-acetylcysteine (NAC) and CAP inhibited the proliferation and migration of A431 skin cancer cells while promoting apoptosis. CONCLUSIONS: These evidences suggest the protective effect of CAP in CSCC, and CAP has the potential clinical application of CSCC.

A General Approach to Patients Presenting With Locally Advanced or Distant Metastatic Disease.

ABSTRACT: The widespread adoption of immune checkpoint inhibitors and small molecule inhibitors of the MAP kinase pathway has transformed the management of locally advanced and metastatic melanoma. Here, we provide a broad overview on the use of these agents in the first-line setting, incorporating a review of the clinical literature as well as the practice patterns of our respective melanoma groups. Throughout, we highlight areas of uncertainty that provide opportunities for future clinical investigation and additional improvement in outcomes for patients with melanoma.

Treatment of Stage III Resectable Melanoma-Adjuvant and Neoadjuvant Approaches.

ABSTRACT: Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

What Is the Timing and Role of Targeted Therapy in Metastatic Melanoma?

ABSTRACT: Melanoma is the most lethal cutaneous malignancy worldwide. The last 15 years have ushered in several regulatory approvals that have dramatically altered the landscape of treatment options for patients with melanoma. Many patients with melanoma harbor activating mutations in the BRAF proto-oncogene, a key component of the mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Therapies targeting BRAF have led to remarkable improvements in both response rates and survival in patients with metastatic disease. In parallel with these developments in MAPK-targeted therapy has been the clinical development of immune checkpoint inhibitors, which also have improved response rates and survival in patients with metastatic disease including randomized trials compared with MAPK-targeted therapy in patients with advanced, BRAF-mutant melanoma. Immune checkpoint inhibitors have become the preferred first-line standard-of-care treatment for patients with newly diagnosed metastatic disease in patients irrespective of BRAF mutational status. Given these developments, it is now less clear how to optimize the use of MAPK-targeted therapy regarding treatment setting and in sequence with immune checkpoint inhibitor.

[Blastic plasmacytoid dendritic cell tumor treated with DVT regimen: a case report and literature review].

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy, there is no standard treatment and the prognosis is very poor. Affiliated Zhongshan Hospital of Dalian University report a case of 85-year-old BPDCN male patient treated with DVT regimen (decitabine combined with Venetoclax and thalidomide) and achieved complete remission. The patient with skin nodules and the pathology diagnosed BPDCN, the next generation sequencing of skin nodules showed mutations of IDH2 and ASXL1. DVT (decitabine combined with Venetoclax and thalidomide) has significant efficacy with rapid and deep remission for BPDCN, and the adverse effects is less, especially suitable for elderly patients who cannot tolerate intense chemotherapy.

The outcome in patients with BRAF-mutated metastatic melanoma treated with anti-programmed death receptor-1 monotherapy or targeted therapy in the real-world setting.

BACKGROUND: Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. METHODS: This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. RESULTS: Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. CONCLUSIONS: Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.

Therapeutic Potential of Fungal Terpenes and Terpenoids: Application in Skin Diseases.

Terpenes and their derivatives comprise a diverse group of natural compounds with versatile medicinal properties. This article elucidates the general characteristics of fungal terpenes and terpenoids, encompassing their structure and biogenesis. The focal point of this work involves a comprehensive overview of these compounds, highlighting their therapeutic properties, mechanisms of action, and potential applications in treating specific skin conditions. Numerous isolated terpenes and terpenoids have demonstrated noteworthy anti-inflammatory and anti-microbial effects, rivalling or surpassing the efficacy of currently employed treatments for inflammation or skin infections. Due to their well-documented antioxidant and anti-cancer attributes, these compounds exhibit promise in both preventing and treating skin cancer. Terpenes and terpenoids sourced from fungi display the capability to inhibit tyrosinase, suggesting potential applications in addressing skin pigmentation disorders and cancers linked to melanogenesis dysfunctions. This paper further disseminates the findings of clinical and in vivo research on fungal terpenes and terpenoids conducted thus far.

Assessing the use of anti-PD1 monotherapy as adjuvant therapy and determinants of treatment choice in stage III cutaneous melanoma in the US.

BACKGROUND: The objective of this study was to describe real-world adjuvant therapy (AT) use by disease substage and assess determinants of treatment choice among patients with stage III melanoma. METHODS: This non-interventional retrospective study included survey responses and data from patient records provided by US medical oncologists. Survey responses, patient demographic/clinical characteristics, treatment utilization, and reasons for treatment were reported descriptively. The association between patient and disease characteristics and AT selection was assessed using logistic and multinomial regression models, overall and stratified by AJCC8 substage (IIIA vs. IIIB/C/D) and type of AT received (anti-PD1 monotherapy, BRAF/MEK, no AT), respectively. RESULTS: In total 152 medical oncologists completed the survey and reviewed the charts of 507 patients (168 stage IIIA; 339 stages IIIB/IIIC/IIID); 405 (79.9%) patients received AT (360/405 (88.9%) received anti-PD1 therapy; 45/405 (11.1%) received BRAF/MEK therapy). Physicians reported clinical guidelines (61.2%), treatment efficacy (37.5%), and ECOG performance status (31.6%) as drivers of AT prescription. Patient-level data confirmed that improving patient outcomes (79%) was the main reason for anti-PD1 prescription; expected limited treatment benefit (37%), patient refusal (36%), and toxicity concerns (30%) were reasons for not prescribing AT. In multivariable analyses stage IIIB/IIIC/IIID disease significantly increased the probability of receiving AT (odds ratio [OR] 1.74) and anti-PD1 therapy (OR 1.82); ECOG 2/3 and Medicaid/no insurance decreased the probability of AT receipt (OR 0.37 and 0.42, respectively) and anti-PD1 therapy (OR 0.41 and 0.42, respectively) among all patients and patients with stage IIIA disease. CONCLUSION: Most patients were given AT with a vast majority treated with an anti-PD1 therapy. Physician- and patient-level evidence confirmed the impact of disease substage on AT use, with stage IIIA patients, patients without adequate insurance coverage, and worse ECOG status having a lower probability of receiving AT.

New Genetic Markers of Skin T-Cell Lymphoma Treatment.

AIM: Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147-CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3'UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells-macrophages, dendritic cells, and B cells. The aim of the study is to test genotype-phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. MATERIALS AND METHODS: A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. RESULTS: The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy-it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. CONCLUSION: Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well.

Multiple Keratoacanthoma-like Syndromes: Case Report and Literature Review.

Keratoacanthoma (KA) is a fast-growing skin tumor subtype that can be observed as a solitary lesion or rarely as multiple lesions in the context of rare genetic syndromes. Syndromes with multiple keratoacanthoma-like lesions have been documented as multiple self-healing squamous epithelioma (Ferguson-Smith syndrome), eruptive keratoacanthoma of Grzybowski, multiple familial keratoacanthoma of Witten and Zak Muir-Torre syndrome, and incontinentia pigmenti. The treatment approach of those entities is challenging due to the numerous lesions, the lesions' undefined nature, and the co-existence of other malignant skin tumors. Herein, we report a case of a 40-year-old woman who developed multiple treatment-resistant Ferguson-Smith-like keratoacanthomas with a co-existing large and ulcerated invasive squamous cell carcinoma and microcystic adnexal carcinoma on the scalp. Multiple keratoacanthomas on her extremities were successfully treated with oral acitretin (0.5 mg/kg/day) in combination with topical Fluorouracil (5-FU) 5%, while excision and plastic surgery restoration were performed to treat the ulcerated cancer lesion on her scalp. Due to the interesting nature of this rare syndrome, we performed a literature review including case reports and case series on multiple-KA-like lesions syndromes and focusing on diagnosis and therapy approaches. We also conducted a comparison of patient reports, which included assessing the clinical appearance of the lesions and evaluating the success and progress or the failure of various treatment approaches that were implemented.

Efficacy of photodynamic therapy using ALAHCl in gel with a lipid nanoemulsion and MALHCl in cream in superficial basal cell carcinoma.

INTRODUCTION AND OBJECTIVE: Photodynamic therapy (PDT) is a therapeutic option for low-risk basal cell carcinoma (BCC). The aim of the study was to assess the efficacy of topical PDT in the treatment of superficial BCC (sBCC) using two different photosensitizers: aminolevulinic acid hydrochloride (ALA-HCl) in a gel formulation with a lipid nanoemulsion (ALA-HCl in gel) and ALA methyl ester hydrochloride (MAL-HCl) in a cream formulation (MAL-HCl in cream). MATERIAL AND METHODS: 21 patients were treated twice with a one week interval between treatments. The formulations were applied onto lesions: 10 patients were treated with MAL-HCl in cream, and 11 with ALA-HCl in gel. After three hours of incubation and removing the preparations, fluorescence was assessed. The skin areas were then irradiated with red light 630 ± 5 nm. RESULTS: At the follow-up visit 12 weeks after the second treatment, complete clinical remission was found in 82% after ALA-HCl in gel and in 80% after MAL-HCl in cream. An excellent cosmetic result was found in 96% of patients after MALHCl in cream and in 100% after ALA-HCl in gel. Faster skin healing and less post-inflammatory hyperpigmentation during follow-up visits was observed after treatment with ALA-HCl in gel. CONCLUSIONS: Both formulations - ALA-HCl in gel and MAL-HCl in cream - were highly effective photosensitisers for PDT. The advantage of ALA-HCl in a gel formulation with a lipid nanoemulsion was faster skin healing, resulting in better cosmetic results.

Case report: A case of advanced gastric cancer with multiple skin metastases, with significant relief from immunotherapy.

Gastric cancer is the fifth leading cause of cancer-related mortality worldwide, with a low 5-year survival rate in advanced stages. Cutaneous metastasis is rare in gastric cancer, with only 0.8-1% incidence. We reported a rare case of female gastric cancer. The patient had undergone subtotal gastrectomy and chemotherapy 13 years ago, followed by a subsequent surgery of residual stomach, partial jejunum, and partial colon resection 11 years later. The pathological examination revealed poorly differentiated stomach adenocarcinoma, Lauren classification: diffuse type. The patient received 2 cycles of SOX chemotherapy. Two years later, cauliflower-like skin nodules, which were surgically excised, appeared on the back. The histopathological examination showed a spindle cell tumor; no specific anti-tumor treatment was administered. Six months later, the skin lesions increased in size and number, spreading to the neck, chest, and abdomen, presenting as erythematous patches with some cauliflower-like elevations. A skin biopsy of a 1cm0.5cm0.3cm lesion on the left abdomen was performed, and based on the immunohistochemistry, clinical history, and the possibility of metastatic or infiltrating adenocarcinoma, the gastrointestinal origin was highly suspected. Genetic testing was performed on the gastric recurrence and skin lesions, revealing 103 shared genetic variations, further suggesting the skin metastasis originated from gastric cancer. Subsequently, the patient received 10 cycles of immunotherapy combined with intravenous chemotherapy (200mg Tislelizumab and 100mg albumin-bound paclitaxel). The treatment response was evaluated as partial remission, with significant improvement in the skin lesions compared to before. This case highlights the possibility of tumor metastasis in patients with extensive skin lesions in advanced gastric cancer. Early examination, diagnosis, skin biopsy, immunohistochemistry, and genetic sequencing are recommended.

Dissolving Microneedle-Based Cascade-Activation Nanoplatform for Enhanced Photodynamic Therapy of Skin Cancer.

Purpose: Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O2 consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ). Methods: TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs). Results: Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process. Conclusion: The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.