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European Journal of Cancer (Oxford,... Oct 2023Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO),... (Review)
Review
Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.
Topics: Aged; Humans; Hedgehog Proteins; Consensus; Carcinoma, Basal Cell; Immunotherapy; Skin Neoplasms
PubMed: 37604067
DOI: 10.1016/j.ejca.2023.113254 -
Nature Aug 2023Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy. Although great progress has been...
Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFβ1 administration-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.
Topics: Animals; Humans; Mice; A549 Cells; Carcinoma, Squamous Cell; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Netrin Receptors; Netrin-1; RNA, Small Interfering; Disease Models, Animal; Skin Neoplasms; Antibodies, Monoclonal; Neoplasm Metastasis; Single-Cell Gene Expression Analysis; RNA-Seq; Epithelial Cell Adhesion Molecule; Xenograft Model Antitumor Assays; Transforming Growth Factor beta1
PubMed: 37532929
DOI: 10.1038/s41586-023-06372-2 -
Biomolecules Jul 2023Non-melanoma skin cancers (NMSCs), which include basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK), are the most common cancer... (Review)
Review
Non-melanoma skin cancers (NMSCs), which include basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK), are the most common cancer diseases in the Caucasian race. If diagnosed late and improperly treated, BCC and SCC can become locally advanced and metastasize. Malignant melanoma (MM) is less frequent but more lethal than NMSC. Given the individual and social burdens of skin cancers, performing an adequate prevention is needed. Ultraviolet (UV) ray exposure is one of the main risk factors for skin cancer. Thus, the first-choice prevention strategy is represented by photoprotection that can be both topical and systemic. The latter consists of the oral administration of molecules which protect human skin against the damaging effects of UV rays, acting through antioxidant, anti-inflammatory, or immunomodulator mechanisms. Although several compounds are commonly used for photoprotection, only a few molecules have demonstrated their effectiveness in clinical trials and have been included in international guidelines for NMSC prevention (i.e., nicotinamide and retinoids). Moreover, none of them have been demonstrated as able to prevent MM. Clinical and preclinical data regarding the most common compounds used for systemic photoprotection are reported in this review, with a focus on the main mechanisms involved in their photoprotective properties.
Topics: Humans; Skin Neoplasms; Melanoma; Carcinoma, Basal Cell; Keratosis, Actinic; Carcinoma, Squamous Cell; Syndrome; Melanoma, Cutaneous Malignant
PubMed: 37509103
DOI: 10.3390/biom13071067 -
Journal of Clinical Oncology : Official... Sep 2023Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.
PATIENTS AND METHODS
In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.
RESULTS
The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).
CONCLUSION
EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.
Topics: Humans; Cisplatin; Antibodies, Monoclonal, Humanized; Carcinoma, Transitional Cell
PubMed: 37369081
DOI: 10.1200/JCO.22.02887 -
Nature Nov 2023The skin epidermis is constantly renewed throughout life. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour...
The skin epidermis is constantly renewed throughout life. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2-a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma-affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.
Topics: Animals; Mice; Cell Transformation, Neoplastic; Collagen; Epidermis; Extracellular Matrix; Skin Neoplasms; Tumor Microenvironment; Carcinoma, Basal Cell; Ear; Collagenases; Aging; Ultraviolet Rays; Mutant Proteins
PubMed: 37968399
DOI: 10.1038/s41586-023-06740-y -
Nature Medicine Aug 2023We investigated whether human preferences hold the potential to improve diagnostic artificial intelligence (AI)-based decision support using skin cancer diagnosis as a...
We investigated whether human preferences hold the potential to improve diagnostic artificial intelligence (AI)-based decision support using skin cancer diagnosis as a use case. We utilized nonuniform rewards and penalties based on expert-generated tables, balancing the benefits and harms of various diagnostic errors, which were applied using reinforcement learning. Compared with supervised learning, the reinforcement learning model improved the sensitivity for melanoma from 61.4% to 79.5% (95% confidence interval (CI): 73.5-85.6%) and for basal cell carcinoma from 79.4% to 87.1% (95% CI: 80.3-93.9%). AI overconfidence was also reduced while simultaneously maintaining accuracy. Reinforcement learning increased the rate of correct diagnoses made by dermatologists by 12.0% (95% CI: 8.8-15.1%) and improved the rate of optimal management decisions from 57.4% to 65.3% (95% CI: 61.7-68.9%). We further demonstrated that the reward-adjusted reinforcement learning model and a threshold-based model outperformed naïve supervised learning in various clinical scenarios. Our findings suggest the potential for incorporating human preferences into image-based diagnostic algorithms.
Topics: Humans; Artificial Intelligence; Algorithms; Skin Neoplasms; Melanoma; Carcinoma, Basal Cell
PubMed: 37501017
DOI: 10.1038/s41591-023-02475-5 -
Cell Reports Nov 2023Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1,...
Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Immune Evasion; Cell Line, Tumor; Adenocarcinoma of Lung; Lung Neoplasms; Mutation; Immunotherapy; Tumor Microenvironment
PubMed: 37889752
DOI: 10.1016/j.celrep.2023.113295 -
Nature Communications Sep 2023Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis...
Cutaneous squamous cell carcinoma (cSCC) is a serious public health problem due to its high incidence and metastatic potential. It may progress from actinic keratosis (AK), a precancerous lesion, or the in situ carcinoma, Bowen's disease (BD). During this progression, malignant keratinocytes activate dermal fibroblasts into tumor promoting cancer-associated fibroblasts (CAFs), whose origin and emergence remain largely unknown. Here, we generate and analyze >115,000 single-cell transcriptomes from healthy skin, BD and cSCC of male donors. Our results reveal immunoregulatory and matrix-remodeling CAF subtypes that may derive from pro-inflammatory and mesenchymal fibroblasts, respectively. These CAF subtypes are largely absent in AK and interact with different cell types to establish a pro-tumorigenic microenvironment. These findings are cSCC-specific and could not be recapitulated in basal cell carcinomas. Our study provides important insights into the potential origin and functionalities of dermal CAFs that will be highly beneficial for the specific targeting of the cSCC microenvironment.
Topics: Male; Humans; Carcinoma, Squamous Cell; Cancer-Associated Fibroblasts; Skin Neoplasms; Carcinoma, Basal Cell; Carcinoma in Situ; Keratosis, Actinic; Tumor Microenvironment
PubMed: 37669956
DOI: 10.1038/s41467-023-41141-9 -
Anais Brasileiros de Dermatologia 2024The vast majority of publications in dermatology refer to lightly pigmented skin, with few addressing the peculiarities of black skin. In addition there is no consensus... (Review)
Review
The vast majority of publications in dermatology refer to lightly pigmented skin, with few addressing the peculiarities of black skin. In addition there is no consensus on what it means to be black in different regions of the world. The lack of knowledge on the subject makes it difficult to recognize and manage dermatoses in this type of skin. This article aims to review the literature on intrinsic characteristics, as well as epidemiological and clinical aspects of the cutaneous manifestations of different dermatoses in black skin. It was found that there are sometimes striking differences, in the structural, biological, and functional aspects when comparing lightly pigmented and black skin. There are also physiological changes that need to be recognized to avoid unnecessary interventions. Some dermatoses have a higher incidence in black skin, such as acne, eczema, dyschromia and dermatophytosis. On the other hand, several dermatoses are more specific to black skin, such as pseudofolliculitis barbae, keloid, dermatosis papulosa nigra, ulcers caused by sickle-cell anemia, dactylolysis spontanea, confluent and reticulated papillomatosis of Gougerot and Carteaud, and some diseases of the hair and scalp (including fragile and brittle hair, traction alopecia, folliculitis keloidalis nuchae, folliculitis dissecans and central centrifugal cicatricial alopecia). A spectrum of peculiar aspects of specific dermatoses, including sarcoidosis, lichen planus (with emphasis on the pigmentosus variant), psoriasis, lupus erythematosus, vitiligo, syphilis, pityriasis versicolor, and neoplasms are highlighted. In the latter, characteristics of basal cell carcinoma, squamous cell carcinoma, and melanoma are compared, in addition to highlighting unusual aspects of primary cutaneous T-cell lymphoma, endemic Kaposi sarcoma, and dermatofibrosarcoma protuberans.
Topics: Humans; Skin Diseases; Skin Pigmentation; Skin; Black People
PubMed: 38310012
DOI: 10.1016/j.abd.2023.10.001 -
Journal For Immunotherapy of Cancer Dec 2023Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological...
BACKGROUND
Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. TLS typically comprise B-cell follicles containing and are encompassed by T- cell zones and dendritic cells. The prognostic and predictive value of TLS in the tumor microenvironment (TME) as potential mediators of antitumor immunity have gained interest. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated.
METHODS
Immunohistochemistry and multispectral fluorescence were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity in 395 patients with ccRCC from two independent cohorts was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration.
RESULTS
Infiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (p=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (p=0.004). In the main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved progression-free survival (PFS, p<0.001) and overall survival (OS, p=0.002). Conversely, the presence of tumor-distal TLS was associated with poor PFS (p=0.02) and OS (p=0.021). These findings were further validated in an external validation set of 105 patients with ccRCC. Notably, the presence of mature TLS (namely secondary follicle-like TLS, with CD23 germinal center) was significantly associated with better clinical outcomes in patients with ccRCC. Furthermore, novel nomograms incorporating the presence of tumor-proximal TLS demonstrated remarkable predictability for the 8-year outcomes of resected ccRCC (area under the curve >0.80). Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher programmed death-ligand 1 tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME.
CONCLUSION
This study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations. Furthermore, our findings corroborate previous research demonstrating that tumor-proximal TLS were associated with favorable clinical outcomes.
Topics: Humans; Carcinoma, Renal Cell; Tertiary Lymphoid Structures; China; Prognosis; Kidney Neoplasms; Tumor Microenvironment
PubMed: 38040418
DOI: 10.1136/jitc-2023-006667