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Singh A, Singh C, Dhaliwal A, Singh N, Kumar V, Sohal A, Schneider J. Incidence, screening, and management of de novo malignancies in liver transplant patients: A review. World J Transplant 2025; 15:101046. [DOI: 10.5500/wjt.v15.i3.101046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 04/18/2025] Open
Abstract
Liver transplantation (LT) is the definitive treatment for end-stage liver disease, acute liver failure, and liver cancer. Although advancements in surgical techniques, postoperative care, and immunosuppressive therapies have significantly improved outcomes, the long-term use of immunosuppression has increased the risk of complications, including infections, cardiovascular disease, and cancer. Among these, de novo malignancies (DNMs) are a major concern, accounting for 20%-25% of deaths in LT recipients surviving beyond the early post-transplant period. Non-melanoma skin cancers, particularly squamous cell carcinoma are the most prevalent DNMs. Other significant malignancies include Kaposi's sarcoma, post-transplant lymphoproliferative disorders, and various solid organ cancers, including head and neck cancers. Compared to the general population, LT patients face a twofold increase in solid organ malignancies and a 30-fold increase in lymphoproliferative disorders. Risk factors for DNM include chronic immunosuppression, alcohol or tobacco use, viral infections, and underlying liver disease. Emerging evidence emphasizes the importance of tailored cancer screening and prevention strategies, including regular dermatological examinations, targeted screenings for high-risk cancers, and patient education on lifestyle modifications. Early detection through enhanced surveillance protocols has been shown to improve outcomes. Management of DNMs involves a combination of standard oncological therapies and adjustments to immunosuppressive regimens, with promising results from the use of mTOR inhibitors in select patients. The review highlights the critical need for ongoing research to refine risk stratification, optimize screening protocols, and improve treatment approaches to mitigate the burden of DNMs in LT recipients. By implementing personalized preventive and therapeutic strategies, we can enhance long-term outcomes and quality of life for this vulnerable population.
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Affiliation(s)
- Anmol Singh
- Department of Medicine, Tristar Centennial Medical Center, Nashville, TN 37203, United States
| | - Carol Singh
- Department of Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Armaan Dhaliwal
- Division of Hematology and Oncology, Lehigh Valley Health Network, Allentown, PA 18103, United States
| | - Navdeep Singh
- Department of Medicine, Government Medical College, Amritsar 143001, Punjab, India
| | - Vikash Kumar
- Division of Gastroenterology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Aalam Sohal
- Division of Gastroenterology, Creighton University School of Medicine, Phoenix, AZ 85012, United States
| | - Jonathan Schneider
- Division of Gastroenterology, Tristar Centennial Medical Center, Nashville, TN 37203, United States
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Quaresma MV, Azevedo LS, David-Neto E, Sotto MN. Histopathological analysis of the skin of renal transplant recipients submitted to three different immunosuppression regimens. An Bras Dermatol 2025:S0365-0596(25)00031-5. [PMID: 40199660 DOI: 10.1016/j.abd.2024.07.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/21/2024] [Accepted: 07/28/2024] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Renal transplant recipients (RTRs) use a combination of immunosuppressive agents: a corticosteroid; a calcineurin inhibitor (cyclosporine or tacrolimus) and an antimetabolic agent (azathioprine [AZA] or a mycophenolic acid precursor [MPA] ‒ Mycophenolate mofetil or sodium) or an mTOR inhibitor (mTORi) ‒ sirolimus or everolimus. These treatments increase the incidence of various neoplasms, especially non-melanoma skin cancers (NMSCs). OBJECTIVES To evaluate the histopathological alterations in the skin of the RTRs under three different immunosuppressive regimens: one mTORi (sirolimus or everolimus); or one antimetabolic agent (MPA or AZA), comparing them by groups and with healthy controls. METHODS This was an observational, cross-sectional, comparative study of 30 patients selected from the Renal Transplant Service and divided into three groups: mTORi (n = 10), MPA (n = 10), and AZA (n = 10). The control group consisted of 10 immunocompetent non-transplanted volunteers. All RTRs were using tacrolimus and prednisone. Each participant underwent two biopsies of intact skin: one in a sun-protected and another in a sun-exposed area. The specimens were analyzed without previous information on which group they belonged to. RESULTS The most significant histopathological change was thinning of the epidermis in the mTORi group, both in photoexposed and photoprotected skin. STUDY LIMITATIONS The study was conducted on a limited number of patients, which may influence the representativeness of the results. CONCLUSIONS Only RTRs treated with mTORi presented interruption of epidermal proliferation. These findings help to understand the influence of these different types of immunosuppressive regimens and their subsequent potential effects on carcinogenesis.
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Affiliation(s)
- Maria Victória Quaresma
- Division of Dermatology, Hospital das Clínicas, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Luiz Sergio Azevedo
- Renal Transplant Service, Hospital das Clínicas, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Elias David-Neto
- Renal Transplant Service, Hospital das Clínicas, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Mírian Nacagami Sotto
- Division of Dermatology, Hospital das Clínicas, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil; Department of Pathology, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, Brazil.
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Handa S, Mehta H, Bishnoi A, Raj D, De D. Efficacy and safety of azathioprine versus mycophenolate mofetil in chronic actinic dermatitis in skin of color: results of a randomized controlled trial. Int J Dermatol 2025; 64:333-340. [PMID: 39092474 DOI: 10.1111/ijd.17412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 08/04/2024]
Abstract
INTRODUCTION Chronic actinic dermatitis (CAD) is an immunologically mediated photodermatosis that has been effectively treated with azathioprine and mycophenolate mofetil (MMF) in uncontrolled studies. We conducted a prospective randomized controlled trial to compare the efficacy and safety of azathioprine and MMF in CAD treatment, aiming to address existing evidence gaps. MATERIALS AND METHODS Consecutive CAD patients were randomized into two groups: azathioprine (Group A) or MMF (Group B) for 12 weeks. Primary outcomes included Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) at baseline and Week 12. Secondary outcomes included various clinicodemographic factors predictive of treatment response, defined at least a 75% reduction in EASI score (EASI75) by Week 12. RESULTS The median (IQR) percentage reduction in EASI at 12 weeks was higher in Group B than in Group A [78.3% (75.0-83.30%) vs. 68.3% (31.2-80.10%), P = 0.034]. Baseline DLQI scores indicated a moderate impact on quality of life, with significant reductions by Week 12 in both groups and no intergroup differences at baseline (P = 0.291) or Week 12 (P = 0.599). Overall, 23 patients were classified as non-responders, with more extended illness duration (P = 0.026) and outdoor occupations (P = 0.042) associated with poorer responses. Adverse effects were consistent with known profiles, with one patient discontinuing azathioprine due to hypersensitivity. CONCLUSION Our study highlights the efficacy and safety of azathioprine and MMF in CAD treatment, with MMF showing superior outcomes. However, further research is warranted to explore emerging therapies and prognostic factors in CAD management.
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Affiliation(s)
- Sanjeev Handa
- Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Hitaishi Mehta
- Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anuradha Bishnoi
- Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Dinesh Raj
- Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Dipankar De
- Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Kreuz M, Cardoso JCO, Sobreira LER, Cavalcanti Souza ME, Campos LE, Kelly FA, de Moraes FCA. Azathioprine and risk of non-melanoma skin cancers in organ transplant recipients: a systematic review and update meta-analysis. Clin Transl Oncol 2025:10.1007/s12094-024-03839-0. [PMID: 39825996 DOI: 10.1007/s12094-024-03839-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/24/2024] [Indexed: 01/20/2025]
Abstract
BACKGROUND Immunosuppression might increase the risk of skin cancer in organ transplant recipients (OTRs), with azathioprine (AZA), exerting a fundamental role in the carcinogenesis of those tumors. This systematic review and meta-analysis aims to address the risk of developing malignant skin neoplasms in OTRs undergoing immunosuppression with AZA. METHODS PubMed, Cochrane and Embase were searched for studies with OTRs who have a treatment regimen involving Azathioprine therapy after transplantation and that analyzed the emergence of skin neoplasia. We performed the meta-analysis using RStudio v4.4.2 software. RESULTS A total of 17 studies comprising a total of 12,708 patients were included, of whom 3567 (28,06%) had a treatment regimen involving AZA therapy after transplantation. The majority of individuals were male 7298 (56,52%) and the median age of patients ranged from 41.5 to 63.2 years. The overall summary estimate showed a significantly increased risk of all types of skin cancer in relation to AZA exposure (OR 1.55; 95% CI 1.07-2.25; p = 0.018; I2 = 82%). These results show that the overall result is statistically significant, which means that the observed effect is unlikely to be caused by chance. CONCLUSION This study highlights the increased risk of developing skin cancer, particularly squamous cell carcinoma (SCC), in OTRs receiving immunosuppressive therapy with AZA, which allows for rigorous screening and appropriate preventive and therapeutic interventions.
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Affiliation(s)
- Michele Kreuz
- Lutheran University of Brazil, 133 Montenegro Street, ap 1201, Novo Hamburgo, Canoas, Rio Grande do Sul, 92425-900, Brazil.
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil.
| | - Jorge Cavalcanti Orestes Cardoso
- University of Pernambuco, Recife, Pernambuco, 50100-130, Brazil
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil
| | - Luis Eduardo Rodrigues Sobreira
- Federal University of Pará, Altamira, Pará, 68371-040, Brazil
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil
| | - Maria Eduarda Cavalcanti Souza
- University of Pernambuco, Recife, Pernambuco, 50100-130, Brazil
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil
| | - Lara Eduardo Campos
- School of Medicine and Surgery of the Federal University of the State of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, 20271-062, Brazil
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil
| | - Francinny Alves Kelly
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil
- Dante Pazzanese Institute of Cardiology, São Paulo, São Paulo, 04012-909, Brazil
| | - Francisco Cezar Aquino de Moraes
- Anhembi University Morumbi, São José dos Campos, São Paulo, 12235-181, Brazil
- Federal University of Pará, Belém, 66073-005, Brazil
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Zhao Y, Shao Y, Zhou J, Pei J, Chong J, Lu C, Chen Y. Erythema nodosum, malignant melanoma and non-melanoma skin cancer in relation to inflammatory bowel disease: a Mendelian randomization study. Sci Rep 2025; 15:1369. [PMID: 39779820 PMCID: PMC11711612 DOI: 10.1038/s41598-025-85249-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/01/2025] [Indexed: 01/11/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a multisystem condition that could affect the cutaneous systems, namely cutaneous extraintestinal manifestations (EIMs). It has been suggested that IBD is associated with erythema nodosum (EN), malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, the potential causal relationship between IBD and the mentioned above cutaneous EIMs is still unclear. This study aims to determine the effect of IBD on EN, MM and NMSC within a Mendelian randomization (MR) design. Summary-level data for IBD, EN, MM, NMSC were obtained from large-scale genome-wide association studies. We utilized five different methods, including the inverse variance weighted model (IVW), MR Egger, Weighted median, Simple mode, Weighted mode in the MR analysis, then the Cochran's Q test, the MR-Egger pleiotropy test, the MR-PRESSO global pleiotropy test and leave-one-out sensitivity test were used to evaluate the heterogeneity and pleiotropy of identified IVs. To further ensure the validity of our findings, we evaluated the strength of the instrumental variables using the F-statistic and estimated the statistical power of our study. Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. MR analysis suggested that genetically determined IBD had a detrimental causal effect on NMSC (IVW: odds ratio [OR] = 1.002037, 95% confidence interval [CI] = 1.0001150-1.003962, P = 0.03776677), but not on EN (IVW: [OR] = 1.0937191, 95% [CI] = 0.9685831-1.235022, P = 0.1484349) and MM (IVW: [OR] = 0.9998064, 95% [CI] = 0.9994885-1.000124, P = 0.2326482). Besides, a positive causal effect of IBD on NMSC was verified in an independent validation dataset (IVW: [OR] = 1.002651, 95% [CI] = 1.0006524-1.004654, P = 0.009307506). The present study corroborated the causal relationship between IBD and NMSC. In contrast, our results showed no evidence of a causal association of IBD on EN and MM. These findings provide new insights into increasing attention to patients with IBD to prevent concurrent NMSC.
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Affiliation(s)
- Yang Zhao
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Yifan Shao
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Jing Zhou
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Jianing Pei
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Jinchen Chong
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Changye Lu
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China
| | - Yugen Chen
- Department of Colorectal Surgery, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China.
- Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China.
- Jiangsu Collaborative Innovation Center of Chinese Medicine in Prevention and Treatment of Tumor, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, PR China.
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Hofbauer GFL. Photocarcinogenesis of Voriconazole Unraveled: A Likeness to Xeroderma Pigmentosum Is Key. J Invest Dermatol 2024; 144:2339-2340. [PMID: 37702640 DOI: 10.1016/j.jid.2023.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 09/14/2023]
Affiliation(s)
- Günther F L Hofbauer
- Medical Faculty, University of Zürich, Zürich, Switzerland; Dermatology Department, University Hospital of Zürich, Zürich, Switzerland.
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Luo L, Tang X, Hu X, Li L, Xu J, Zhong X. The causal effects of inflammatory bowel disease on skin carcinoma: A two-sample Mendelian randomization study. Medicine (Baltimore) 2024; 103:e39997. [PMID: 39465853 PMCID: PMC11479435 DOI: 10.1097/md.0000000000039997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 09/19/2024] [Indexed: 10/29/2024] Open
Abstract
Observational studies have indicated that inflammatory bowel disease (IBD) patients have higher incidence of skin carcinoma (SC), including melanoma skin carcinoma (MSC) and nonmelanoma skin carcinoma (NMSC) than healthy people. However, whether there is a causal relationship between the 2 is unclear. The purpose of this study was to evaluate the causality of IBD on SC using the Mendelian randomization (MR) analysis. We performed a two-sample MR analysis using publicly available genome-wide association study data. Eligible instrumental variables were selected based on the 3 core assumptions of MR analysis. The inverse-variance weighted (IVW) approach served as the primary analytical method. Supplementary analyses were conducted using MR-Egger regression, the weighted median, the weighted mode, and MR pleiotropy residual sum and outlier methods. Genetically predicted IBD (IVW odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.02-1.13, P = .011) and ulcerative colitis (UC; IVW OR = 1.09, 95% CI: 1.03-1.16, P = .003) were associated with an increased risk of MSC. Results of complementary methods were consistent with those of the IVW method with the exception of the weighted mode. In addition, Crohn disease (CD; IVW OR = 1.04, 95% CI: 0.99-1.08, P = .128) did not have a causal effect on MSC. Moreover, IBD (IVW OR = 1.03, 95% CI: 1.00-1.07, P = .034) and CD (IVW OR = 1.03, 95% CI: 1.00-1.06, P = .045) were associated with an increased risk of NMSC. However, UC (IVW OR = 1.00, 95% CI: 0.97-1.04, P = .803) was not significantly associated with an increased risk of NMSC. Our study revealed genetically predicted associations between IBD and the risks of MSC and NMSC in European populations. Furthermore, UC was associated with an increased risk of MSC, while CD was associated with a higher risk of NMSC. However, the potential influence of immunosuppressive agents or biologics cannot be excluded.
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Affiliation(s)
- Lian Luo
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Xiaowei Tang
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Xinyue Hu
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Limin Li
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Jia Xu
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
| | - Xiaolin Zhong
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou City, Sichuan Province, China
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Maier JA, Castiglioni S, Petrelli A, Cannatelli R, Ferretti F, Pellegrino G, Sarzi Puttini P, Fiorina P, Ardizzone S. Immune-Mediated Inflammatory Diseases and Cancer - a dangerous liaison. Front Immunol 2024; 15:1436581. [PMID: 39359726 PMCID: PMC11445042 DOI: 10.3389/fimmu.2024.1436581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/29/2024] [Indexed: 10/04/2024] Open
Abstract
Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.
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Affiliation(s)
- Jeanette A Maier
- Department of Biomedical and Clinical Sciences, Università di Milano, Milano, Italy
| | - Sara Castiglioni
- Department of Biomedical and Clinical Sciences, Università di Milano, Milano, Italy
| | - Alessandra Petrelli
- Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy
| | | | | | | | - Piercarlo Sarzi Puttini
- Department of Biomedical and Clinical Sciences, Università di Milano, Milano, Italy
- IRCCS Ospedale Galeazzi-Sant'Ambrogio, Milano, Italy
| | - Paolo Fiorina
- Department of Biomedical and Clinical Sciences, Università di Milano, Milano, Italy
| | - Sandro Ardizzone
- Gastroenterology Unit, ASST Fatebenefratelli-Sacco, Milano, Italy
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Li L, Teng J, Kou N, Yue Y, Wang H. ANCA-associated vasculitis and lung cancer: an immunological perspective. Clin Exp Med 2024; 24:208. [PMID: 39230721 PMCID: PMC11374858 DOI: 10.1007/s10238-024-01475-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 08/20/2024] [Indexed: 09/05/2024]
Abstract
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe autoimmune disease that often involves the upper and lower respiratory tracts. In recent years, numerous studies have found a significant increase in the incidence of cancer among AAV patients, but the association between lung cancer and AAV remains inconclusive, with relatively low clinical attention. This review summarizes the current literature on the risk of lung cancer in patients with ANCA-associated vasculitis (AAV), detailing the potential mechanisms by which AAV may contribute to lung cancer, and further elucidates the inherent carcinogenic risks of immunosuppressants.There is a correlation between AAV and lung cancer, which is related to T cell senescence and damage, as well as the abnormal expression of cytokines such as IL-6 and IL-10. In AAV patients, the use of cyclophosphamide and azathioprine (AZA) alone has a clear carcinogenic risk, with frequent use of CYC potentially posing a high risk for lung cancer. Although TNF inhibitors (TNFi) combined with CYC have carcinogenic risks, there is insufficient evidence to link them directly to an increased risk of lung cancer. For patients at high risk for lung cancer, the judicious use of immunosuppressants, timely computed tomography (CT), and lung cancer screening can reduce the risk of lung cancer in AAV patients.
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Affiliation(s)
- Longzhao Li
- Respiratory Disease Center, Dongzhimen Hospital, Beijing University of Chinese Medicine, No.116 Cuiping West Road, Tongzhou District, 101121, Beijing, China
- Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Jun Teng
- Respiratory Disease Center, Dongzhimen Hospital, Beijing University of Chinese Medicine, No.116 Cuiping West Road, Tongzhou District, 101121, Beijing, China
- Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Na Kou
- Respiratory Disease Center, Dongzhimen Hospital, Beijing University of Chinese Medicine, No.116 Cuiping West Road, Tongzhou District, 101121, Beijing, China
| | - Yuan Yue
- Respiratory Disease Center, Dongzhimen Hospital, Beijing University of Chinese Medicine, No.116 Cuiping West Road, Tongzhou District, 101121, Beijing, China
| | - HongWu Wang
- Respiratory Disease Center, Dongzhimen Hospital, Beijing University of Chinese Medicine, No.116 Cuiping West Road, Tongzhou District, 101121, Beijing, China.
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Khaddour K, Murakami N, Ruiz ES, Silk AW. Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression. Cancers (Basel) 2024; 16:3083. [PMID: 39272941 PMCID: PMC11394667 DOI: 10.3390/cancers16173083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/26/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.
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Affiliation(s)
- Karam Khaddour
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - Naoka Murakami
- Harvard Medical School, Boston, MA 02115, USA
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Emily S Ruiz
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Ann W Silk
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA 02115, USA
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11
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Chu CY, Chan Y, Wananukul S, Cheng H, Chandran NS, Bhat R, Son SW, Liao HF, Gardiner S, Ng QQ, Yeo SH, Chen SB, Kataoka Y. Management of Moderate-to-Severe Atopic Dermatitis in Adults: A Cross-Sectional Survey of Dermatologists Within the Asia-Pacific Region. Dermatol Ther (Heidelb) 2024; 14:2559-2576. [PMID: 39162764 PMCID: PMC11393370 DOI: 10.1007/s13555-024-01246-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/25/2024] [Indexed: 08/21/2024] Open
Abstract
INTRODUCTION Limited evidence is available on real-world management of atopic dermatitis (AD) among Asian adults. This cross-sectional study aimed to assess current approaches in AD diagnosis and management in Asia. METHODS Practising dermatologists regularly treating patients with moderate-to-severe AD were recruited from eight Asia-Pacific territories, namely Mainland China, Hong Kong, India, Japan, Singapore, South Korea, Taiwan, and Thailand. A survey was administered to eligible dermatologists after screening and taking informed consent. Data from fully completed submissions were analysed using descriptive statistics. The study was reviewed by the institutional review board in each territory. RESULTS Data from 271 dermatologists were included for analysis. About one-third (31.7%) reported that they referred to the Hanifin and Rajka criteria during diagnosis. The majority of dermatologists used clinical impression when assessing AD severity and treatment response. Reduction of eczema and pruritus was the primary treatment objective when managing both acute (98.1%) and chronic (69.1%) AD. More than half of dermatologists preferred adding systemic anti-inflammatory medication for patients who did not respond to maximized topical treatment, while 43.6% would switch to another systemic medication for those failing to respond to maximized systemic treatment. Topical corticosteroids were frequently selected by dermatologists. For systemic therapies, oral corticosteroids were most frequently used, followed by cyclosporin and dupilumab. Narrow-band ultraviolet B was the most common phototherapy reported (84.9%). There was considerable variation in estimated average and maximum durations of therapies used to treat AD. CONCLUSION This study has provided insights on the real-world management of moderate-to-severe AD in the Asia-Pacific region. The diverse approaches in diagnosis and treatment highlight the multifactorial nature of AD, reliance on clinical judgement, and importance of personalized care. To improve outcomes in patients with AD, it will be crucial to develop biomarkers for diagnosis, reduce subjectivity in assessment, as well as promote access to newer and effective therapies.
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Affiliation(s)
- Chia-Yu Chu
- Department of Dermatology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yung Chan
- Apex Dermatology Institute, Hong Kong, China
| | - Siriwan Wananukul
- Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Hao Cheng
- Department of Dermatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nisha Suyien Chandran
- Division of Dermatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Ramesh Bhat
- Father Muller Medical College, Mangalore, India
| | - Sang Wook Son
- Department of Dermatology, Korea University College of Medicine, Seoul, South Korea
| | | | - Sean Gardiner
- Pfizer Singapore, 80 Pasir Panjang Road, #16-81/82 Mapletree Business City II, Singapore, 117372, Singapore.
| | - Qi Qing Ng
- IQVIA Solutions Asia, Real World Solutions, Singapore, Singapore
| | - See-Hwee Yeo
- IQVIA Solutions Asia, Real World Solutions, Singapore, Singapore
| | | | - Yoko Kataoka
- Department of Dermatology, Osaka Habikino Medical Center, Habikino, Japan
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12
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Taylor MM, Nelson KC, Dimitriou F. Skin Cancer Precursors: From Cancer Genomics to Early Diagnosis. Hematol Oncol Clin North Am 2024; 38:851-868. [PMID: 38782646 DOI: 10.1016/j.hoc.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Skin cancers, including melanoma and keratinocyte carcinomas, are responsible for increasing health care burden internationally. Risk stratification and early detection are paramount for prevention and less risky treatment to overall improve patient outcomes and disease morbidity. Here, the authors discuss the key concepts leading to skin cancer initiation and progression. The authors also outline precursor and progression models for melanoma and keratinocyte carcinomas, including discussion of genetic alterations associated with the various stages of progression. Finally, the authors discuss the significance of immunoediting and the drivers behind increased risk of cutaneous malignancy in the state of immune dysregulation.
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Affiliation(s)
- Madison M Taylor
- John P. and Kathrine G. McGovern Medical School, The University of Texas Health Science Center, 6431 Fannin Street, Houston, TX 77030, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1452, Houston, TX 77030, USA
| | - Kelly C Nelson
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1452, Houston, TX 77030, USA.
| | - Florentia Dimitriou
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1484, Houston, TX 77030, USA; Department of Dermatology, University Hospital of Zurich, University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland
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13
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Szeimies RM, Ulrich C, Ferrándiz-Pulido C, Hofbauer GFL, Lear JT, Lebbé C, Piaserico S, Hædersdal M. The "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) Project: An Expert Panel Opinion. Dermatol Ther (Heidelb) 2024; 14:1739-1753. [PMID: 38902589 PMCID: PMC11264500 DOI: 10.1007/s13555-024-01215-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/11/2024] [Indexed: 06/22/2024] Open
Abstract
Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.
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Affiliation(s)
- Rolf-Markus Szeimies
- Department of Dermatology & Allergology, Klinikum Vest GmbH Academic Teaching Hospital, Recklinghausen, Germany.
| | - Claas Ulrich
- GmbH & Department of Dermatology, Collegium Medicum, Charité Universitätsmedizin, Berlin, Germany
| | - Carla Ferrándiz-Pulido
- Department of Dermatology, University Hospital Vall d'Hebron, Barcelona, Spain
- Factultad de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Gunther F L Hofbauer
- Universität Zürich, Zurich, Switzerland
- Dermatologische Klinik, Universitätsspital Zürich, Zurich, Switzerland
| | - John Thomas Lear
- Department of Dermatology, Mid Cheshire Hospitals NHS Foundation Trust, Crewe, UK
- Manchester Academic Health Science Centre, Manchester, UK
| | - Celeste Lebbé
- Dermato-Oncology and CIC AP-HP Hôpital Saint Louis, INSERM U976, Université Paris Cite, Paris, France
| | - Stefano Piaserico
- Dermatology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Merete Hædersdal
- Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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14
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Moon W, Park JJ. [Risks of Cancer Associated with Therapeutic Drugs for Inflammatory Bowel Disease]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 83:233-242. [PMID: 38918036 DOI: 10.4166/kjg.2024.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 06/27/2024]
Abstract
Crohn's disease and ulcerative colitis are lifelong chronic inflammatory conditions, with many patients requiring ongoing immunomodulatory drug therapy for maintenance treatment. Recent therapeutic goals in inflammatory bowel disease (IBD) are not only aimed at symptomatic remission but also at achieving mucosal healing to improve the natural course of the disease. In this context, therapeutic approaches are being applied in clinical settings that involve early and appropriate use of drugs, such as immunomodulators or biologics, that have the potential to induce healing of the inflamed intestine before irreversible intestinal damage occurs. All drugs that continuously control intestinal inflammation in IBD can heal the mucosa and potentially reduce the incidence of colitis-associated bowel cancer; however, the continuous use of immunosuppressants can potentially increase the risk of malignancies. The safety issues of the drugs used in clinical practice are partly confirmed during their development processes or shortly after initial marketing, but in other cases, they are estimated through post-marketing case reports or epidemiological studies, sometimes decades after drug approval. This review explores the risks associated with malignancies related to the treatment of IBD, focusing on drugs currently approved in Republic of Korea.
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Affiliation(s)
- Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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15
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Zwald FO, Sargen MR, Austin AA, Hsieh MC, Pawlish K, Li J, Lynch CF, Yu KJ, Engels EA. Outcomes in solid organ transplant recipients with a pretransplant diagnosis of melanoma. Am J Transplant 2024; 24:993-1002. [PMID: 38387619 PMCID: PMC11144558 DOI: 10.1016/j.ajt.2024.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 02/24/2024]
Abstract
Melanoma causes significant morbidity in solid organ transplant recipients (SOTRs). Melanomas diagnosed before transplantation can recur with intensive immunosuppression, but outcomes have not been well studied. We evaluated 901 non-Hispanic White SOTRs with a pretransplant melanoma identified using linked transplant and cancer registry data in the United States. Most pretransplant melanomas were invasive (60.7%), and the median time from diagnosis to transplantation was 5.1 years. After transplantation, 41 SOTRs developed a new invasive melanoma, corresponding to 9-fold increased risk compared with the general population (standardized incidence ratio, 9.2; 95% confidence interval [CI], 6.6-12). Twenty-two SOTRs died from melanoma after transplantation, corresponding to 52-fold increased risk (standardized mortality ratio, 52; 95% CI, 33-79). Risk factors for posttransplant melanoma included age at transplantation (adjusted hazard ratio [HR], 2.86; 95% CI, 1.24-6.60; for age 55+ vs <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR, 2.53; 95% CI, 1.08-5.90). Melanoma mortality was strongly elevated after a posttransplant melanoma diagnosis (HR, 35.6; 95% CI, 14.0-90.4; adjusted for cyclosporine/azathioprine maintenance therapy and calendar year of transplantation). In conclusion, SOTRs with a pretransplant melanoma are at risk of adverse melanoma-related outcomes after transplantation. These findings support thorough dermatologic evaluation prior to transplantation and frequent posttransplant surveillance.
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Affiliation(s)
- Fiona O Zwald
- Department of Dermatology, University of Colorado, Aurora, Colorado, USA
| | - Michael R Sargen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | | | - Mei-Chin Hsieh
- Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Karen Pawlish
- New Jersey Department of Health, New Jersey State Cancer Registry, Trenton, New Jersey, USA
| | - Jie Li
- New Jersey Department of Health, New Jersey State Cancer Registry, Trenton, New Jersey, USA
| | - Charles F Lynch
- Department of Epidemiology, The University of Iowa, Iowa City, Iowa, USA
| | - Kelly J Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
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16
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Lozano-Rosas R, Ramos-Garcia R, Salazar-Morales MF, Robles-Águila MJ, Spezzia-Mazzocco T. Evaluation of antifungal activity of visible light-activated doped TiO 2 nanoparticles. Photochem Photobiol Sci 2024; 23:823-837. [PMID: 38568410 DOI: 10.1007/s43630-024-00557-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 03/04/2024] [Indexed: 06/11/2024]
Abstract
Titanium dioxide (TiO2) is a well-known material for its biomedical applications, among which its implementation as a photosensitizer in photodynamic therapy has attracted considerable interest due to its photocatalytic properties, biocompatibility, high chemical stability, and low toxicity. However, the photoactivation of TiO2 requires ultraviolet light, which may lead to cell mutation and consequently cancer. To address these challenges, recent research has focused on the incorporation of metal dopants into the TiO2 lattice to shift the band gap to lower energies by introducing allowed energy states within the band gap, thus ensuring the harnessing of visible light. This study presents the synthesis, characterization, and application of TiO2 nanoparticles (NPs) in their undoped, doped, and co-doped forms for antimicrobial photodynamic therapy (APDT) against Candida albicans. Blue light with a wavelength of 450 nm was used, with doses ranging from 20 to 60 J/cm2 and an NP concentration of 500 µg/ml. It was observed that doping TiO2 with Cu, Fe, Ag ions, and co-doping Cu:Fe into the TiO2 nanostructure enhanced the visible light photoactivity of TiO2 NPs. Experimental studies were done to investigate the effects of different ions doped into the TiO2 crystal lattice on their structural, optical, morphological, and chemical composition for APDT applications. In particular, Ag-doped TiO2 emerged as the best candidate, achieving 90-100% eradication of C. albicans.
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Affiliation(s)
- Ricardo Lozano-Rosas
- Instituto Nacional de Astrofísica, Óptica y Electrónica, Departamento de Óptica, Luis Enrique Erro #1 Sta María Tonantzintla, 72840, Puebla, Mexico
| | - Rubén Ramos-Garcia
- Instituto Nacional de Astrofísica, Óptica y Electrónica, Departamento de Óptica, Luis Enrique Erro #1 Sta María Tonantzintla, 72840, Puebla, Mexico
| | - Mayra F Salazar-Morales
- Instituto Nacional de Astrofísica, Óptica y Electrónica, Departamento de Óptica, Luis Enrique Erro #1 Sta María Tonantzintla, 72840, Puebla, Mexico
| | - María Josefina Robles-Águila
- Centro de Investigación en Dispositivos Semiconductores, Benemérita Universidad Autónoma de Puebla, Instituto de Ciencias, Edificio 105 C, Boulevard 14 Sur y Av. San Claudio, Col. San Manuel, C. P. 72570, Puebla, Puebla, Mexico
| | - Teresita Spezzia-Mazzocco
- Instituto Nacional de Astrofísica, Óptica y Electrónica, Departamento de Óptica, Luis Enrique Erro #1 Sta María Tonantzintla, 72840, Puebla, Mexico.
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17
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Liu D, Youssef MM, Grace JA, Sinclair M. Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care. World J Hepatol 2024; 16:650-660. [PMID: 38689747 PMCID: PMC11056899 DOI: 10.4254/wjh.v16.i4.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/30/2024] [Accepted: 03/19/2024] [Indexed: 04/24/2024] Open
Abstract
BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients. AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation. METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria. RESULTS A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients. CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.
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Affiliation(s)
- Dorothy Liu
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Victorian Liver Transplant Unit, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia.
| | - Mark M Youssef
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
| | - Josephine A Grace
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
| | - Marie Sinclair
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Victorian Liver Transplant Unit, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
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18
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Gierke AM, Hessling M. Photoinactivation by UVA radiation and visible light of Candida auris compared to other fungi. Photochem Photobiol Sci 2024; 23:681-692. [PMID: 38446403 DOI: 10.1007/s43630-024-00543-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 01/22/2024] [Indexed: 03/07/2024]
Abstract
In addition to the rising number of patients affected by viruses and bacteria, the number of fungal infections has also been rising over the years. Due to the increase in resistance to various antimycotics, investigations into further disinfection options are important. In this study, two yeasts (Candida auris and Saccharomyces cerevisiae) and a mold (Cladosporium cladosporioides) were irradiated at 365, 400, and 450 nm individually. The resulting log 1 reduction doses were determined and compared with other studies. Furthermore, fluorescence measurements of C. auris were performed to detect possible involved photosensitizers. A roughly exponential photoinactivation was observed for all three fungi and all irradiation wavelengths with higher D90 doses for longer wavelengths. The determined log 1 reduction doses of C. auris and S. cerevisiae converged with increasing wavelength. However, S. cerevisiae was more photosensitive than C. auris for all irradiation wavelengths and is therefore not a suitable C. auris surrogate for photoinactivation experiments. For the mold C. cladosporioides, much higher D90 doses were determined than for both yeasts. Concerning potential photosensitizers, flavins and various porphyrins were detected by fluorescence measurements. By excitation at 365 nm, another, so far unreported fluorophore and potential photosensitizer was also observed. Based on its fluorescence spectrum, we assume it to be thiamine.Graphic abstract.
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Affiliation(s)
- Anna-Maria Gierke
- Institute of Medical Engineering and Mechatronics, Ulm University of Applied Sciences, Albert-Einstein-Allee 55, 89081, Ulm, Germany.
| | - Martin Hessling
- Institute of Medical Engineering and Mechatronics, Ulm University of Applied Sciences, Albert-Einstein-Allee 55, 89081, Ulm, Germany
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Wunderlich K, Suppa M, Gandini S, Lipski J, White JM, Del Marmol V. Risk Factors and Innovations in Risk Assessment for Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma. Cancers (Basel) 2024; 16:1016. [PMID: 38473375 DOI: 10.3390/cancers16051016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
Skin cancer is the most frequently diagnosed cancer globally and is preventable. Various risk factors contribute to different types of skin cancer, including melanoma, basal cell carcinoma, and squamous cell carcinoma. These risk factors encompass both extrinsic, such as UV exposure and behavioral components, and intrinsic factors, especially involving genetic predisposition. However, the specific risk factors vary among the skin cancer types, highlighting the importance of precise knowledge to facilitate appropriate early diagnosis and treatment for at-risk individuals. Better understanding of the individual risk factors has led to the development of risk scores, allowing the identification of individuals at particularly high risk. These advances contribute to improved prevention strategies, emphasizing the commitment to mitigating the impact of skin cancer.
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Affiliation(s)
- K Wunderlich
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - M Suppa
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
- Department of Dermatology, Institute Jules Bordet, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - S Gandini
- Molecular and Pharmaco-Epidemiology Unit, Department of Experimental Oncology, European Institute of Oncology, IRCCS, 20139 Milan, Italy
| | - J Lipski
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - J M White
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - V Del Marmol
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
- Department of Dermatology, Institute Jules Bordet, Université Libre de Bruxelles, 1070 Brussels, Belgium
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Order KE, Rodig NM. Pediatric Kidney Transplantation: Cancer and Cancer Risk. Semin Nephrol 2024; 44:151501. [PMID: 38580568 PMCID: PMC11734768 DOI: 10.1016/j.semnephrol.2024.151501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
Children with end-stage kidney disease (ESKD) face a lifetime of complex medical care, alternating between maintenance chronic dialysis and kidney transplantation. Kidney transplantation has emerged as the optimal treatment of ESKD for children and provides important quality of life and survival advantages. Although transplantation is the preferred therapy, lifetime exposure to immunosuppression among children with ESKD is associated with increased morbidity, including an increased risk of cancer. Following pediatric kidney transplantation, cancer events occurring during childhood or young adulthood can be divided into two broad categories: post-transplant lymphoproliferative disorders and non-lymphoproliferative solid tumors. This review provides an overview of cancer incidence, types, outcomes, and preventive strategies in this population.
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Affiliation(s)
- Kaitlyn E Order
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Boston, MA
| | - Nancy M Rodig
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Boston, MA.
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21
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Bakker D, Bakker WJ, Bekkenk MW, Luiten RM. Immunity against Non-Melanoma Skin Cancer and the Effect of Immunosuppressive Medication on Non-Melanoma Skin Cancer Risk in Solid Organ Transplant Recipients. Cells 2023; 12:2441. [PMID: 37887285 PMCID: PMC10605268 DOI: 10.3390/cells12202441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/22/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants.
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Affiliation(s)
- Dixie Bakker
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Walbert J. Bakker
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
| | - Marcel W. Bekkenk
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
- Amsterdam University Medical Centers, VU University of Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Rosalie M. Luiten
- Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, 1081 HV Amsterdam, The Netherlands
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Sengupta D, Naskar S, Mandal D. Reactive oxygen species for therapeutic application: Role of piezoelectric materials. Phys Chem Chem Phys 2023; 25:25925-25941. [PMID: 37727027 DOI: 10.1039/d3cp01711g] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/21/2023]
Abstract
This perspective article emphasizes the significant role of reactive oxygen species (ROS) in in vivo remedial therapy of various diseases and complications, capitalizing on their potential reactivity. Among the various influencers, herein, piezoelectric materials driven ROS generation activity is primarily considered. Intrinsic non-centrosymmetry of piezoelectric materials makes them suitable for distinct dipole formation in the presence of external mechanical stimuli. Such characteristics prompt the positioning of opposite charged carriers to execute associated redox transformations that effectively participate to generate ROS in the aqueous media of the cell cytoplasm, organelles and nucleus. The immense reactivity of piezoelectric material driven ROS is fostered to terminate cellular toxicity or curtail tumor cell growth, due to their higher specificity. This perspective considers the conjugated performance of piezoelectric materials and ultrasound which can remotely generate electrical charges that promote ROS production for therapeutic application. In particular, a substantial synopsis is provided for the remedial activity of numerous piezocatalytic materials in tumor cell apoptosis, antibacterial treatment, dental care and neurological disorders. Subsequently, the report precisely demonstrates the methods involving various spectrophotometric approaches for the analysis of the ROS. Finally, the key challenges of piezoelectric material-based therapy are discussed and systematic future progress is outlined.
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Affiliation(s)
- Dipanjan Sengupta
- Quantum Materials and Devices Unit, Institute of Nano Science and Technology, Knowledge City, Sector81, Mohali 140306, India.
- Department of Chemistry, Faculty of Engineering, Teerthanker Mahaveer University, Moradabad 244001, India
| | - Sudip Naskar
- Quantum Materials and Devices Unit, Institute of Nano Science and Technology, Knowledge City, Sector81, Mohali 140306, India.
| | - Dipankar Mandal
- Quantum Materials and Devices Unit, Institute of Nano Science and Technology, Knowledge City, Sector81, Mohali 140306, India.
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23
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Tang H, Seykora JT, Ko CJ. Squamous carcinogenesis: potential truncal mutations. Hum Pathol 2023; 140:32-38. [PMID: 37001739 DOI: 10.1016/j.humpath.2023.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
Squamous carcinogenesis is incompletely understood, but more recent genetic studies support that the order of acquired mutations is important. This paper will review more recent genetic studies with an emphasis on the potential truncal mutations, mutations critical to the trunk of the cancer evolutionary tree, in actinic keratosis, squamous cell carcinoma in situ, cutaneous squamous cell carcinoma, keratoacanthoma, and keratoacanthoma-like squamous proliferation.
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Affiliation(s)
- Haiming Tang
- Department of Pathology, School of Medicine, Yale University, New Haven, CT, 06510, USA.
| | - John T Seykora
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christine J Ko
- Department of Pathology, School of Medicine, Yale University, New Haven, CT, 06510, USA; Department of Dermatology, School of Medicine, Yale University, New Haven, CT, 06510, USA
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24
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Jansen FM, den Broeder N, Lubeek SFK, Savelkoul EHJ, Marcus CM, Hoentjen F, van Dop WA. Cumulative thiopurine dosing and keratinocyte skin cancer in inflammatory bowel disease: a case-control study. Eur J Gastroenterol Hepatol 2023; 35:1123-1130. [PMID: 37665613 DOI: 10.1097/meg.0000000000002617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
BACKGROUND AND AIM Patients with inflammatory bowel disease (IBD) treated with thiopurines are at increased risk of keratinocyte skin cancer (KSC). Most international guidelines recommend yearly dermatological screening of thiopurine-treated patients. Whether the association between the development of KSC and the use of thiopurines is dose-dependent remains unclear. The aim of this study was to investigate the association between the cumulative thiopurine dose and KSC development in patients with IBD which can be helpful to assist in further skin cancer risk stratification and personalization of screening recommendations in patients with IBD. METHODS We performed a single-center case-control study, including patients with IBD with and without a history of KSC (cases and controls, respectively). The primary outcome was the association of cumulative azathioprine, mercaptopurine and thioguanine dose with KSC development. Univariable and multivariable logistic regression analyses were performed, the latter corrected for age and smoking, known risk factors of KSC. RESULTS We included 50 cases and 150 controls, predominantly white population. Age and current azathioprine use were univariably significantly associated with KSC development. In multivariable logistic regression analyses, age at inclusion remained significantly associated. Cumulative doses of thiopurines (separate or combined) or duration of thiopurine use did not impact KSC risk, also after correcting for age and smoking. CONCLUSION Cumulative thiopurine dose and duration did not show an association with KSC development. Future KSC risk stratification, based on all available KSC risk factors, may aid in selecting individuals who can benefit most from dermatologic screening programs.
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Affiliation(s)
- Fenna M Jansen
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Nathan den Broeder
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Satish F K Lubeek
- Department of Dermatology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Edo H J Savelkoul
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Carlijne M Marcus
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
| | - Frank Hoentjen
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Willemijn A van Dop
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences
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25
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Bommakanti KK, Kosaraju N, Tam K, Chai-Ho W, St John M. Management of Cutaneous Head and Neck Squamous and Basal Cell Carcinomas for Immunocompromised Patients. Cancers (Basel) 2023; 15:3348. [PMID: 37444461 DOI: 10.3390/cancers15133348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/11/2023] [Accepted: 06/15/2023] [Indexed: 07/15/2023] Open
Abstract
The incidence of non-melanoma skin cancer (NMSC) continues to rise, and more than one million cases are diagnosed in the United States each year. The increase in prevalence has been attributed to increased lifespan and improvements in survival for conditions that increase the risk of these malignancies. Patients who are immunocompromised have a higher risk of developing NMSC compared to the general population. In immunosuppressed patients, a combination of prevention, frequent surveillance, and early intervention are necessary to reduce morbidity and mortality. In this review, we collate and summarize current knowledge regarding pathogenesis of head and neck cutaneous SCC and BCC within immunocompromised patients, examine the potential role of the immune response in disease progression, and detail the role of novel immunotherapies in this subset of patients.
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Affiliation(s)
- Krishna K Bommakanti
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Nikitha Kosaraju
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Kenric Tam
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Wanxing Chai-Ho
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
| | - Maie St John
- Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
- UCLA Head and Neck Cancer Program (HNCP), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1624, USA
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26
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Shaw R, Haque AR, Luu T, O’Connor TE, Hamidi A, Fitzsimons J, Varda B, Kwon D, Whitcomb C, Gregorowicz A, Roloff GW, Bemiss BC, Kallwitz ER, Hagen PA, Berg S. Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation. Front Oncol 2023; 13:1146002. [PMID: 37397376 PMCID: PMC10313202 DOI: 10.3389/fonc.2023.1146002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/09/2023] [Indexed: 07/04/2023] Open
Abstract
Objective This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types. Methods This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy. Results A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia. Conclusion Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.
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Affiliation(s)
- Reid Shaw
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Ali R. Haque
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Tyler Luu
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Timothy E. O’Connor
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Adam Hamidi
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Jack Fitzsimons
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Bianca Varda
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Danny Kwon
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Cody Whitcomb
- Department of Internal Medicine, Loyola University Medical Center, Maywood, United States
| | - Alex Gregorowicz
- Department of Pharmacy, Hines Veterans Affairs Hospital, Hines, United States
| | - Gregory W. Roloff
- Section of Hematology and Oncology, The University of Chicago, Chicago, United States
| | - Bradford C. Bemiss
- Division of Pulmonary and Critical Care Medicine, Loyola University Medical Center, Maywood, United States
| | - Eric R. Kallwitz
- Division of Hepatology, Loyola University Medical Center, Maywood, United States
| | - Patrick A. Hagen
- Division of Hematology and Oncology, Loyola University Medical Center, Maywood, United States
| | - Stephanie Berg
- Department of Medical Oncology, Lank Center for Genitourinary (GU) Dana-Farber Cancer Institute (DFCI), Harvard Medical School, Boston, MA, United States
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27
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Winge MCG, Kellman LN, Guo K, Tang JY, Swetter SM, Aasi SZ, Sarin KY, Chang ALS, Khavari PA. Advances in cutaneous squamous cell carcinoma. Nat Rev Cancer 2023:10.1038/s41568-023-00583-5. [PMID: 37286893 DOI: 10.1038/s41568-023-00583-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/06/2023] [Indexed: 06/09/2023]
Abstract
Human malignancies arise predominantly in tissues of epithelial origin, where the stepwise transformation from healthy epithelium to premalignant dysplasia to invasive neoplasia involves sequential dysregulation of biological networks that govern essential functions of epithelial homeostasis. Cutaneous squamous cell carcinoma (cSCC) is a prototype epithelial malignancy, often with a high tumour mutational burden. A plethora of risk genes, dominated by UV-induced sun damage, drive disease progression in conjunction with stromal interactions and local immunomodulation, enabling continuous tumour growth. Recent studies have identified subpopulations of SCC cells that specifically interact with the tumour microenvironment. These advances, along with increased knowledge of the impact of germline genetics and somatic mutations on cSCC development, have led to a greater appreciation of the complexity of skin cancer pathogenesis and have enabled progress in neoadjuvant immunotherapy, which has improved pathological complete response rates. Although measures for the prevention and therapeutic management of cSCC are associated with clinical benefit, the prognosis remains poor for advanced disease. Elucidating how the genetic mechanisms that drive cSCC interact with the tumour microenvironment is a current focus in efforts to understand, prevent and treat cSCC.
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Affiliation(s)
- Mårten C G Winge
- Program in Epithelial Biology, Stanford University, Stanford, CA, USA
- Department of Dermatology, Stanford University, Redwood City, CA, USA
| | - Laura N Kellman
- Program in Epithelial Biology, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Stanford Program in Cancer Biology, Stanford University, Stanford, CA, USA
| | - Konnie Guo
- Program in Epithelial Biology, Stanford University, Stanford, CA, USA
| | - Jean Y Tang
- Department of Dermatology, Stanford University, Redwood City, CA, USA
| | - Susan M Swetter
- Department of Dermatology, Stanford University, Redwood City, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA
| | - Sumaira Z Aasi
- Department of Dermatology, Stanford University, Redwood City, CA, USA
| | - Kavita Y Sarin
- Department of Dermatology, Stanford University, Redwood City, CA, USA
| | - Anne Lynn S Chang
- Department of Dermatology, Stanford University, Redwood City, CA, USA
| | - Paul A Khavari
- Program in Epithelial Biology, Stanford University, Stanford, CA, USA.
- Department of Dermatology, Stanford University, Redwood City, CA, USA.
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
- Stanford Program in Cancer Biology, Stanford University, Stanford, CA, USA.
- Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA.
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28
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Jedlowski PM. Association of Nonmelanoma Skin Cancers, Melanoma, and Merkel Cell Carcinoma with Dermatologic Medications: A Case-Control Pharmacovigilance Study of the FDA Adverse Events Reporting System. Dermatology 2023; 239:694-699. [PMID: 37054693 DOI: 10.1159/000530107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/06/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Medications used in the treatment of dermatologic conditions have been associated with squamous cell carcinoma (SCC), basal cell carcinoma (BCC), melanoma, and Merkel cell carcinoma (MCC). OBJECTIVE The objective of the study was to examine the relationship between systemic dermatologic medications and skin cancer in the FDA Adverse Event Reporting System (FAERS). METHODS Case-control analyses were performed in FAERS from 1968 to 2021 to examine the reporting odds ratios (RORs) for SCC, BCC, melanoma, and MCC. RESULTS The oral immunosuppressants were all associated with increased ROR of SCC, BCC, melanoma, and MCC. Azathioprine had the highest ROR for SCC (34.13, 95% CI 29.07-40.08), BCC (21.15, 95% CI 20.63-25.98), and MCC (44.76, 95% CI 31.52-63.55), while quinacrine and guselkumab had the highest ROR for melanoma (13.14, 95% CI 1.84-93.89 vs. 12.73, 95% CI 10.60-15.30, respectively). The TNF-α inhibitors were associated with an increased ROR for all skin cancers investigated. CONCLUSIONS The oral immunosuppressants and many biologic medications were associated with an increased ROR of skin cancers including TNF-α inhibitors (etanercept, adalimumab, infliximab), IL-23 or IL-12/23 inhibitors (ustekinumab, risankizumab), and the CD-20 inhibitor rituximab but not dupilumab or IL-17 inhibitors.
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29
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Sergi MC, Lauricella E, Porta C, Tucci M, Cives M. An update on Merkel cell carcinoma. Biochim Biophys Acta Rev Cancer 2023; 1878:188880. [PMID: 36914034 DOI: 10.1016/j.bbcan.2023.188880] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/07/2023] [Accepted: 03/07/2023] [Indexed: 03/13/2023]
Abstract
Merkel cell carcinoma (MCC) is a rare cancer of the skin characterized by a neuroendocrine phenotype and an aggressive clinical behavior. It frequently originates in sun-exposed body areas, and its incidence has steadily increased in the last three decades. Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) radiation exposure are the main causative agents of MCC, and distinct molecular features have been documented in virus-positive and virus-negative malignancies. Surgery remains the cornerstone of treatment for localized tumors, but even when integrated with adjuvant radiotherapy is able to definitively cure only a fraction of MCC patients. While characterized by a high objective response rate, chemotherapy is associated with a short-lasting benefit of approximately 3 months. On the other hand, immune checkpoint inhibitors including avelumab and pembrolizumab have demonstrated durable antitumor activity in patients with stage IV MCC, and investigations on their use in the neoadjuvant or adjuvant setting are currently underway. Addressing the needs of those patients who do not persistently benefit from immunotherapy is currently one of the most compelling unmet needs in the field, and multiple clinical trials of new tyrosine kinase inhibitors (TKIs), peptide receptor radionuclide therapy (PRRT), therapeutic vaccines, immunocytokines as well as innovative forms of adoptive cellular immunotherapies are under clinical scrutiny at present.
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Affiliation(s)
- Maria Chiara Sergi
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Eleonora Lauricella
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Camillo Porta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Marco Tucci
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Mauro Cives
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy.
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30
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The Current Treatment Landscape of Cutaneous Squamous Cell Carcinoma. Am J Clin Dermatol 2023; 24:25-40. [PMID: 36512176 DOI: 10.1007/s40257-022-00742-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 12/15/2022]
Abstract
Non-melanoma skin cancers (NMSCs) are the most common form of skin cancer worldwide. The global incidence of cutaneous squamous cell carcinoma (CSCC) is rising, with an estimated 2.4 million cases diagnosed in 2019. Chronic exposure to ultraviolet (UV) radiation is a major risk factor for developing CSCC. Most early-stage CSCCs are treated successfully with surgery or radiotherapy; however, locally advanced or metastatic disease can be associated with significant morbidity or mortality. Recently, the treatment paradigm for advanced CSCC has been revolutionised by the introduction of immunotherapy, which can achieve a response rate of approximately 50% with durable cancer control, and significant improvement in quality of life. With the regulatory approval of programmed death-1 (PD-1)-targeting drugs since 2018, immunotherapy is now recognised as the standard of care for first-line systemic therapy in advanced or metastatic CSCC.
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31
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Granata S, Tessari G, Stallone G, Zaza G. Skin cancer in solid organ transplant recipients: still an open problem. Front Med (Lausanne) 2023; 10:1189680. [PMID: 37153100 PMCID: PMC10160421 DOI: 10.3389/fmed.2023.1189680] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
In the last two decades, the optimization of organ preservation and surgical techniques, and the personalized immunosuppression have reduced the rate of acute rejections and early post-transplant complications. However, long-term graft survival rates have not improved over time, and evidence suggest a role of chronic calcineurin inhibitor toxicity in this failure. Solid organ transplant recipients may develop chronic dysfunction/damage and several comorbidities, including post-transplant malignancies. Skin cancers, mostly non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), are the most common malignancies in Caucasian solid organ transplant recipients. Several factors, together with immunosuppression, may contribute to the susceptibility for skin cancers which, although often treatable, could be associated with a much higher mortality rate than in the general population. The rapid identification and treatment (including reduction of immunosuppression and early surgical treatments) have an important role to avoid an aggressive behavior of these malignancies. Organ transplant recipients with a history of skin cancer should be followed closely for developing new and metastatic lesions. Additionally, patient education on the daily use of sun-protective measures and the recognition of the early signs (self-diagnosis) of coetaneous malignancies are useful preventive measures. Finally, clinicians should make themselves aware of the problem and build, in every clinical follow-up center, collaborative network involving transplant clinicians, dermatologists and surgeons who should work together to easily identify and rapidly treat these complications. In this review, we discuss the current literature regarding the epidemiology, risk factors, diagnosis, preventive strategies and treatments of skin cancer in organ transplantation.
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Affiliation(s)
- Simona Granata
- Renal, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianpaolo Tessari
- Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy
| | - Giovanni Stallone
- Renal, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Renal, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- *Correspondence: Gianluigi Zaza,
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32
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Mechanistic investigation of the deamination reaction of 6-thioguanine: a theoretical study. Struct Chem 2022. [DOI: 10.1007/s11224-022-02121-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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33
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UVA induces retinal photoreceptor cell death via receptor interacting protein 3 kinase mediated necroptosis. Cell Death Dis 2022; 8:489. [PMID: 36509771 PMCID: PMC9744841 DOI: 10.1038/s41420-022-01273-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 11/22/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022]
Abstract
Ultraviolet light A (UVA) is the only UV light that reaches the retina and can cause indirect damage to DNA via absorption of photons by non-DNA chromophores. Previous studies demonstrate that UVA generates reactive oxygen species (ROS) and leads to programmed cell death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor interacting protein 1 and 3 (RIPK1 and RIPK3) kinases, key signaling molecules of PCD, in UVA-induced photoreceptor injury using in vitro and ex vivo models. UVA irradiation activated RIPK3 but not RIPK1 and mediated necroptosis through MLKL that lie downstream of RIPK3 and induced apoptosis through increased oxidative stress. Moreover, RIPK3 but not RIPK1 inhibition suppresses UVA-induced cell death along with the downregulation of MLKL and attenuates the levels of oxidative stress and DNA fragmentation. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced necroptosis cell death in photoreceptors and highlight RIPK3 potential as a neuroprotective target.
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34
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Zhuang Y, Wang H, Ding J, Zhang X, Liu X, Zhang S, Xing X, Kaudimba KK, He M, Zhang S, Guo S, Kong X, Jin L, Liu T. PARP1 inhibition enhances reactive oxygen species on gut microbiota. J Cell Physiol 2022; 237:4169-4179. [PMID: 35998296 PMCID: PMC9805012 DOI: 10.1002/jcp.30861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/25/2022] [Accepted: 08/09/2022] [Indexed: 01/09/2023]
Abstract
Poly(ADP-ribose) polymerase 1 (PARP1) plays a key role in genome stability by modulating DNA-damage responses. Activated by DNA interruptions through ultraviolet (UV) exposure, PARylation is synthesized by PARP1 and serves as a survival mechanism for cancer and metabolic diseases. Several strategies including ROS and antimicrobial peptides (AMPs) function in host defenses, while the targeted tissue and mechanism under DNA damage are unknown. Here, we show that DNA damage induces responses specifically in the gut tissue. The knockdown of PARP1 reduces the activation of PARylation. Parp1 knockdown under DNA damage results in over-accumulated ROS and secretion of AMPs through the regulation of Relish, a subunit of nuclear factor-κB (NF-κB). Double-knockdown of Parp1 and Relish specifically in the gut inhibits AMP secretion. In conclusion, the host defense is achieved through ROS accumulation rather than the AMPs under DNA damage. In contrast, the knockdown of PARP1 exacerbates ROS accumulation to a harmful level. Under this circumstance, NF-κb targeted AMP secretion is provoked for host defense. Microbiome and functional analysis provide evidence for the hazard of DNA damage and show variations in the metabolic pathways following Parp1 inhibition. Our findings suggest the notion that PARP1 inhibition contributes to ROS accumulation under DNA damage and its role in NF-κb activation for host defense.
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Affiliation(s)
- Yixiao Zhuang
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
| | - Hui Wang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative BiologyFudan UniversityShanghaiChina
| | - Jiyang Ding
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
| | - Xinyi Zhang
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
| | - Xiaoyu Liu
- College of Life SciencesInner Mongolia UniversityHohhotInner MongoliaChina
| | - Shuai Zhang
- College of Life SciencesInner Mongolia UniversityHohhotInner MongoliaChina
| | - Xiaorui Xing
- School of Kinesiology, Key Laboratory of Exercise and Health Sciences of Ministry of EducationShanghai University of SportShanghaiChina
| | - Keneilwe Kenny Kaudimba
- School of Kinesiology, Key Laboratory of Exercise and Health Sciences of Ministry of EducationShanghai University of SportShanghaiChina
| | - Muyang He
- Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Shuang Zhang
- School of Kinesiology, Key Laboratory of Exercise and Health Sciences of Ministry of EducationShanghai University of SportShanghaiChina
| | - Shanshan Guo
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
| | - Xingxing Kong
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina
| | - Li Jin
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina,Human Phenome InstituteFudan UniversityShanghaiChina
| | - Tiemin Liu
- State Key Laboratory of Genetic Engineering, School of Life SciencesFudan UniversityShanghaiChina,Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative BiologyFudan UniversityShanghaiChina,College of Life SciencesInner Mongolia UniversityHohhotInner MongoliaChina,Human Phenome InstituteFudan UniversityShanghaiChina
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Blosser CD, Portuguese AJ, Santana C, Murakami N. Transplant Onconephrology: An Update. Semin Nephrol 2022; 42:151348. [PMID: 37209580 PMCID: PMC10330527 DOI: 10.1016/j.semnephrol.2023.151348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
Transplant onconephrology is a growing specialty focused on the health care of kidney transplant recipients with cancer. Given the complexities associated with the care of transplant patients, along with the advent of novel cancer therapies such as immune checkpoint inhibitors and chimeric antigen-receptor T cells, there is a dire need for the subspecialty of transplant onconephrology. The management of cancer in the setting of kidney transplantation is best accomplished by a multidisciplinary team, including transplant nephrologists, oncologists, and patients. This review addresses the current state and future opportunities for transplant onconephrology, including the roles of the multidisciplinary team, and related scientific and clinical knowledge.
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Affiliation(s)
- Christopher D Blosser
- Division of Nephrology, University of Washington, Seattle, WA; Division of Nephrology, Seattle Children's Hospital, Seattle, WA.
| | | | | | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA.; Harvard Medical School, Boston, MA
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Liu SW, Wang WM, Chiang CP, Chung CH, Tsao CH, Chien WC, Hung CT. Risk of skin cancer in kidney, liver and heart recipients: A nationwide population-based study in Taiwan. Indian J Dermatol Venereol Leprol 2022; 89:372-377. [DOI: 10.25259/ijdvl_366_2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 03/01/2022] [Indexed: 11/04/2022]
Abstract
Background
Previous population-based studies in western countries had revealed increased skin cancer risk among transplant recipients compared to the general population. However, population-based studies in Asia on skin cancer among recipients of different transplanted organs were lacking in the literature.
Aims
This study aims to estimate skin cancer risk among recipients in Taiwan, examine the association between each specific type of skin cancer and each type of transplanted organ, and compare skin cancer risk between different immunosuppressive regimens.
Methods
This population-based retrospective cohort study identified 7550 patients with heart, lung, kidney or liver transplantation and 30,200 controls matched for gender, age and comorbidity index from the National Health Insurance Research Database in Taiwan between 2000 and 2015. Using multivariable Cox proportional hazard models, we estimated the hazard ratios and 95% confidence intervals for the correlation of skin cancer with organ transplantation as well as immunosuppressive regimen.
Results
Organ transplant recipients in Taiwan had an increased risk of skin cancer with adjusted hazard ratios of 4.327 (95% confidence intervals 2.740-6.837, P < 0.001), with the greatest risk, observed among heart recipients (adjusted hazard ratios 6.348, 95% confidence intervals 3.080-13.088, P < 0.001). The risk of non-melanoma skin cancer and melanoma was 4.473 (95% confidence intervals 2.568-7.783, P < 0.001) and 3.324 (95% confidence intervals 1.300-8.172, P < 0.001), respectively. When comparing immunosuppressants, those with calcineurin inhibitors carried the highest risk of skin cancer (adjusted hazard ratios 4.789, 95% confidence intervals 3.033-7.569, P < 0.001), followed by those with antimetabolites (adjusted hazard ratios 4.771, 95% confidence intervals 3.025-7.541, P < 0.001).
Limitations
We could not evaluate confounding behavioural risk factors of skin cancers that were not documented in the database, nor could we recognize patients’ compliance with immunosuppressants.
Conclusion
Organ recipients have a greater risk of skin cancer. Clinicians should inform recipients of the importance of photoprotection and regular dermatologic follow-up.
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Affiliation(s)
| | | | | | - Chi-Hsiang Chung
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chang-Huei Tsao
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Giró Benet J, Seo M, Khine M, Gumà Padró J, Pardo Martnez A, Kurdahi F. Breast cancer detection by analyzing the volatile organic compound (VOC) signature in human urine. Sci Rep 2022; 12:14873. [PMID: 36050339 PMCID: PMC9435419 DOI: 10.1038/s41598-022-17795-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 07/31/2022] [Indexed: 11/12/2022] Open
Abstract
A rising number of authors are drawing evidence on the diagnostic capacity of specific volatile organic compounds (VOCs) resulting from some body fluids. While cancer incidence in society is on the rise, it becomes clear that the analysis of these VOCs can yield new strategies to mitigate advanced cancer incidence rates. This paper presents the methodology implemented to test whether a device consisting of an electronic nose inspired by a dog's olfactory system and olfactory neurons is significantly informative to detect breast cancer (BC). To test this device, 90 human urine samples were collected from control subjects and BC patients at a hospital. To test this system, an artificial intelligence-based classification algorithm was developed. The algorithm was firstly trained and tested with data resulting from gas chromatography-mass spectrometry (GC-MS) urine readings, leading to a classification rate of 92.31%, sensitivity of 100.00%, and specificity of 85.71% (N = 90). Secondly, the same algorithm was trained and tested with data obtained with our eNose prototype hardware, and class prediction was achieved with a classification rate of 75%, sensitivity of 100%, and specificity of 50%.
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Affiliation(s)
- Judit Giró Benet
- Center for Embedded Cyber-Physical Systems (CEPS), University of California Irvine (UCI), Irvine, 92697, USA.
| | - Minjun Seo
- Center for Embedded Cyber-Physical Systems (CEPS), University of California Irvine (UCI), Irvine, 92697, USA
| | - Michelle Khine
- Department of Biomedical Engineering, University of California Irvine (UCI), Irvine, 92697, USA
| | - Josep Gumà Padró
- South Catalonia Oncology Institute (IOCS), Sant Joan de Reus University Hospital, IISPV, Rovira i Virgili University, 43204, Reus, Spain
| | - Antonio Pardo Martnez
- Department of Electronic and Biomedical Engineering, Universitat de Barcelona (UB), 08028, Barcelona, Spain
| | - Fadi Kurdahi
- Center for Embedded Cyber-Physical Systems (CEPS), University of California Irvine (UCI), Irvine, 92697, USA
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Piovani D, Hassan C, Repici A, Rimassa L, Carlo-Stella C, Nikolopoulos GK, Riboli E, Bonovas S. Risk of Cancer in Inflammatory Bowel Diseases: Umbrella Review and Reanalysis of Meta-analyses. Gastroenterology 2022; 163:671-684. [PMID: 35643170 DOI: 10.1053/j.gastro.2022.05.038] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS To summarize the epidemiologic evidence and assess the validity of claimed associations of inflammatory bowel diseases (IBDs) with overall and site-specific cancer risk. METHODS We systematically searched PubMed, Embase, and Scopus from inception to May 10, 2021, to identify and comprehensively reanalyze the data of meta-analyses on associations between IBDs (ie, Crohn's disease [CD] and ulcerative colitis [UC]) and subsequent risk of cancer. The strength of epidemiologic evidence was graded as high, moderate, or weak, by applying prespecified criteria that included the random effects estimate, its 95% confidence interval, and P value, estimates of heterogeneity, small-study effects, and robustness to unmeasured confounding. RESULTS This study critically appraised 277 estimates derived from 24 published meta-analyses and our own meta-analyses. The association between pediatric-onset IBDs and overall risk of cancer showed high epidemiologic evidence. Twenty associations (15 cancer types) demonstrated moderate evidence: any cancer (pediatric-onset UC), mouth to terminal ileum (CD), small bowel (CD/UC), colon (CD), rectum (CD/UC), colon-rectum (IBDs, pediatric-onset CD/UC), bile ducts and liver (CD/UC), liver (CD), intrahepatic cholangiocarcinoma (IBDs), bile ducts (CD), skin (CD), squamous cell carcinoma of the skin (CD), nonmelanoma skin cancer (UC), kidney (CD), and thyroid cancer (IBDs). Another 40 associations (23 cancer types) showed statistical significance; however, our confidence in these effect estimates was weak. No statistical significance was found regarding further 47 associations. CONCLUSIONS Associations between IBDs and different types of malignancy showed varying levels of evidence and magnitude of risk. Further primary research investigating the impact of a consistent set of risk factors that are known to affect cancer risk is warranted. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021254996.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Cesare Hassan
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Carmelo Carlo-Stella
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Georgios K Nikolopoulos
- Laboratory of Medical Statistics, Epidemiology and Public Health, Medical School, University of Cyprus, Nicosia, Cyprus
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
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Bigagli E, Mugelli A, Mancia G. A reverse translational pharmacological approach to understand the underlying mechanisms of the reported association between hydrochlorothiazide and non-melanoma skin cancer. J Hypertens 2022; 40:1647-1649. [PMID: 35822584 PMCID: PMC9451910 DOI: 10.1097/hjh.0000000000003167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Elisabetta Bigagli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence
| | - Alessandro Mugelli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence
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40
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Narous M, Nugent Z, Singh H, Bernstein CN. Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis. Inflamm Bowel Dis 2022:6656176. [PMID: 35929649 DOI: 10.1093/ibd/izac171] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND We compared risks of nonmelanoma skin cancers (NMSCs) and melanoma preceding and following a diagnosis of inflammatory bowel disease (IBD) and to evaluate the effect of thiopurines and anti-tumor necrosis factor α (anti-TNF-α) on skin cancer risk in IBD. METHODS This was a retrospective, historical cohort study using the population-based University of Manitoba IBD Epidemiology Database (11 228 IBD cases and 104 725 matched controls) linked to the Manitoba Cancer Registry. Logistic and Cox regression analyses were performed to calculate skin cancer risks prior to and after IBD diagnosis. RESULTS Persons with ulcerative colitis (UC) were more likely to have basal cell carcinoma (BCC) predating their UC diagnosis (odds ratio, 1.32; 95% confidence interval [CI], 1.08-1.60). Risks of squamous cell carcinoma (SCC), other NMSCs, or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risks of BCC (hazard ratio, 1.53; 95% CI, 1.37-1.70) and SCC (hazard ratio, 1.61; 95% CI, 1.29-2.01) were significantly increased across all IBD groups except for SCC in UC. There was no significant association between melanoma and IBD post-IBD diagnosis. The risks of BCC and melanoma were increased in thiopurine and anti-TNF users, and risk of SCC was increased in only thiopurine users. Nested cohort analysis of persons with IBD with censoring at both thiopurines and anti-TNF use confirmed a higher baseline risk of BCC and no effect on SCC, comparable to pre-IBD diagnosis findings. CONCLUSIONS The risk of BCC preceding a diagnosis of UC is higher than in non-UC controls, compared with a generally increased risk of all NMSCs post-IBD diagnosis. Thiopurine and anti-TNF therapy increase the risks for skin cancers in persons with IBD after their diagnoses.
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Affiliation(s)
- Mariam Narous
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.,Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Zoann Nugent
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.,CancerCare Manitoba, Winnipeg, Manitoba, Canada
| | - Harminder Singh
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.,CancerCare Manitoba, Winnipeg, Manitoba, Canada
| | - Charles N Bernstein
- University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada.,Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canadaand
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Owens TJ, Patel SA, Greiner TC, Cannatella JJ, Grant WJ, Langnas AN, Vo HD. High-grade myelodysplastic syndrome in a pediatric multi-organ transplant recipient: A case report and literature review. Pediatr Transplant 2022; 26:e14287. [PMID: 35403329 DOI: 10.1111/petr.14287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/27/2021] [Accepted: 03/31/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Pediatric myelodysplastic syndrome is a rare but life-threatening condition requiring prompt recognition and management. METHODS We herein present the only reported case of a pediatric multi-organ transplant recipient developing myelodysplastic syndrome. RESULTS The patient was a 14-year-old girl on chronic calcineurin inhibitor therapy who presented with peri-rectal pain approximately 13 years after liver, small bowel, and pancreas transplant. The initial workup revealed pancytopenia and parvovirus B19 viremia. Her definitive diagnosis was complicated by a lack of adequate bone marrow biopsy specimens and expert consultation that resulted in treatment for hemophagocytic lymphohistiocytosis. She was later diagnosed with high-grade myelodysplastic syndrome. Although curative treatment with chemotherapy and hematopoietic stem cell transplantation was strongly considered, it was not performed due to the child's rapid clinical progression, ventilator status, and active infections. The patient died approximately 6 months following symptom onset. CONCLUSIONS This case emphasizes the importance of early recognition of myelodysplastic syndrome in multi-organ transplant recipients on chronic immunosuppression. Pancytopenia is a common presentation in the post-transplant period that requires thorough investigation. Multiple confounding considerations such as infection, immunosuppression, and systemic inflammation can delay the diagnosis of underlying hematological malignancies. Transplant care providers should be aware of myelodysplastic syndrome and advocate for a comprehensive evaluation, given early recognition and intervention can significantly improve outcomes.
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Affiliation(s)
- Trudie J Owens
- Department of Surgery, Transplantation Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Sachit A Patel
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Timothy C Greiner
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Jeffrey J Cannatella
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Wendy J Grant
- Department of Surgery, Transplantation Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Alan N Langnas
- Department of Surgery, Transplantation Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Hanh D Vo
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Chaiprasongsuk A, Panich U. Role of Phytochemicals in Skin Photoprotection via Regulation of Nrf2. Front Pharmacol 2022; 13:823881. [PMID: 35645796 PMCID: PMC9133606 DOI: 10.3389/fphar.2022.823881] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
Ethnopharmacological studies have become increasingly valuable in the development of botanical products and their bioactive phytochemicals as novel and effective preventive and therapeutic strategies for various diseases including skin photoaging and photodamage-related skin problems including abnormal pigmentation and inflammation. Exploring the roles of phytochemicals in mitigating ultraviolet radiation (UVR)-induced skin damage is thus of importance to offer insights into medicinal and ethnopharmacological potential for development of novel and effective photoprotective agents. UVR plays a role in the skin premature aging (or photoaging) or impaired skin integrity and function through triggering various biological responses of skin cells including apoptosis, oxidative stress, DNA damage and inflammation. In addition, melanin produced by epidermal melanocytes play a protective role against UVR-induced skin damage and therefore hyperpigmentation mediated by UV irradiation could reflect a sign of defensive response of the skin to stress. However, alteration in melanin synthesis may be implicated in skin damage, particularly in individuals with fair skin. Oxidative stress induced by UVR contributes to the process of skin aging and inflammation through the activation of related signaling pathways such as the mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1), the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), the nuclear factor kappa B (NF-κB) and the signal transducer and activator of transcription (STAT) in epidermal keratinocytes and dermal fibroblasts. ROS formation induced by UVR also plays a role in regulation of melanogenesis in melanocytes via modulating MAPK, PI3K/Akt and the melanocortin 1 receptor (MC1R)-microphthalmia-associated transcription factor (MITF) signaling cascades. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidant defenses can affect the major signaling pathways involved in regulation of photoaging, inflammation associated with skin barrier dysfunction and melanogenesis. This review thus highlights the roles of phytochemicals potentially acting as Nrf2 inducers in improving photoaging, inflammation and hyperpigmentation via regulation of cellular homeostasis involved in skin integrity and function. Taken together, understanding the role of phytochemicals targeting Nrf2 in photoprotection could provide an insight into potential development of natural products as a promising strategy to delay skin photoaging and improve skin conditions.
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Affiliation(s)
| | - Uraiwan Panich
- Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- *Correspondence: Uraiwan Panich,
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Analysis of mono-, di-, and triphosphates of thioguanosine and methylthioinosine in children with acute lymphoblastic leukemia by LC-MS/MS. J Pharm Biomed Anal 2022; 217:114813. [PMID: 35550492 DOI: 10.1016/j.jpba.2022.114813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/05/2022] [Accepted: 05/02/2022] [Indexed: 11/24/2022]
Abstract
Mercaptopurine (6-MP) is an indispensable, first-line, drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, 6-MP has several intrinsic drawbacks, such as large individual variability in the drug response, undesirable adverse reactions, and drug resistance in patients with release ALL, which requires therapeutic drug monitoring (TDM). Several studies analyzed the total concentration of thiopurine nucleotides in red blood cells (RBCs) after hydrolysis, and two studies detected them separately and accurately by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, we developed a rapid and robust LC-MS/MS method for simultaneous quantitation of mono-, di-, and triphosphates of thioguanosine and methylthioinosine. Not only EDTA and DTT were added, but also EHT1864, a new Rac family small GTPases inhibitor, was innovatively added to ensure the stability of the analytes. Commercial availability and relatively low cost compound methotrexate-D3 was selected as internal standards. The linearity, accuracy, precision, recovery, matrix effect and stability of the method were all in line with the guidelines. This method provide an accurate and robust new solution for the determination of 6 metabolites of MP in RBCs from ALL patients with maintenance therapy.
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Cutaneous squamous cell carcinoma arising in immunosuppressed patients: a systematic review of tumor profiling studies. JID INNOVATIONS 2022; 2:100126. [PMID: 35620703 PMCID: PMC9127418 DOI: 10.1016/j.xjidi.2022.100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 02/08/2022] [Accepted: 03/04/2022] [Indexed: 12/01/2022] Open
Abstract
As solid organ transplantation becomes more prevalent, more individuals are living as members of the immunosuppressed population with an elevated risk for cutaneous squamous cell carcinoma (cSCC). Although great progress has been made in understanding the pathogenesis of cSCC in general, little is known about the drivers of tumorigenesis in immunosuppressed patients and organ-transplant recipients, specifically. This systematic review sought to synthesize information regarding the genetic and epigenetic alterations as well as changes in protein and mRNA expression that place this growing population at risk for cSCC, influence treatment response, and promote tumor aggressiveness. This review will provide investigators with a framework to identify future areas of investigation and clinicians with additional insight into how to best manage these patients.
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45
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Sands BE, Long MD, Reinisch W, Panés J, Loftus EV, Nduaka CI, Soonasra A, Mundayat R, Lawendy N, Chan G, Friedman GS, Su C. Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program. Inflamm Bowel Dis 2022; 28:234-245. [PMID: 33742652 PMCID: PMC8804509 DOI: 10.1093/ibd/izab056] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. METHODS Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. RESULTS Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. CONCLUSIONS For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.
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Affiliation(s)
- Bruce E Sands
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Millie D Long
- University of North Carolina, Center for Gastrointestinal Biology and Disease, Chapel Hill, North Carolina, USA
| | | | - Julian Panés
- Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | | | | | - Gary Chan
- Pfizer Inc, Collegeville, Pennsylvania, USA
| | | | - Chinyu Su
- Pfizer Inc, Collegeville, Pennsylvania, USA
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Bohne AS, Kähler KC. Update aktinische Keratosen – Neuigkeiten und Relevanz für den Alltag. AKTUELLE DERMATOLOGIE 2022. [DOI: 10.1055/a-1487-3992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Zusammenfassung
Ziel der Arbeit Die im März 2020 zuletzt überarbeitete Leitlinie „Aktinische Keratosen und Plattenepithelkarzinome der Haut“ hat aufgrund der Zunahme der klinischen Studien zum Thema aktinische Keratosen den höchsten Grad für Methodik (S3) erreicht, da diese nicht nur konsensbasiert sondern auch evidenzbasiert verfasst wurde. Diesen Entwicklungen gerecht zu werden und den klinisch relevanten Teil des aktuellen Stands des Wissens zu vermitteln, ist Ziel dieses Artikels.
Methodik Anhand der aktuellen epidemiologischen Lage wird der dramatisch wachsende Bedarf für das bessere Verständnis der Ätiologie aktinischer Keratosen deutlich. Ebenso gilt es, Patienten mit aktinischen Keratosen und therapiebedürftigen Ko-Morbiditäten vor einem therapiebedingten, erhöhten Risiko für die Entwicklung weiterer aktinischer Keratosen oder Plattenepithelkarzinomen zu bewahren. Die Möglichkeit der Spontanremission aktinischer Keratosen sollte ebenso wenig vernachlässigt werden wie eine mögliche Progredienz in ein Plattenepithelkarzinom. Die kontroverse Diskussion der fortwährend postulierten, sequenziellen Abfolge der histologischen Grade aktinischer Keratosen zum Plattenepithelkarzinom beinhaltet klinische und histologische Fallstricke. Diese sollten bei der Therapieentscheidung ebenso bedacht werden wie die Wünsche und Erwartungen der Patienten an ein Therapieregime. Eine bleibende Schwierigkeit ist die fehlende Standardisierung erhobener Daten zu den zahlreichen zur Verfügung stehenden Therapieoptionen. Das Potenzial dieses Forschungsgebietes für neue Therapiealternativen und präventive Maßnahmen lässt nach wie vor auf weitere, interessante Entwicklungen hoffen.
Ergebnisse Der gut etablierte kausale Zusammenhang zwischen kumulativer UV-Strahlung in der Entwicklung von Plattenepithelkarzinomen und aktinischer Keratosen hat zur Anerkennung berufsbedingter UV-Exposition als Berufserkrankung geführt, die auch die Anerkennung multipler aktinischer Keratosen als Berufserkrankung beinhaltet. Das therapeutische Handeln sollte durch die Gesamtanzahl der aktinischen Keratosen, das Ausmaß der betroffenen Fläche, die Dynamik des Krankheitsgeschehens und den Wunsch des Patienten bestimmt werden. Ein besonderes Augenmerk sollte auf den Patienten liegen, denen die Krankheitseinsicht fehlt oder die nur wenig motiviert zur Therapie sind. Es könnte der Schlüssel zur Verbesserung der Therapieadhärenz und Akzeptanz sein, diese Patienten zu erkennen und ihre Bedürfnisse in das Arzt-Patienten-Gespräch zu integrieren. Die Differenzierung zwischen lokalisierten aktinischen Keratosen und einer Feldkanzerisierung stellt ein wichtiges Entscheidungskriterium für die Wahl der empfohlenen Therapie dar. Die Rücknahme der Zulassung von Ingenolmebutat in der EU durch die EMA im Jahr 2020 hat das Spektrum der lokaltherapeutischen Optionen eingeschränkt. Der periinterventionelle Schmerz ist nach wie vor der limitierende Faktor für die konventionelle photodynamische Therapie, jedoch schreitet die Entwicklung für schmerzärmere Varianten weiter voran. Es ist zu erwarten, dass sich in den kommenden Jahren durch eine bessere Evidenzlage für weitere systemische oder lokaltherapeutische Optionen neue Behandlungsstrategien ergeben werden. Besonders im Fokus wird sicherlich nach wie vor die Präventionsforschung stehen, die v. a. den Erhalt einer erzielten Remission beinhaltet.
Schlussfolgerung Die aktuellen Forschungsergebnisse und -bestrebungen zur Thematik der aktinischen Keratosen sind aufgrund des zukünftig gesteigerten Bedarfes zum einen notwendig und zum anderen sehr ermutigend. Das Ende des therapeutischen Horizonts ist gegenwärtig noch nicht erreicht.
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Affiliation(s)
- Ann-Sophie Bohne
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel
| | - Katharina C. Kähler
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel
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Principles and Guidelines of Immunotherapy in Neuromuscular Disorders. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00007-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Dong J, Huang C, Guo S, Xia Y, Hou Y, Yang C, Zhang X, Jie J, Zhu BZ, Su H. Free-Radical-Mediated Photoinduced Electron Transfer between 6-Thioguanine and Tryptophan Leading to DNA-Protein-Like Cross-Link. J Phys Chem B 2021; 126:14-22. [PMID: 34951313 DOI: 10.1021/acs.jpcb.1c03380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The nucleobase analog 6-thioguanine (6-TG) has emerged as important immunosuppressant, anti-inflammatory, and anticancer drug in the past few decades, but its unique photosensitivity of absorbing strongly ultraviolet UVA light elicits photochemical hazards in many ways. The particularly intriguing yet unresolved question is whether the direct photoreaction of 6-TG can promote DNA-protein cross-links (DPCs) formation, which are large DNA adducts blocking DNA replication and physically impede DNA-related processes. Herein, by real-time observation of radical intermediates using time-resolved UV-vis absorption spectroscopy in conjunction with product analysis by HPLC-MS, we discover that UVA excitation of 6-TG triggers direct covalent cross-linking with tryptophan (TrpH) via an exquisite radical mechanism of electron transfer. The photoexcitation prepares the redox-active triplet 36-TG*, which initiates electron transfer with TrpH, creating TrpH•+ and 6-TG•- in the first step. The deprotonated Trp• undergoes radical-recombination with its geminate partner 6-TG•- and eliminates a H2S, leading to the cross-linking product 6-TG-Trp. The photoadduct structures (two chiral isomers and one constitutional isomer) are identified unambiguously, validating further the mechanism. These findings pinpoint the exact amino acid that is vulnerable to photo-cross-linking with 6-TG and establish a mechanistic framework for understanding mutagenic DPCs formation and developing photoprobes based on this new type of photo-cross-linking.
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Affiliation(s)
- Junjie Dong
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Chunhua Huang
- State Key Lab of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, P. R. China
| | - Shaoshi Guo
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Ye Xia
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Yue Hou
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Chunfan Yang
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Xianwang Zhang
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Jialong Jie
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
| | - Ben-Zhan Zhu
- State Key Lab of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, P. R. China
| | - Hongmei Su
- College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China
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Nguyen ALH, Sparrow MP. Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules. Dig Dis Sci 2021; 66:3250-3262. [PMID: 33073334 DOI: 10.1007/s10620-020-06662-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/06/2020] [Indexed: 12/09/2022]
Abstract
In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.
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Affiliation(s)
- Anke L H Nguyen
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia.,Monash University, Melbourne, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia. .,Monash University, Melbourne, Australia.
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Ortiz-Rodríguez LA, Ortiz-Zayas G, Pollum M, Hoehn SJ, Jockusch S, Crespo-Hernández CE. Intramolecular Charge Transfer in the Azathioprine Prodrug Quenches Intersystem Crossing to the Reactive Triplet State in 6-Mercaptopurine †. Photochem Photobiol 2021; 98:617-632. [PMID: 34480764 DOI: 10.1111/php.13513] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/30/2021] [Indexed: 11/26/2022]
Abstract
The thiopurine prodrugs 6-mercaptopurine and azathioprine are among the world's essential medications for acute lymphoblastic leukemia, immunosuppression and several autoimmune conditions. Thiopurine prodrugs are efficient UVA absorbers and singlet oxygen generators and the long-term treatment with these prodrugs correlates with a high incidence of sunlight-induced skin cancer in patients. In this contribution, we show that the electronic relaxation mechanisms and photochemical properties of azathioprine are remarkably different from those of 6-mercaptopurine upon absorption of UVA radiation. UVA excitation of 6-mercaptopurine results in nearly 100% triplet yield and up to 30% singlet oxygen generation, whereas excitation of azathioprine with UVA leads to triplet yields of 15-3% depending on pH of the aqueous solution and <1% singlet oxygen generation. While photoexcitation of 6-mercaptopurine and other thiopurine prodrugs can facilitate oxidatively generated cell damage, azathioprine's poor photosensitization ability reveals the use of interchromophoric charge-transfer interactions for the molecular design of photostable prodrugs exhibiting a remarkable reduction in photocytotoxic side effects before drug metabolization.
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Affiliation(s)
| | | | - Marvin Pollum
- Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA
| | - Sean J Hoehn
- Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA
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