Article(id=1193674743082615067, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193674740352119804, articleNumber=1001-2494(2025)06-0652-06, orderNo=null, doi=10.11669/cpj.2025.06.012, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1733760000000, receivedDateStr=2024-12-10, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1762523836154, onlineDateStr=2025-11-07, pubDate=1742572800000, pubDateStr=2025-03-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762523836154, onlineIssueDateStr=2025-11-07, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762523836154, creator=13701087609, updateTime=1762523836154, updator=13701087609, issue=Issue{id=1193674740352119804, tenantId=1146029695717560320, journalId=1190317699101192196, year='2025', volume='60', issue='6', pageStart='553', pageEnd='662', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762523835503, creator=13701087609, updateTime=1762524041683, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1193675605205025683, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193674740352119804, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1193675605205025684, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193674740352119804, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=652, endPage=657, ext={EN=ArticleExt(id=1193674743296524572, articleId=1193674743082615067, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Literature Case Analysis of Cutaneous Squamous Cell Carcinoma Induced by Voriconazole, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To investigate the occurrence and clinical characteristics of cutaneous squamous cell carcinoma (SCC) induced by voriconazole in order to provide references for clinical safe use of the drug. METHODS The case reports of cutaneous SCC induced by voriconazole were retrieved from PubMed, Embase, Web of science, CNKI, Wanfang and VIP database from establishment of each database to June 2024. The relevant data were collected and analyzed. RESULTS A total of 36 cases from 22 articles were identified and included in the analysis. There were 29 males (80.6%) and 7 females (19.4%), and the patients were aged from 6 to 69 years with an average age of (36.7±19.6) years. Voriconazole was used for antifungal treatment in 21 cases (58.3%) and prevention of fungal infection in 15 cases (41.7%), with a dose of 50-800 mg·d-1 and a course of 35 d-168 months. Fourteen cases (38.9%) of cutaneous SCC occurred at 36 months and above, and 23 cases (63.9%) occurred in the head and neck, 97.2% of the patients had a history of immune function abnormalities, 75.0% had a history of sun exposure, 72.2% had a history of using immunosuppressive drugs, and 61.1% had a history of hematopoietic stem cell transplantation or organ transplantation. Approximately 70% of the patients received surgical treatment, especially Mohs surgery. After surgery, chemoradiotherapy and other treatment, 13 patients (36.1%) had a good outcome, 7 patients (19.4%) had cancer metastasis or death, 16 patients (44.4%) did not have description on the outcome. The recovery time was 14 days to 2 years. CONCLUSION Voriconazole can cause cutaneous SCC, especially in male patients, and most occur at 36 months and above after start of medication. In the clinical use of voriconazole, clinicians should pay attention to the cutaneous lesions of the patients, and assess the risk as early as possible and actively take preventive measures.For patients who need to be treated with voriconazole for a long time, regular follow-up or regular skin examination is recommended, and combined treatment with traditional Chinese medicine can also be considered to shorten the course of the disease, improve the efficacy and reduce the toxic side effects. There are many potential factors in the current study, and further prospective studies are required to determine the rationality of the appropriate dosage and duration of voriconazole administration.

, correspAuthors=Yulan QIAN, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Yan LI, Yi LI, Cheng XIE, Yinghua GONG, Zongqi CHENG, Liyan MIAO, Yulan QIAN), CN=ArticleExt(id=1193674819670606127, articleId=1193674743082615067, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=伏立康唑致皮肤鳞状细胞癌的文献病例分析, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 探讨伏立康唑(voriconazole,VCZ)致皮肤鳞状细胞癌(squamous cell carcinoma,SCC)的发生情况和特点,为临床安全使用VCZ提供参考。方法 检索建库至2024年6月收录在PubMed、Embase、Web of science、中国知网、万方和维普数据库有关VCZ致皮肤鳞状细胞癌的病例报道,并对相关数据进行统计和分析。结果 共检索到22篇文献合计36例患者,男性29例(80.6%),女性7例(19.4%),年龄6~69岁(36.7±19.6)岁。VCZ用于抗真菌治疗21例(58.3%),预防真菌感染15例(41.7%),给药剂量50~800 mg·d-1,疗程35 d~168月。14例(38.9%)皮肤SCC发生时间在36月及以上,23例(63.9%)发生在头颈部。患者中97.2%有免疫功能异常史,75.0%有日晒史,72.2%有用免疫抑制剂史,61.1%有造血干细胞或器官移植史。约70%患者采用手术治疗,以莫式显微手术居多。经过手术、放化疗等治疗后好转13例(36.1%)好转,7例(19.4%)癌转移或死亡,16例(44.4%)未说明结局,转归时间14 d~2年。结论 VCZ可导致皮肤SCC,且男性居多,多发生在用药36月及以上。临床在使用VCZ过程中应关注患者皮肤病变情况,尽早评估风险并积极采取预防措施。对长期需要用VCZ治疗的患者,建议定期随访或定期皮肤检查,也可考虑联合中医药方式治疗,缩短病程,提高疗效,降低毒副作用。目前研究中潜在因素较多,需要进一步前瞻性研究来确定VCZ给药剂量和持续时间的合理性。

, correspAuthors=钱玉兰, authorNote=null, correspAuthorsNote=
*钱玉兰,女,硕士,副主任药师 研究方向:临床药学 Tel:(0512)67780997
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李岩,男,学士,主管药师 研究方向:医院药学;

李轶,男,学士,副主任药师 研究方向:医院药学。李岩和李轶为共同第一作者

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李岩,男,学士,主管药师 研究方向:医院药学;

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李轶,男,学士,副主任药师 研究方向:医院药学。李岩和李轶为共同第一作者

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性别 年龄/岁 n 构成比
/%
<18 18~50 51~70 >70 未提及
8 12 8 0 1 29 80.6
1 4 2 0 0 7 19.4
合计 9 16 10 0 1 36 100.0
), ArticleFig(id=1193712779661116246, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674743082615067, language=CN, label=表1, caption=

伏立康唑(VCZ)致皮肤鳞状细胞癌(SCC)患者性别及年龄分布

, figureFileSmall=null, figureFileBig=null, tableContent=
性别 年龄/岁 n 构成比
/%
<18 18~50 51~70 >70 未提及
8 12 8 0 1 29 80.6
1 4 2 0 0 7 19.4
合计 9 16 10 0 1 36 100.0
), ArticleFig(id=1193712779732419415, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674743082615067, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
时间/月 n 构成比/%
<12 2 5.6
12~23 2 5.6
24~35 5 13.9
≥36 14 38.9
未提及 13 36.1
合计 36 100.0
), ArticleFig(id=1193712779816305496, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1193674743082615067, language=CN, label=表2, caption=

VCZ致皮肤SCC的发生时间

, figureFileSmall=null, figureFileBig=null, tableContent=
时间/月 n 构成比/%
<12 2 5.6
12~23 2 5.6
24~35 5 13.9
≥36 14 38.9
未提及 13 36.1
合计 36 100.0
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药物不良反应(ADR)评分 n 构成比/% 关联性评价
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5~8 17 47.2 很可能
1~4 18 50.0 可能
合计 36 100.0
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VCZ致皮肤SCC的关联性评价

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药物不良反应(ADR)评分 n 构成比/% 关联性评价
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5~8 17 47.2 很可能
1~4 18 50.0 可能
合计 36 100.0
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伏立康唑致皮肤鳞状细胞癌的文献病例分析
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李岩 , 李轶 , 谢诚 , 龚银华 , 程宗琦 , 缪丽燕 , 钱玉兰 *
中国药学杂志 | 论著 2025,60(6): 652-657
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中国药学杂志 | 论著 2025, 60(6): 652-657
伏立康唑致皮肤鳞状细胞癌的文献病例分析
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李岩, 李轶, 谢诚, 龚银华, 程宗琦, 缪丽燕, 钱玉兰*
作者信息
  • 苏州大学附属第一医院药学部, 江苏 苏州 215006
  • 李岩,男,学士,主管药师 研究方向:医院药学;

    李轶,男,学士,副主任药师 研究方向:医院药学。李岩和李轶为共同第一作者

通讯作者:

*钱玉兰,女,硕士,副主任药师 研究方向:临床药学 Tel:(0512)67780997
Literature Case Analysis of Cutaneous Squamous Cell Carcinoma Induced by Voriconazole
Yan LI, Yi LI, Cheng XIE, Yinghua GONG, Zongqi CHENG, Liyan MIAO, Yulan QIAN*
Affiliations
  • Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
出版时间: 2025-03-22 doi: 10.11669/cpj.2025.06.012
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目的 探讨伏立康唑(voriconazole,VCZ)致皮肤鳞状细胞癌(squamous cell carcinoma,SCC)的发生情况和特点,为临床安全使用VCZ提供参考。方法 检索建库至2024年6月收录在PubMed、Embase、Web of science、中国知网、万方和维普数据库有关VCZ致皮肤鳞状细胞癌的病例报道,并对相关数据进行统计和分析。结果 共检索到22篇文献合计36例患者,男性29例(80.6%),女性7例(19.4%),年龄6~69岁(36.7±19.6)岁。VCZ用于抗真菌治疗21例(58.3%),预防真菌感染15例(41.7%),给药剂量50~800 mg·d-1,疗程35 d~168月。14例(38.9%)皮肤SCC发生时间在36月及以上,23例(63.9%)发生在头颈部。患者中97.2%有免疫功能异常史,75.0%有日晒史,72.2%有用免疫抑制剂史,61.1%有造血干细胞或器官移植史。约70%患者采用手术治疗,以莫式显微手术居多。经过手术、放化疗等治疗后好转13例(36.1%)好转,7例(19.4%)癌转移或死亡,16例(44.4%)未说明结局,转归时间14 d~2年。结论 VCZ可导致皮肤SCC,且男性居多,多发生在用药36月及以上。临床在使用VCZ过程中应关注患者皮肤病变情况,尽早评估风险并积极采取预防措施。对长期需要用VCZ治疗的患者,建议定期随访或定期皮肤检查,也可考虑联合中医药方式治疗,缩短病程,提高疗效,降低毒副作用。目前研究中潜在因素较多,需要进一步前瞻性研究来确定VCZ给药剂量和持续时间的合理性。

伏立康唑  /  皮肤鳞状细胞癌  /  药品不良反应  /  文献病例分析

OBJECTIVE To investigate the occurrence and clinical characteristics of cutaneous squamous cell carcinoma (SCC) induced by voriconazole in order to provide references for clinical safe use of the drug. METHODS The case reports of cutaneous SCC induced by voriconazole were retrieved from PubMed, Embase, Web of science, CNKI, Wanfang and VIP database from establishment of each database to June 2024. The relevant data were collected and analyzed. RESULTS A total of 36 cases from 22 articles were identified and included in the analysis. There were 29 males (80.6%) and 7 females (19.4%), and the patients were aged from 6 to 69 years with an average age of (36.7±19.6) years. Voriconazole was used for antifungal treatment in 21 cases (58.3%) and prevention of fungal infection in 15 cases (41.7%), with a dose of 50-800 mg·d-1 and a course of 35 d-168 months. Fourteen cases (38.9%) of cutaneous SCC occurred at 36 months and above, and 23 cases (63.9%) occurred in the head and neck, 97.2% of the patients had a history of immune function abnormalities, 75.0% had a history of sun exposure, 72.2% had a history of using immunosuppressive drugs, and 61.1% had a history of hematopoietic stem cell transplantation or organ transplantation. Approximately 70% of the patients received surgical treatment, especially Mohs surgery. After surgery, chemoradiotherapy and other treatment, 13 patients (36.1%) had a good outcome, 7 patients (19.4%) had cancer metastasis or death, 16 patients (44.4%) did not have description on the outcome. The recovery time was 14 days to 2 years. CONCLUSION Voriconazole can cause cutaneous SCC, especially in male patients, and most occur at 36 months and above after start of medication. In the clinical use of voriconazole, clinicians should pay attention to the cutaneous lesions of the patients, and assess the risk as early as possible and actively take preventive measures.For patients who need to be treated with voriconazole for a long time, regular follow-up or regular skin examination is recommended, and combined treatment with traditional Chinese medicine can also be considered to shorten the course of the disease, improve the efficacy and reduce the toxic side effects. There are many potential factors in the current study, and further prospective studies are required to determine the rationality of the appropriate dosage and duration of voriconazole administration.

voriconazole  /  cutaneous squamous cell carcinoma  /  adverse drug reaction  /  literature case analysis
李岩, 李轶, 谢诚, 龚银华, 程宗琦, 缪丽燕, 钱玉兰. 伏立康唑致皮肤鳞状细胞癌的文献病例分析. 中国药学杂志, 2025 , 60 (6) : 652 -657 . DOI: 10.11669/cpj.2025.06.012
Yan LI, Yi LI, Cheng XIE, Yinghua GONG, Zongqi CHENG, Liyan MIAO, Yulan QIAN. Literature Case Analysis of Cutaneous Squamous Cell Carcinoma Induced by Voriconazole[J]. Chinese Pharmaceutical Journal, 2025 , 60 (6) : 652 -657 . DOI: 10.11669/cpj.2025.06.012
皮肤鳞状细胞癌(squamous cell carcinoma,SCC)是介于基底细胞癌和黑色素瘤之间的第二常见皮肤恶性肿瘤[1]。SCC是源于鳞状上皮的一种恶性肿瘤,在非黑色素瘤皮肤癌中约占20%,与基底细胞癌相比,鳞状细胞癌有非常强的恶性趋势,可转移到淋巴结及其他脏器,危及生命[2]
伏立康唑(voriconazole,VCZ)是一种广谱的三唑类抗真菌药物,用于治疗侵袭性曲霉病、非中性粒细胞减少患者的念珠菌病、食管念珠菌病和播散性念珠菌感染,以及由尖孢梭菌和镰刀菌引起的感染。它的抗真菌谱、口服生物利用度和普遍耐受良好的副作用使得该药被广泛用于治疗侵袭性曲霉菌病[3]。VCZ是典型的慢性肺曲霉病一线抗真菌药物,也被广泛用于抗真菌的药物预防[4-5],在造血干细胞移植后具有高危侵袭性真菌感染的患者中也作为长期预防性使用[6-7]。VCZ常见的药物不良反应(adverse drug reaction,ADR)包括视力异常、肝转氨酶升高和皮疹[8-9],而与皮肤光毒性相关ADR罕见,但近年来VCZ致皮肤SCC临床病例报道越来越多,对患者造成严重不良影响,值得临床重视。鉴于此,本研究对VCZ引起皮肤SCC的病例报道进行回顾性分析,以为临床安全使用VCZ提供参考。
以“伏立康唑” “威凡” “鳞状细胞癌” “皮肤鳞状细胞癌”为检索词检索中国知网、万方和维普数据库,以 “voriconazole” “Vfend” “VCZ” “squamous cell carcinoma” “SCC” “cutaneous squamous cell carcinoma ” “cSCC”为检索词检索PubMed、Embase和Web of science数据库,获取伏立康唑致皮肤鳞状细胞癌的病例报道。检索时间为建库至 2024年6月。
①VCZ皮肤SCC的病例报道,包括个案或群案;②病例描述包括患者的基本信息、用药信息、SCC的表现、结局等;③经Naranjo量表[10]对其关联性进行评估,关联性评估结果为“可能”“很可能”或“肯定”;④中文或英文文献。
①重复文献,综述、论著以及基础研究性文献;②无法获取原文或病例记载不完整的文献;③动物实验。
详细阅读纳入的病例报道,提取作者姓名和发表年限,患者国别、性别、年龄、原患疾病,VCZ的用法用量、疗程、合并用药、皮肤SCC的表现、处置及转归等信息,并利用Excel 2020进行统计分析。
共获得文献209篇,通过去除重复文献、阅读题目和摘要后排除与本研究明显无关的文献共计180篇,对剩下的29篇文献进一步查看全文,最终纳入22篇文献[11-32],共计36例患者。
36例患者中男性29例(80.6%),女性7例(19.4%);年龄6~69岁(36.7±19.6)岁;年龄<18岁9例(25.0%),18~50岁16例(44.4%),51~70岁10例(27.8%),1例(2.8%)未提及具体年龄(表1)。患者中来自美国21例,法国6例,澳大利亚、加拿大和日本各2例,比利时、西班牙和德国各1例。
36例使用伏立康唑中,用于治疗真菌感染21例(58.3%),预防真菌感染15例(41.7%)。真菌类型包括曲霉菌感染16例,球孢子菌感染1例,念珠菌感染1例,青霉菌合并球孢菌感染1例,未说明真菌类型2例。伏立康唑给药剂量50[14]~800[11]mg·d-1,疗程35 d[32]~168月[29](中位疗程42月)。36例患者中有28例存在合并用药,1例无合并用药,7例未提及。28例合并用药中,联用免疫抑制剂21例,激素类20例,细胞毒性药物或靶向药物9例,联用其他药物(如其他抗菌药物、辅助用药等)10例。
36例患者中,有13例未提及皮肤SCC发生时间,其余23例患者发生皮肤SCC的时间跨度较大,有14例(38.9%)发生在36月及以上(表2)。
36例SCC诊断中,包括多发性SCC 6例,扩散性SCC 4例,原位SCC 3例,中度分化和低分化SCC各2例,浸润性SCC 2例,低分化合并浸润性SCC 1例,复发性低分化SCC 1例,多发性合并高度扩散性SCC 1例,浸润性SCC合并原位SCC 1例,13例未具体描述。SCC癌变部位主要发生在身体光暴露区域,如头颈部、面部、手臂、手背、胸口等,其中头颈部23例,面部10例,手背8例,手臂5例,胸部、背部、腿部各1例,4例未提及具体病变部位。
36例患者中免疫功能异常35例(97.2%),有日晒史27例(75.0%),有免疫抑制剂治疗史26例(72.2%),移植史22例(61.1%)。患者中免疫功能异常以血液病患者为主,有17例(47.2%)。日晒(26例)或因紫外线治疗[32](1例)引起光敏反应的表现主要以斑样和光化性角化病(actinic keratosis,AK)出现次数最多,其他有色素沉着、痣、脱皮、水泡、唇炎、脓肿、溃疡、糜烂等多种表现,其中有斑样症状22例(61.1%),AK样症状19例(52.8%),同时有斑和AK样表现有9例(25.0%),另有1例表现为色素沉着及多发痣,3例未提及光敏反应。移植史包括血液移植13例(36.1%),肺移植8例(22.2%),肾移植1例(2.8%)。另有人类免疫缺陷病毒(HIV)感染和肉芽肿病患者各2例(5.6%)。
确诊皮肤SCC后,手术治疗25例(69.4%),放化疗或靶向治疗6例(16.7%),冷冻治疗和移植修复治疗各5例(13.9%),局部药膏外用治疗3例(8.3%)。手术治疗提到最多的是莫式显微手术(Mohs手术),占比28%(7/25),靶向和/或化疗治疗药物有西妥昔单抗、卡培他滨,局部治疗药物有5%氟尿嘧啶乳膏和咪喹莫特乳膏。另外患者停用VCZ 12例,其中9例更换其他治疗真菌感染药物,分别为泊沙康唑7例,伊曲康唑、卡泊芬净、氟康唑各1例,其中有1例先换用卡泊芬净,又换用泊沙康唑。最终治愈/好转有13例(36.1%),癌转移或死亡7例(19.4%),16例(44.4%)未说明结局。ADR转归时间14 d~2年。
ADR 相关性经Naranjo量表评估后,36例报道中肯定相关1例(2.8%),很可能相关的17例(47.2%),可能相关的18例(50.0%)(表3)。
VCZ是一种广谱的三唑类抗真菌药物,具有广泛的抗真菌活性和较好的生物利用度,其发生皮肤相关不良反应约为8.6%[33],最常见的是身体曝光区域的晒伤反应,其表现为红斑、口唇炎、脱皮性皮炎、假性迟发性皮肤卟啉病或红斑狼疮病变等,一般停药后这些反应是可逆的[34-37]。在美国食品药品监督管理局不良事件报告系统中,关于VCZ与皮肤SCC的报道有256例[38],说明VCZ与皮肤SCC有很强的相关性,而本研究共收集到相关个案报道36例,通过归纳分析其使用VCZ后发生皮肤SCC的情况和特点,为临床安全使用伏立康唑提供参考。
皮肤SCC的发生在年龄、性别、种族、地理位置和遗传上均有不同,其易发生于高加索人群和老年患者,50岁以上居多,男性患病率高于女性[3,38]。36例患者中,男女比例约29:7,男性超过女性4倍多,男性发生皮肤SCC的比例远高于女性。本研究SCC发病年龄<50岁24例,占比较多,50~70岁11例,70岁及以上无,与报道不相符,可能原因是本研究患者免疫功能异常占比高达97.2%(35/36),而伏立康唑相关的光毒性可能会加速免疫功能低下患者SCC形成的风险[14]。另有可能是皮肤SCC在不同年龄中的潜伏时间不同。有研究表明在早期发病年龄中发生皮肤癌的风险是不相同的,在60岁以上的异体移植受者中首次皮肤癌形成的潜伏期约为3年,而在40岁以下的患者中潜伏期增加至8年[39]
患者使用VCZ时,应严密监测ADR情况,根据患者自身情况及时调整剂量,而对于6个月以上长期治疗或预防使用VCZ患者,需要评估效益与风险平衡,发生光毒性相关病变而继续使用VCZ时,需要定期进行皮肤病变评估,如确诊癌前病变或者皮肤SCC,应停用VCZ。伏立康唑可能需要长期使用甚至终身使用[29],本研究中疗程5年及以上的患者约占27.8%(10/36)[14,16,18,25-26,29-31],其中一位疗程长达14年,该患者因慢性隐球菌性脑膜炎服用VCZ黏膜,其他唑类药物无效,其ADR主要是非黑色素瘤皮肤癌和骨氟中毒,另有VCZ黏膜继发的视觉毒性,这使得患者即使存在长期合并毒性和多种毒性,VCZ黏膜也需要终身使用[29]
Mccarthy等[11]报道了第一例多灶性高浸润性鳞状细胞癌,该病例是在使用VCZ黏膜后立即发生严重光敏反应,3年后确诊皮肤SCC。在法国的另一项研究中,Epaulard等[40]描述了61例VCZ黏膜致皮肤光毒性ADR,其中78.9%(15/19)患者在VCZ黏膜治疗3年及以上时间转变为SCC。本研究23例描述SCC发生时间患者中,有14例(60.9%)发生在3年及以上时间,占比最多,与报道一致。
皮肤SCC皮肤损伤发展快,破坏性大,癌变深部浸润性生长,可能会发生区域性淋巴结转移。皮肤SCC主要发生在头颈部、面部、手背等阳光暴露区域[3,41]。本研究大部分SCC发生在头颈部,占比63.9%,其次是面部和手部,分别占比27.8%和22.2%。
本研究发现患者发生皮肤SCC会伴有光敏反应、患者免疫功能异常、使用免疫抑制剂、移植状态等潜在危险因素。97.2%(35/36)患者存在免疫功能异常,如血液病、移植、HIV等,这类患者往往需要长期使用VCZ黏膜治疗或预防真菌感染,而在紫外线作用下,其身体暴露区域容易出现光敏现象,继而导致皮肤AK样病变,甚至皮肤SCC。Hamandi等[42]在一项研究中调查了肺移植和免疫抑制治疗后预防用VCZ黏膜患者的皮肤SCC发病率,发现单独暴露于VCZ的患者皮肤SCC发病率增加(aHR=2.39,95%CI=1.31~4.37),差异有统计学意义,表明移植和免疫抑制治疗是其潜在风险因素。也有报道称,那些经常暴露在强烈的日光下,对皮肤没有适当的保护的人的患病风险也很高[3]。本研究病例中,75%患者有日晒史,表明了紫外线作用易引起光敏反应,是皮肤SCC的潜在危险因素之一。
VCZ黏膜产生光敏性和光致癌作用的机制尚不明确。可能机制一是VCZ主要的代谢产物氮氧化伏立康唑(voriconazole N-oxide,VNO),可能是引起光毒性的主要原因。VNO没有抗菌活性,占VCZ血浆中循环代谢产物的72%。光毒性反应的活性光谱大多在长波紫外线UVA的波长范围(320~400 mn),分光光度分析显示VCZ不吸收紫外光,而VNO可吸收紫外光,后者可作为生色团导致光毒性[43]。二是VCZ可以抑制肝药酶(如CYP2C9、CYP3A4等)的活性[44],增加体内维A酸的浓度导致光毒性。Cheng等[45]认为VCZ作为肝药酶抑制剂可以阻碍维A酸的代谢,使得体内维A酸的浓度增加,而高浓度的维A酸具有光毒性,会增强紫外线作用而导致严重光毒性作用。
皮肤SCC患者的总体预后良好,本研究提及转归的20例患者中,停药后治愈/好转13例,占比65%(13/20)。本研究中也有8例患者换用泊沙康唑、伊曲康唑等后,ADR症状消退或改善[11,13,15,24-25],泊沙康唑、伊曲康唑等真菌感染防治药物或可作为VCZ出现皮肤ADR后的替代药物。皮肤SCC首选治疗方法是手术治疗,本研究约70%采用了手术治疗方式,与文献[46]报道一致。本研究中提到最多的是Mohs手术(28%),Mohs手术是一种旨在确保完全切除肿瘤和避免不必要切除健康组织的技术,被认为是局部侵入性、高风险皮肤癌切除的外科手术[47]。Mohs手术也被证明对原发性皮肤SCC的控制非常有效,术后的局部复发率、淋巴结转移和疾病特异性死亡非常低[48]。另外,考虑到癌变位置、病变数量和手术切除后复发情况等,手术并不适合所有皮肤SCC患者,若不能手术可考虑手术替代治疗(如光动力或冷冻疗法)、放射疗法(强烈推荐用于有淋巴结和/或腮腺转移患者[49])、化学疗法(如顺铂)、靶向疗法(如西妥昔单抗)、免疫疗法(如西米普利单抗)等。
在防治方面,早期预防和发现皮肤SCC至关重要,建议长期(6个月以上)使用VCZ患者,应每6~12个月接受一次全身皮肤检查,同时避免阳光照射,并使用紫外线防护剂[50]。在真菌感染防治过程中,VCZ等西药具有一定的优势,但中医药防治方面也起到了积极作用。中医药角度认为继发性深部真菌感染发病的特点是假热真寒,正虚邪实[51]。因为免疫力低下的患者往往容易发生真菌感染,在防治真菌感染时,应提高患者机体免疫力,而中医疗法恰恰是遵循“补虚为要,兼顾祛邪”的治则[52]。另外,中西药联合治疗真菌感染具有协同作用,可缩短病程,提高临床疗效,降低抗真菌药物的不良反应,在临床治疗真菌感染中发挥着重要的作用。有研究对2例恶性血液病化疗后合并曲霉菌肺炎感染的患者采用中西医结合治疗方式,应用伊曲康唑、大蒜素等药物控制感染,应用胸腺肽提高机体免疫功能,同时应用中药千金苇茎汤加味,以清热解毒、宣肺化痰,患者治疗后病情明显好转,取得了良好效果[53]。一项Meta分析结果也显示中医药联合西医常规治疗慢性阻塞性肺疾病合并真菌感染较单独运用西医常规治疗能提高临床有效率,减少不良反应发生[54]。Wei等[55]等研究也发现,以黄芪-当归-金银花-甘草,蛇床子-苦参-干姜,红花-白术-陈皮,枳壳-陈皮-柴胡等为核心药物组合的中药方剂,能发挥补益虚损、清热解毒、利湿化痰、活血祛瘀等作用,与传统抗真菌药物相结合,在治疗重症医学科真菌性脓毒症患者中取得了良好的疗效,表明了中医不仅能治疗病原菌感染,还能治疗被病原菌影响而失衡的体内环境——治虚实、治寒热、治水、治血。
本研究局限性为:①关于VCZ与皮肤SCC的个案报道本研究仅收集到36例,存在漏报或未报情况,结果可能存在偏差;②本研究纳入人群90%以上(35/36)存在免疫功能异常情况,可能影响研究结果;③无我国病例,可能与我国实际情况存在偏差。
在接受VCZ预防和治疗真菌感染时,患者应注意防晒,特别是男性患者,临床应关注患者皮肤光敏性病变情况,尽早评估风险并积极采取预防措施。对长期(6个月以上)需要用VCZ治疗的患者,建议定期随访或定期皮肤检查,也可考虑中西药联合治疗方式,缩短病程,提高疗效,降低不良反应。目前研究中VCZ致皮肤SCC存在多种潜在因素,如日晒强度、免疫功能异常、移植状态、免疫抑制剂等,可能会混淆VCZ与皮肤SCC之间的关系,需要进一步前瞻性研究来确定VCZ给药剂量和持续时间的合理性。
  • 江苏省医学重点学科(临床药学)建设项目资助(ZDXK202247)
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2025年第60卷第6期
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doi: 10.11669/cpj.2025.06.012
  • 接收时间:2024-12-10
  • 首发时间:2025-11-07
  • 出版时间:2025-03-22
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  • 收稿日期:2024-12-10
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江苏省医学重点学科(临床药学)建设项目资助(ZDXK202247)
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    苏州大学附属第一医院药学部, 江苏 苏州 215006

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*钱玉兰,女,硕士,副主任药师 研究方向:临床药学 Tel:(0512)67780997
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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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