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2023 年 3 月 11 日,保加利亚皮肤病外科学会第五届全国代表大会在索非亚举行,主要议题包括:亚硝胺是皮肤癌发展和恶化的最强诱因;作为一种可能的皮肤癌治疗选择,个性化一步法黑素瘤手术。

CONGRESS REPORT OF THE 5TH NATIONAL CONGRESS OF THE BULGARIAN SOCIETY FOR DERMATOLOGIC SURGERY, SOFIA, 11TH MARCH 2023 WITH MAIN TOPICS: NITROSAMINES AS MOST POWERFUL TRIGGER FOR SKIN CANCER DEVELOPMENT AND PROGRESSION/PERSONALISED ONE STEP MELANOMA SURGERY AS POSSIBLE SKIN CANCER TREATMENT OPTION.

机构信息

1Onkoderma - Clinic for Dermatology, Venereology and Dermatologic Surgery, Sofia, Bulgaria.

2Department of Dermatology and Venereology, University Hospital of Coimbra, Coimbra, Portugal.

出版信息

Georgian Med News. 2023 Apr(337):89-95.

Abstract

Deciphering the mutational pattern of skin tumours, remains a major challenge for clinicians and researchers. Over 80% of mutations in tumours are acquired, which in practice also means preventable. The surgical treatment of skin cancer and cancer in general is a worldwide, unsolved but at the same time not unsolvable problem. The problem concerning the dilemma of acquired mutations lies in the circumstance of their being allowed and subsequently treated. A more logical solution would be to eliminate the problem by making contact with mutagens in drugs public, clarifying it, studying it in detail and definitively stopping it. At present, there is an alarming and unexplained tendency worldwide : 1) Potential acquired mutations, caused in all probability by contact with known exogenous mutagens- the nitrosamines in most commonly prescribed drugs, are allowed to occur. 2) And subsequently, the diseases generated by them- treated (at a later stage) by multiple surgical interventions and unjustifiably expensive targeted therapy; 3) Mutagens - such as nitrosamines for example, to be in a permissive or possibly permissive availability regime. Moreover, this permissible availability turns out to be ubiquitous and affects the most common medicines worldwide: metformin, ranitidine, propranolol, rifampicin, irbesartan, olmesartan, valsartan, telmisartan, eprosartan, losartan, ACE inhibitors, thiazide diuretics, etc. In certain geographical regions, there is almost no patient taking this type of medication who has not had at least one tumour detected. These significant correlations (nitrosamines/cancer) are labeled by the regulatory institutions as possible, probable, or not currently relevant. But in spite of ˝this inconclusiveness˝, the drugs, containing nitrosamines, are withdrawn from the pharmaceutical market: quickly and quietly, despite the fact that ˝they did not pose a threat˝. The FDA was the only organization and the most important regulatory body worldwide, which lifted the veil from this ominous picture back in 2018: nitrosamines in blood medicines and cancer risk. Unfortunately, at the moment, the problems with this issue are proving to be more than the solutions, and at the same time it remains completely unclear who is to blame for this 'sporadic contamination': the packaging of the drug, the humidity in the rooms where the preparations are stored or the synthesis process itself - the explanations are divergent, the responsibility is blurred. This fuzzy liability does not affect the manufacturers and distributors of the preparations/nitrosamines themselves in the manner required by law for this (mis)act. The Bulgarian Society of Dermatological Surgery remains to be the only organization worldwide that for the 5th consecutive year continues to seek solutions to the above-mentioned problems by: 1) Officialising all cases of skin tumors (but not only) occurring after intake of nitrosamine-contaminated drugs, 2) also officialising a significant number of cases of patients with cutaneous melanomas treated by the one-stage surgical removal method within one surgical session (OSMS). The main priorities of the organization remain: 1) the complete elimination of nitrosamines from drugs worldwide, 2) the optimization of melanoma surgical treatment guidelines with the goal of treatment within 1 surgical session: for thin melanomas, dysplastic nevi and melanoma in situ, a surgical margin of safety of 1 cm in all directions and without detection and removal of the draining sentinel lymph node. Whereas for medium and thick melanomas, the focus should be directed to the following recommendation: 2 cm surgical margin of safety plus detection and removal of the draining lymph node within one surgical session. The indication for the surgical removal of these lesions should be made on the basis of radically different criteria from those used to date by the AJCC/EJC, namely: based on 1) clinical presentation/ clinical morphology, 2) dermatoscopic finding, and if there is a melanoma suspected lesion with possible tumour thickness greater than 1 mm , 3) ultrasonographic measurement for preoperative determination of tumor thickness should be additionally performed. The methodology is applicable in up to 80% of cases, excluding only some rare findings such as: amelanotic cutaneous melanomas, cutaneous melanomas with regression zones or those with localization in the neck and head. However, after careful individual assessment and a subsequent selected approach, even these exceptions could be included in the innovative algorithm for one step surgical removal of cutaneous melanomas. The resulting problems of not resolving these two dilemmas could lead to: 1) Generation of skin cancer (but not only), through the availability of nitrosamines in drugs. 2) Unnecessary and stressful /surgeries for the patients- 2 in number, which not infrequently lead to complication of their status (due to delay of histopathological analysis/ desire for second opinion/ delay regarding the timeframe for the second surgical intervention/ uncertainty regarding the resection lines within the first intervention/ failure to respect the recommended surgical security resection margins already within the first surgical session, etc.). 3) Huge additional costs to health care systems on the order of probably/roughly calculated about $50 billion per year. Resolution of these two dilemmas would likely result in a dramatic drop in cancer incidence worldwide and a significant improvement in the effectiveness/efficiency of surgical treatment for cutaneous melanoma.

摘要

解析皮肤肿瘤的突变模式仍然是临床医生和研究人员面临的主要挑战。超过 80%的肿瘤突变是后天获得的,实际上也是可以预防的。皮肤癌和一般癌症的手术治疗是一个全球性的、未解决但并非无法解决的问题。关于后天获得的突变的困境在于允许这些突变发生,然后对其进行治疗。更合理的解决方案是公开药物中的接触诱变剂,并阐明其情况,详细研究并最终阻止它。目前,全世界都存在一种令人担忧且无法解释的趋势:1)可能由接触已知外源性诱变剂(大多数常用药物中的亚硝胺)引起的潜在后天获得性突变正在发生。2)随后,由它们引起的疾病——通过多次手术干预和不合理昂贵的靶向治疗进行治疗(在后期);3)诱变剂——例如亚硝胺,处于允许或可能允许的可获得状态。此外,这种允许的可用性无处不在,影响着全球最常见的药物:二甲双胍、雷尼替丁、普萘洛尔、利福平、厄贝沙坦、奥美沙坦、缬沙坦、替米沙坦、厄贝沙坦、氯沙坦、血管紧张素转换酶抑制剂、噻嗪类利尿剂等。在某些地理区域,几乎没有服用这类药物的患者没有至少发现一个肿瘤。这些显著的相关性(亚硝胺/癌症)被监管机构标记为可能、可能或目前不相关。但尽管存在“这种不确定性”,含有亚硝胺的药物仍从药品市场撤出:迅速而悄然地撤出,尽管“它们没有构成威胁”。FDA 是唯一一家也是全球最重要的监管机构,早在 2018 年就揭开了这一不祥图景的面纱:血液药物中的亚硝胺与癌症风险。不幸的是,目前,与这个问题相关的问题多于解决方案,同时,对于这种“偶然污染”,究竟该归咎于谁,仍然完全不清楚:药物包装、存放制剂的房间湿度还是合成过程本身——解释各不相同,责任模糊。这种模糊的责任不会按照法律要求对药物/亚硝胺的制造商和分销商产生影响。保加利亚皮肤外科学会仍然是全球唯一一家连续第五年通过以下方式寻求解决上述问题的组织:1)正式确定所有因摄入含有亚硝胺的药物而发生的皮肤肿瘤(不仅限于皮肤肿瘤)病例,2)正式确定大量接受一期手术切除法(OSMS)治疗的皮肤黑色素瘤患者的病例。该组织的主要优先事项仍然是:1)从全球药物中完全消除亚硝胺,2)优化黑色素瘤手术治疗指南,目标是在一次手术中进行治疗:对于薄黑色素瘤、发育不良痣和原位黑色素瘤,在所有方向上安全切缘为 1 厘米,不检测和切除引流的前哨淋巴结。而对于中厚黑色素瘤,重点应指向以下建议:2 厘米安全切缘加上在一次手术中检测和切除引流淋巴结。这些病变的手术切除适应证应根据与 AJCC/EJC 迄今使用的截然不同的标准制定,即:基于 1)临床表现/临床形态学,2)皮肤镜检查结果,如果怀疑有黑色素瘤可疑病变且可能的肿瘤厚度大于 1 毫米,3)术前应进行超声测量以确定肿瘤厚度。该方法适用于多达 80%的病例,仅排除一些罕见的发现,如:无黑色素皮肤黑色素瘤、有退行区的皮肤黑色素瘤或位于颈部和头部的黑色素瘤。然而,经过仔细的个体评估和随后的选择性方法,即使是这些例外也可以纳入皮肤黑色素瘤的一步式手术切除的创新算法中。未能解决这两个困境可能导致:1)通过药物中的亚硝胺供应产生皮肤癌(但不仅限于皮肤癌)。2)对患者造成不必要的紧张/手术——两次手术,这些手术经常导致他们的病情恶化(由于延迟进行组织病理学分析/希望获得第二意见/延迟第二次手术干预的时间范围/对第一次干预中的切除线不确定/未能遵守建议的安全切除边缘等)。3)医疗保健系统的巨额额外费用,每年可能/粗略计算约为 500 亿美元。解决这两个困境可能会导致全球癌症发病率大幅下降,并显著提高皮肤黑色素瘤的手术治疗效果/效率。

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