DRUG RELATED NITROSOGENESIS, PHOTOCARCINOGENESIS AND ONCOPHARMACOGENESIS OF NODULAR MELANOMA: A CASE RELATED ANALYSIS CONCERNING THE POLYCONTAMINATION OF THE POLYMEDICATION WITH VALSARTAN/HYDROCHLOROTHIAZIDE AND BISOPROLOL.

Despite the fact that the pathogenesis of cutaneous melanoma is shrouded in mystery, factors that have been neglected or unnoticed until now have come to the attention in recent years, and in all likelihood, they could also be pivotal. These factors, known as nitrosamines or NDSRIs, are characterized by high carcinogenic and mutagenic potency, and some of them have demonstrated these properties to human DNA as well. Unfortunately, these ingredients also turn up as contaminants in about 300 of the most widely distributed drugs worldwide. According to the most recent literature, some of these ingredients are also identified as potent photocarcinogens, as well as human carcinogens. The intake of these carcinogens in the context of polycontamination of polymedication, has been associated for years with the occurrence of melanomas. The need for cataloguing of nitrosamines , as well as their accurate labelling on drug packaging, would help to classify them even more accurately as carcinogens affecting human DNA. We present once again a patient , who developed nodular melanoma within the context of the intake of 3 potentially nitrosamine/ NDSRIs contaminated antihypertensive drugs (valsartan/ Hydrochlorothiazide/ bisoprolol). Pathogenetic aspects concerning drug-induced nitrosogenesis, photocarcinogenesis and oncopharmacogenesis of skin cancer are discussed. Nitrosogenesis' of Cancer as concept in the medical literature has been known for decades, but in relation to other forms of human cancer. Exogenously mediated drug-mediated nitrosogenesis is a logically conditioned and newly defined concept whose significance with respect to the clinical manifestation of skin cancer is only beginning to grow.

Fine scalpel surgery: preserving the dartos muscle in a patient with scrotal and perigenital giant Buschke-Löwenstein tumors.

Giant condyloma acuminatum (GCA), alternatively referred to as a Buschke-Löwenstein tumor (BLT), is an uncommon, benign, but locally aggressive form of verrucous carcinoma. The condition usually affects the male population under the age of 50 years; however, there have been rare reports of pediatric cases. Various risk factors such as smoking, diabetes, promiscuous behavior, poor hygiene, immunosuppression, and others are linked to the development of this condition. We present the case of a 26-year-old male patient who came to the dermatology department with primary complaints of 10-year-old verrucous tumor formations located in the perigenital and perianal areas. Serological tests for AIDS, hepatitis B, hepatitis C, Chlamydia trachomatis, and syphilis were negative. The routine blood tests were slightly abnormal. Histological verification of condylomata acuminata of Buschke-Löwenstein was made. Given the sensitive areas, surgery was advised. With several fine undermining scalpel excisions, the lesions in the scrotal and perigenital areas were removed and the dartos muscle was preserved. Electrodissection and shave curettage were not performed. The postoperative period passed without complications and no recurrences in the perigenital area were reported. We believe that our case report represents the first documented surgical approach for scrotal Buschke-Löwenstein tumor using exclusively fine undermining scalpel surgery. A brief literature review of the condition is presented, focusing on the currently available treatment options and highlighting the potential effectiveness of the surgical approach.

THIN MELANOMA ARISING IN NEVUS SPILUS: DERMATOSURGICAL APPROACH WITH FAVOURABLE OUTCOME.

Nevus spilus is a term in the literature used for a benign pigmented cutaneous lesion, occurring shortly after birth or in the early stages of infancy. The lesion itself is very distinguishable in most cases with numerous small papules or macules on a "café au lait" background pigmentation. It can be seen on different parts of the body with predominance in the areas of the extremities. Although benign, in some cases malignant transformation can occur. Malignant melanoma arising within a nevus spilus lesion is not so unlikely anymore. We report a 36-year-old female patient with a thin cutaneous melanoma developing within a congenital nevus spilus lesion successfully treated with surgery. The complete surgical removal of melanoma and nevus spilus ensures the absence of recurrences as well as the need for follow-up of patients. This surgical approach should be discussed with patients, and clinicians' recommendations depend on 1) the morphology of the lesion, 2) the size of the lesion, 3) the localization of the lesion, and last but not least : the presence or absence of stigmatization in the patients themselves. Our main focus in this article will be on the importance of an early diagnosis and eradication of such lesions while reviewing the existing literature.

"THE DANGEROUS BRASSIERE" AND THE NEVUS ASSOCIATED POLYPOID MELANOMA: CONNECTION SEEMS PLAUSIBLE?

The development of cutaneous melanoma of the skin based on dysplastic nevus is not uncommon. The causes of the progression of nevi to melanomas are numerous and not well understood at present. Certain genetic and epigenetic factors have a major influence on this evolution. We describe a 46-year-old female patient with multiple dermal melanocytic nevi who developed a polypoid melanoma in one of them. After a carefully performed anamnesis, the mole that developed into melanoma was found to be localized in the dorsal area adjacent to the brassiere and underwent permanent and daily mechanical irradiation during the last 6-7 years. Around this mole there were 5 other moles with similar clinical and dermatoscopic morphology, which did not transform into melanomas and were not subjected to mechanical irritation. The patient had a dermatological examination 6 years ago and it was suggested that this lesion has to be surgically removed, which she declined. The patient was treated surgically and the lesion suspicious for cutaneous melanoma was removed in two stages according to the generally accepted AJCC/EJC recommendations. In parallel, 5 additional melanocytic nevi were removed, which histologically had features of dysplastic dermal melanocytic nevi but no signs of progression to melanoma. This article discusses the causes of nevus -associated melanomas and emphasizes the thesis of potential malignant transformation through mechanical irritation - in this case that of the brassiere. The moles localized in this area, although clinically and dermatoscopically inapparent, should be treated surgically. This painless, short-term manipulation has a preventive effect on the future development of cutaneous melanomas.

BULGARIAN PATIENT WITH ATROPHODERMA OF PASINI AND PIERINI- DESCRIPTION OF A CASE AND SHORT UPDATE.

Atrophoderma of Pasini and Pierini is a rare, considered benign, skin disease characterized by single or multiple asymptomatic atrophic plaques. Lesions can occur everywhere on the body with the trunk being the most often reported affected site. It appears in the second or third decade of life and affects mostly the female population, with male to female ratio of 1:6, commonly of white European descent. Different risk factors were described in the literature - genetic predisposition, infections with Epstein-Barr virus, varicella zoster and Borrelia burgdorferi, vaccinations, local trauma and more. Since the pandemic with COVID-19, skin manifestations after the viral infection with COVID-19 were reported. After a thorough search of the existing medical literature, we believe, we present the first case of a rapid progression of Atrophoderma of Pasini and Pierini after COVID-19 infection. Due to its similarity to morphea in some aspects, the condition is often misdiagnosed, and the proper treatment is often delayed. Sometimes the dilemma "Is it atrophoderma Pasini-Pierini or is it in fact morphea?" stays, but the exact histopathological verification and the "diagnostic clues" which can be used during the examination stage, are usually enough to diagnose the condition. We present a 63-year-old female with a rapid progression of atrophoderma of Pasini and Pierini after a COVID-19 infection. The lesion that she presented with was single, asymptomatic, with central hypopigmentation and slight atrophy, with a smooth, shiny surface and ivory color, and peripheral hyperpigmentation, measured 18x5cm, without the presence of perilesional erythema. The patient was initially diagnosed clinically with localized scleroderma (morphea) and treated with hydroxychloroquine 200 mg once daily for a 5-year period without improvement. Years later two biopsies from different lesional sites were taken, resulting in absence of sclerosis and dermal atrophy, but - reduction in the thickness of the dermis with fragmentation and hyalinization of collagen fibers forming a parallel orientation, dilated vascular vessels of small caliber and reduced number of skin appendages, confirming the diagnosis of atrophoderma Pasini-Pierini. The patient's therapy was switched to methotrexate with good therapeutic response. Often, the two conditions - morphea and atrophoderma of Pasini and Pierini can be mistaken due to its clinical similarity and sometimes coexistence. Therefore, we will shortly review the existing literature with key points on the similarities and differences.

CONGENITAL LYMPHANGIOMA OF THE FOOT MIMICKING MULTIPLE VIRAL WARTS: DERMATOSURGICAL APPROACH WITH SECONDARY WOUND HEALING AND FAVOURABLE FINAL OUTCOME.

The problems with lymphangiomas in general stem from the fact that on the one hand they most often show an atypical clinical picture, and on the other hand their localization does not always allow the desired complete surgical removal. Lymphangiomas are rare and benign tumors of the lymphatic vessels. In the higher percentage of cases, they are defined as congenital malformations. The acquired type can manifest due to a variety of external factors, resulting in a benign distinct lesion, which can often be mistaken for another benign or malignant one. Although benign and even surgically treated , the recurrence rate is high. The pathogenesis of these tumours is unclear and is presumed to be due to an error in the fetal/embryonal development. Nosologically, these lesions belong to the group of so-called low flow lesions. Within the framework of their differentiation, it is important to distinguish them from hemangiomas and venous malformations, as although overlapping to some extent, at times- therapeutic options differ. This differentiation is most adequately accomplished by the application of MRI and Doppler, necessarily accompanied by histopathologic verification of the lesion. Spontaneous regression, although rare, occurs in up to 6% of cases. Surgical removal remains the safest method of treatment to date, and according to the literature this is possible in only 18 to 50% of cases. Often, however, the atypical clinical presentation of some of the lesions could be confusing for clinicians and could be the reason for prolonged and unsuccessful conservative or semi-invasive therapy. We present a 23-year-old patient with a history of complaints of more than 15 years in the form of itching, burning, and discomfort in the left foot area. The finding was treated under the diagnosis of viral warts with variable results and subsequent achievement of short-term remissions for no more than 5 -6 months. Due to an increase in pain symptomatology and an increase in the size of the lesion after the last cryotherapy, a skin biopsy was taken to confirm the diagnosis of lymphangioma. During hospitalization, the patient underwent MRI/Doppler of the vessels to determine the depth of infiltration and the presence/exclusion of communication to larger vascular formations for preoperative planning. Surgery was performed with secondary wound healing resulting in a favourable outcome.

SUBUNGUAL HEMATOMA OVERLAPPING WITH SUBUNGUAL LOCATED FOCAL MELANOCYTIC HYPERPLASIA: DERMATOSURGICAL APPROACH AS OPTIMAL TREATMENT CHOICE.

Subungual lesions present a serious challenge for clinicians. The following factors can cause certain problems in interpreting the data: 1) Changes in lesion morphology over time: It may indicate the presence of a malignant lesion (increased pigmentation over time and lack of distal growth) but may actually be a benign lesion (chronic persistent subungual hematoma). 2) Patient's medical history can be misleading or difficult to verify, especially in problematic patients, or those with mental health problems or communication disorders (e.g., Asperger's syndrome, autism, schizoid psychosis, etc.). 3) The morphology of the lesion itself can be difficult to determine in the presence of simultaneously overlapping lesions. These patient dilemmas primarily concern the differentiation between subungual hematomas from subungual melanomas. The clinicians's concerns are based on the potential for metastasis and the risk of significantly worse prognosis for patients affected by nail biopsy. We present a 19-year-old patient with a subungual pigmented lesion with a clinical/dermatoscopic suspicion for subungual melanoma. Primary complaints for about 3-4 months. Intensified pigmentation and increase in size within two months led to a partial surgical resection of the nail plate and nail bed, followed by adaptation of the wound edges with single interrupted sutures. The histopathological finding was indicative of a subungual hematoma located above a focal melanocytic hyperplasia of the nail bed, clear resection lines. After a literature review, we believe that this is the first case of a patient with simultaneously present subungual benign focal melanocytic hyperplasia overlapping with a chronic persistent subungual hematoma.

NITROSOGENESIS OF SKIN (HUMAN) CANCER- THE HIDDEN TRUTH OF A NEVERENDING STORY: NITROSAMINE CONTAMINATION IN OLMESARTAN, VALSARTAN AND HCT AS MAIN RISK FACTOR FOR THE DEVELOPMENT OF KERATINOCYTE CANCER.

The pathogenesis of skin cancer remains shrouded in mystery. Nevertheless, a substantial amount of new data is now available to provide a logical explanation regarding the possible link between 1) the occurrence of single or multiple acquired/somatic mutations and 2) the generation and progression of skin cancer, as well as 3) the potential association of the above two facts with the availability of nitrosamines in drugs for hypertension, diabetes, gastritis, acne, tuberculosis, various other antibiotics, etc. The nitrosogenesis of skin cancer is slowly but surely being established as a significant concept that could not be ignored for longer periods of time. It should only be analysed in detail with a view to future prevention for the benefit of public health. The nitrosogenesis of skin cancer is slowly but surely being established as a significant concept that cannot be ignored for longer periods of time. It should only be analysed in detail with a view to future prevention for the benefit of public health. Although this information has been known for decades (but in relation to the development of other cancers), there is still no comparative analysis of the mutations that occur after ingestion of a particular mutagen, also known as nitrosamine. This analysis could to some extent highlight/support or reject to some extent the thesis of the role of nitrosamines and genetic instability leading to the subsequent generation of a malignant cell clone. The notion of skin cancer nitrosogenesis should become a priority concept very soon, but it should also become an evidential memory, a byword, and an equivalent of the ignorance with which modern civilization has treated its own health for decades within the processes of globalization. It is these processes that include nitrosamines as a major component of the "medicinal and nutritional menu" of patients. It remains unclear at present why regulatory authorities are making endless attempts to legalise the availability of a number of mutagens/human carcinogens in the most commonly distributed medicines worldwide. And to persuade "others" that there is no risk from their permanent, controlled and long-term intake. The newly introduced regulatory norms in practice concern the potential/permissive availability of nitrosamines in a serious number of drugs: drugs with radically different mechanisms of action such as: ranitidine, metformin, ACE inhibitors, beta blockers, thiazide diuretics, sartans, rifampicin, but also probably a number of others. However, the occurrence of identical, similar patterns of cancers (skin cancers) following their administration (after ingestion of different classes of drugs) makes the ubiquitous permissive availability of nitrosamines (in each class of these drugs) the most potent and most likely pathogenetic inducer of cancer. These comparative patterns of skin tumor occurrence should have even stronger evidentiary value than even so-called prospective follow-ups. Nitrosamines are and remain one of the best studied mutagens/carcinogens that can alter/modify the human genome. A fact underlined repeatedly over the years (also based on in vivo data, repeatedly ignored) and a fact that, according to the literature, concerns mainly tire industry workers (British rubber workers). It is in this category of patients and after exposure to high doses of nitrosamines (potential inhalation intake) that high mortality has been found in bladder, lung, stomach, oesophageal cancer, multiple myeloma, leukaemia, prostate cancer, pancreatic cancer, and liver cancer. Similar international observations (in vivo/Sweden) concerning intensive human exposure (Swedish rubber workers) to high doses of nitrosamines in a working atmosphere (inhalation type of carcinogen uptake) emphasize the resulting direct subsequent risk of other alarming symptoms such as: nasal bleeds, eye and throat symptoms, hoarseness, cough, nausea, headache, and altered levels of eosinophils and total immunoglobulin G (IgG), compared with unexposed patients. The neglect of these important observations over the years has led to the ubiquitous and currently difficult to counteract and unpunished prevalence of nitrosamines in even the most commonly distributed drugs worldwide (except in the food industry). It is precisely because of this fact that it should come as no surprise to anyone that there is new evidence of an avalanche in the number of new cancers after ingestion of potentially nitrosamine-contaminated preparations. Skin cancer could be seen in the near future precisely as a model of a side reaction after application or long-term contact with mutagens called nitrosamines. Based on the above, and wishing to add to the worldwide data on the heterogeneous cancers that occur after contact with nitrosamines, we draw the attention of the scientific community to the risk of developing keratinocytic cancer after ingestion of nitrosamine-contaminated drugs: sartans and thiazide diuretics. We believe that the role of the generic substance in these drugs could also contribute to some extent to the progression of an already present tumour branch, but this influence is rather minor and without significant clinical relevance. We present a patient who had been taking 2 sartans (valsartan/ olmesartan) over the years as monotherapy and in combination with hydrochlorothiazide, who developed over time and within this intake two forms of keratinocytic cancer: verrucous carcinoma and basal cell carcinoma. The focus of discussion concerns a newly introduced medical concept: nitrosogenesis of skin cancer. The detailed study of nitrosogenesis should be a major, primary task for regulators, researchers, clinicians, and pharmaceutical companies.

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.

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.

MULTIFOCAL FIXED DRUG ERUPTION MIMICKING ACQUIRED DERMAL MELANOCYTOSIS.

Fixed drug eruptions (FDEs) are adverse drug reactions manifesting in the skin after exposure to a certain drug. The lesions can manifest as single or multiple eruptions followed by a post-inflammatory hyperpigmentation. The condition is very common among the young adult population and can be located on different parts of the body: the trunk, extremities, face, lips, etc. We report a case of a multifocal FDE following oral intake of Loratadine, Cetirizine dihydrochloride, Ibuprofen and/or Acetylsalicylic acid. Patch testing was recommended but later on declined by the patient. However, a small punch biopsy confirmed the diagnosis of multifocal fixed drug eruption. The lesions are often misdiagnosed or mistaken for other skin conditions. Differential diagnosis with an acquired dermal melanocytosis or other cutaneous eruptions could be done. Therefore, a brief review of the above-mentioned medications in the pathogenesis of the condition will be discussed.

METATYPICAL BCCS OF THE NOSE TREATED SUCCESSFULLY VIA BILOBED TRANSPOSITION FLAP: NITROSAMINES IN ACES (ENALAPRIL), ARBS (LOSARTAN) AS POSSIBLE SKIN CANCER KEY TRIGGERING FACTOR.

The pathogenesis of keratinocytic skin cancer has been well-studied over the years, with a main focus on the influence of UV radiation and the subsequent changes in the genome regulator p53, which affects the cell cycle and the programmed cell death, apoptosis. Alarming and relatively new trend is the link between nitrosamines in blood pressure medications (but not only) and the development of both melanocytic and keratinocytic skin tumors. In the recent past, high concentrations (above the so-called daily acceptable intake dose) of nitrosamines in ACE inhibitors and sartans became the reason for some of these medications to be officially withdrawn from the drug market. As of now, and according to the lawsuits filed, contamination with even or just one nitrosamine could be the cause of lawsuits for between 5 to 10 forms of cancer overall. Single case reports, but also large-scale retrospective international studies, find a connection between the intake of possibly nitrosamine contaminated ACE inhibitors/sartans with the subsequent development of basal cell carcinomas. The same studies also found a serious risk of developing melanomas and squamous cell carcinomas after taking ACE inhibitors, thiazide diuretics and sartans. This, in turn, leads clinicians to ponder the following dilemma: Is it possible that the key pathogenetic link concerning the development of skin cancer is due to their radically different mechanism of action (ACEs/ARBs/Thiazides)? Or, more likely, in all three antihypertensive drug classes, such as sartans, ACE inhibitors, and thiazide diuretics, there is another cancer-causing contaminant, the so-called nitrosamines? Systemic intake of potentially nitrosamine-contaminated sartans and ACE inhibitors would logically lead to the generation of relatively uniform skin tumors. Proceeding precisely from this thesis, we present two non-related cases of metatypical basal cell carcinomas in the nasal area, which occurred during the administration of ACE inhibitors/angiotensin receptor blockers and were successfully treated by transpositional reconstructive flap - bilobed flap. Possible contamination with nitrosamines as a pathogenetically significant factor is discussed.

MULTIPLE BCCS AND DYSPLASTIC NEVI AFTER ACE INHIBITORS (ENALAPRIL/PERINDOPRIL): THE ROLE OF NITROSAMINE CONTAMINATION/AVAILABILITY AS SUBSTANTIAL SKIN CANCER TRIGGERING FACTOR.

Nitrosamines as contaminants in a wide variety of drugs are also found to be one of the most likely causes of skin cancer. A detailed analysis of this contamination could in the near future solve to a large extent the puzzle of carcinogenesis concerning the keratinocytic forms of cancer and melanoma. But also, probably cancer in general. Over 80% of skin cancer is due to acquired mutations, and nitrosamines, which are contained as contamination in certain batches of the most commonly distributed drugs worldwide (such as sartans, ACE inhibitors, ranitidine, metformin, hydrochlorothiazide, rifampicin, and a number of others.) are considered among the most powerful external mutagens, carcinogens. Carcinogens that until 2021 were not supposed to be present in medicines and carcinogens for which it was subsequently decided to create a regulatory regime for permissible availability. Regardless of whether these contaminants are applied within the so-called daily acceptable intake dose or many times above it, the problem with the availability of nitrosamines continues to be present. It is also caused by the lack of reflection of the concentration of the corresponding nitrosamine in a certain drug. Thus, it is impossible to calculate the ˝permissible daily intake of the total number of mutagens and their concentration based on polymedication˝. In practice, drug manufacturers distribute nitrosamines in parallel with drugs, although they are not listed as a component of the product but are identified and allowed as contamination or substances with permissible availability by the EMA/FDA. From another point of view, the fact that is not commented on is also of interest, namely that not all batches are affected by this contamination. This suggests that the contamination may have been controlled, since in a manufacturing error the contamination should be widespread. The registration of the potential contamination of a heterogeneous type of medicinal products on the European market to the executive agencies for drug control in certain geographical areas has remained for years without any answer and opens a number of questions. The problem with ACE inhibitors is similar to that with sartans, hydrochlorothiazide, metformin, and ranitidine. The ˝special impression˝ of the clinicians is determined by the fact that the patterns of manifestation of the skin tumors during the administration of a heterogeneous class of medications are similar to completely identical. From this it could be concluded that the unifying factor between the pattern of occurrence could not be based on the action of the main substance of each drug class, since it remains to be radically different. The unifying link remains the sole and only contamination or the permissible already availability of a new ingredient known as nitrosamines. We present cases of multiple basal cell carcinomas and dysplastic nevi following enalapril and perindopril administration. The role of potential contamination of ACE inhibitors with nitrosamines for the development of skin cancer is discussed.

KARAPANDZIC FLAP FOR SQUAMOUS CELL CARCINOMA OF THE LOWER LIPP: POTENTIAL ROLE OF NITROSAMINES IN EPROSARTAN AS CANCER TRIGGERING FACTORS.

Chronic alcohol use, smoking, poor dental hygiene, absorbed sun radiation over the years, fair skin (Fitzpatrick type 1), light eyes, painful sunburns, congenital or acquired immunosuppression, certain rare syndromes, as well as infections with human papillomaviruses are perceived as risk factors for the development of squamous cell carcinoma of the lips. The new and at the same time modern aspects involving the pathogenesis of keratinocyte tumors in practice prove to be quite problematic for both patients and clinicians. These aspects are involved in the contamination or increased availability of certain nitrosamines in the antihypertensive medications. A serious international study in the last year has linked the intake of potentially contaminated (established availability without data on whether it exceeds the so-called ADI/acceptable daily intake dose) with nitrosamines valsartan with a relatively low, but still present risk of melanoma development. On the other hand, data from 2017 associate individual monotherapy of arterial hypertension with sartans with a significantly increased/statistically significant risk of squamous cell carcinomas development: more than a two-fold increased risk. It should be noted that at that time the problems with nitrosamines were completely unknown to the medical community. At the moment, there are numerous case studies that connect the use of sartans with the development of keratinocyte tumors - either single or multiple. We describe the first case of a patient who took eprosartan at a dose of 600 mg once a day for a total period of about 15 years with intake interruptions of no more than 6 years. Primary complaints in the lower lip area are from about 6 months. The preoperative biopsy showed evidence of squamous cell carcinoma. A multidisciplinary team performed a successful surgical treatment using the Karapandzic method, achieving an optimal aesthetic result. Based on the available literature data, the possible role of nitrosamines as a potential trigger for the development of squamous cell carcinoma is discussed.