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.

(N-NITROSO) PROPAFENONE INDUCED ADVANCED NODULAR MELANOMA-FIRST REPORTED CASE IN THE WORLD LITERATURE: THE INEXTRICABLE LINKS BETWEEN THE PHOTOCARCINOGENESIS, DRUG RELATED NITROSOGENESIS AND PHARMACO-ONCOGENESIS.

Onco-pharmacogenesis or pharmaco-oncogenesis of skin cancer is a concept , which could also be considered as an "end product" of drug-mediated Nitrosogenesis or of the permissive regime for carcinogens to be (un)controlled released in drugs. Their controlled distribution remains until 2025 as a forced and non-alternative and there is no indication of any possibility to introduce a full elimination regime against the already mentioned carcinogenic availability. There are three main worrying facts that determine the need for these elimination regimes: 1) the clinicopathological correlations concerning the intake of a heterogeneous class of drugs and the subsequent development of relatively homogeneous tumours/ such as melanoma, 2) the recently proven mutagenic/ carcinogenic action of certain nitrosamines, but this time directly on human DNA, and 3) the fact that some of the nitrosamines are potent photocarcinogens that exert their genotoxic effects only after irradiation with UVA/ also recently proven/. In addition to the rhetoric mentioned above, there is also an overlap in mutational patterns between the genes previously generally accepted to affect melanomas - p53 / RAS oncogenes , with those identified as target genes, but being affected "mutationally", by certain nitrosamines. The processes of photocarcinogenesis, nitrosogenesis and oncopharmacogenesis of skin cancer are inextricably linked and should not be considered and analysed unilaterally or in a semi-invasive manner. Cataloguing the type of nitrosamines and their precise concentration on drug leaflets and prescription/official websites with permanent access to clinicians and end-users remains the only safe and effective weapon in the fight against (un)controlled contamination. The pharmaceutical industry and regulators remain the creators, the 'parents' of onco-pharmacogenesis, nitrosogenesis, and therefore the processes involved in the generation and progression of skin cancer. The impossibility of establishing elimination regimes for certain mutagens and/or carcinogens already proven to be present in medicines remains a mystery. In practice, end consumers find themselves in a state of enforced tolerance of certain genotoxic substances that are not even declared as available. Clinicians in the face of dermatologists/ dermatological surgeons remain the analysers and identifiers of these globalization processes. Once again, we present a patient who took the antiarrhythmic (nitroso-) drug propafenone and developed a relatively short-term nodular melanoma with a subsequent fatal outcome. We comment on the role of drug-mediated nitrosogenesis and its relationship to photocarcinogenesis and onco-pharmacogenesis.

MUSTARDE ROTATION FLAP AS ADEQUATE OPTION FOR HIGH-RISK BCC NEAR THE LOWER EYE LID: THE ADDITIONAL INTAKE OF N-NITROSO-FOLIC-ACID AND N-NITROSO-RIVOROXABAN AS COFACTORS/TRIGGERS OF THE METABOLIC REPROGRAMMING OF THE FUTURE CANCER CELL.

Contamination of a heterogeneous class of drugs with nitrosamines of an also different type underlies or defines the occurrence of drug-induced skin cancer Nitrosogenesis or keratinocyte cancer Oncopharmacogenesis. Further identification of some of these carcinogens in drugs as both phototoxic and genotoxic in turn defines concepts such as Drug-Mediated Nitroso-Photo Carcinogenesis. Its first formal representative was and remains at present Nitrosomorpholine (Nmor). Unfortunately, further data on the propensity of individual nitrosamines and/or their derivatives to absorb photons and generate phototoxicity are lacking. The simultaneous intake of a heterogeneous class of drugs in the context of Nitrosocontamination, now officially announced by regulators, makes the initiation of cutaneous carcinogenesis a perfectly possible scenario. Continuous, permanent intake of several types of carcinogens/mutagens or nitrosamines in the context of potential/or real Nitrosocontamination is probably able to activate certain oncogenes such as RAS oncogenes and neutralize certain tumor suppressor genes such as p53. We report another case of a female patient who developed over the years 3 high-risk basal cell carcinomas in the facial area in a stepwise fashion in the context of potentially contaminated drug treatment with ACE inhibitor/Ramipril/Beta blocker/bisoprolol/, anticoagulant/ rivaroxaban/ and folic acid. The possible role of Nitroso contamination in polymedication in the context of drug related Nitroso-Photocarcinogenesis for the triggering of multiple basal cell carcinomas is commented. The performed Mustardé rotation flap for the tumour near the lower eyelid was with optimal final reconstructive result. Nitroso-Folic acid and Nitroso- Riviroxabanan are described for the first time in the medical literature as possible key elements that could have an activating effect on skin carcinogenesis on the background of the so-called metabolic reprogramming of the future tumour cell.

PERIOCULAR HIGH RISK BCCS AFTER ADDITIONAL/PARALLEL INTAKE OF TORASEMIDE, MOXONIDINE AND MIRABEGRON: IMPORTANT LINKS TO SKIN CANCER RELATED (PHOTO-) NITROSOGENESIS IN THE CONTEXT OF PHARMACO-ONCOGENESIS.

The Nitrosogenesis of skin cancer is a modern newly introduced concept in medicine, mainly concerning melanoma, but also keratinocytic cancers such as basal cell carcinoma. The nitroso-contamination of more than 300 drugs worldwide and the permanent (relatively short-term) intake of mutagen-contaminated drugs could create serious prerequisites for the development of skin cancer. Retrospective but also prospective analyses following potentially contaminated polymedication with a heterogeneous type of nitrosamines in real patients are indicative of a causal connection rather than a sporadic association between 1) intake of a possibly nitrosamine-contaminated drug and 2) generation of keratinocytic skin cancer. The pathogenesis of high-risk periocular localized basal cell carcinomas was until recently shrouded in mystery as it was mainly and until now associated with 1) intake of phototoxic drugs and 2) intense exposure to UV radiation (without intake of drugs), 3) congenital or acquired immunodeficiencies, and 4) Goltz Gorlin syndrome or 5) Xeroderma pigmentosum. Nitrosamines/ NDSRIs within the framework of polycotaminated drug intake appear to be one reasonable additional explanation for the association between carcinogen intake and subsequent skin cancer development and progression, and a relatively short-term one at that. Recently published scientific data provide information on a new ability of some of the nitrosamines - namely that some of them are photocarcinogenic or genotoxic after activation with UVA radiation. We present 4 patients who developed high-risk periocular localized basal cell carcinomas of the skin after/within the intake of potentially nitrosamine-contaminated drugs. The presented data are confirmatory with respect to previously published scientific observations on the carcinogenic effects of valsartan, candesartan, bisoprolol, metoprolol, perindopril, lisinopril and amlodipine. The contribution of newly validated data concerning potential/actual carcinogenic/genotoxic activity in the article is also due to the following newly announced nitroso preparations: torasemide, moxonidine and mirabegron. The expansion of the ˝bases of the pyramid˝ determining the stability of drug related (Photo) Nitrosogenesis/ Carcinogenesis (in terms of skin cancer generation) is growing daily. Exogenously/drug-induced Nitrosogenesis and the subsequently triggered carcinogenesis are a completely new explanatory concepts concerning the pathogenesis of skin tumors that remained unanalyzed and hidden for decades. Until now. The official lack of 1) availability, and of 2) precise concentrations regarding nitrosamines in medicinal preparations, are some of the most unexplained acts of irresponsibility to end-users and remain for the moment without a definitive answer from either regulators and manufacturers respectively. Polycontamination of polymedication in polymorbid patients remains highly problematic, at least as a cofactor in the development and progression of keratinocytic cancers, and this in the short term. Recently published data but also data from the past are suggestive that nitrosamines in tobacco are pivotal in the development of acquired mutations in p53 and RAS oncogenes in humans and rodents. The same genes are also affected by mutations in keratinocytic cancer patients. The overlapping mutation patterns of UV radiation-induced mutations in target genes such as p53 and RAS with those caused by some nitrosamines is indicative of a synergism available in terms of gene toxicity or possibly photocarcinogenicity of the latter. What leads the scientific community to believe that the nitrosamines in drugs, similar in composition and carcinogenic potency, act differently, is unclear. The link between drug intake, nitrosamine contamination, generation of some acquired mutations and subsequent cancer development becomes more than obvious and logically conditioned. The thesis of the controlled spread of cancer sounds more than logical today because: whoever controls and regulates the spread of carcinogens/mutagens/nitrosamines is also able to control the occurrence and spread of skin cancer. The Pharmaco-oncogenesis of skin cancer is determined by exogenously mediated Nitrosogenesis or the permissive availability for certain nitrosamines in drugs worldwide.

EDUCATION FROM DERMATOLOGISTS: THE SIMULTANEOUSLY DEVELOPMENT OF 16 KERATINOCYTIC CANCERS AFTER USE OF METFORMIN IN COMBINATION WITH LOSARTAN/ HYDROCHLOROTHIAZIDE, METOPROLOL AND NIFEDIPINE- IMPORTANT LINKS TO DRUG RELATED (PHOTO)-NITROSO-CARCINOGENESIS AND ONCOPHARMACOGENESIS.

Oncopharmacogenesis and Drug-Induced Skin cancer related Nitrosogenesis are newly introduced concepts in the medical literature that owe their genesis or presence to the carcinogens/ mutagens, also known as nitrosamines/NDSRIs, which are present in a heterogeneous class of drugs. The contribution to the origin of these 2 concepts is entirely due to 1) the functions and efficacy of FDA in terms of control and identification of these carcinogens, and 2) the establishment of clinicopathological correlations by the dermatologists, occurring during drug intake. According to recent FDA data, the concentration of NDMA in just one metformin tablet could be up to more than 5-fold increased. The intake of 3 to 6 tablets per day should result in a carcinogen intake that is 15 to 30 times elevated within the day and within the monomedication alone. It is these circumstances that paraphrase/ ˝betonate˝ concepts such as Onco-Pharmacogenesis and Drug-mediated Nitrosogenesis of skin cancer. Although not officially declared, these mutagens are present and have been in forced tolerance mode for the last 30-40 years. And after their intake, multiple cancers have been found to develop. The concomitant use of other nitrosamine-contaminated drugs such as losartan/hydrochlorothiazide, metoprolol and nefidipine should certainly not be surprising when it could also be associated with the development of exactly 16 keratinocytic tumours as in the case presented by us. Recent evidence in medical literature has linked the nitrosamine N-nitrosomorpholine (NMOR) with the direct development of its subsequent mutagenic action in rodents following irradiation with UVA. This fact leaves open the question of the potentially available photocarcinogenic action of the other nitrosamines in humans found in medicinal preparations. This is what necessitates a clarification of the concept of Photo-Nitroso-Carcinogenesis/ Oncogenesis in humans and its relationship to skin cancer. The overlap of the mutational patterns of some of the nitrosamine-induced mutations in target genes such as p53 and RAS oncogenes, with those of UV light-induced mutations - or practically the same ones mentioned above, suggest a possible significant role of the Drug-Induced Photo-Nitroso-Carcinogenesis of keratinocyte cancer in the context of Onco-Pharmacogenesis. Future analyses should focus on elucidating the photocarcinogenic effect of nitrosamines in drug preparations and differentiating Skin cancer Nitrosogenesis from ˝pure˝ Photo-Carcinogenesis and Nitroso-Photo-Carcinogenesis. The localization of the tumors in the area of the UV-exposed sites within the potential/actual contamination of the 4 preparations (simultaneously) in the described patient are indicative of a possible pathogenetic influence in the context of the already mentioned Nitroso-(Photo)carcinogenesis. Polycontamination of polymedication remains a so far unresolvable problem.

(NDMA) METFORMIN AND (NTTP) SITAGLIPTIN INDUCED CUTANEOUS MELANOMAS: LINKS TO NITROSOGENESIS, NITROSO-PHOTOCARCINOGENESIS, ONCOPHARMACOGENESIS AND THE METABOLIC REPROGRAMMING.

Changing the vision, understanding, interpretation and analysis of certain data or scientific dilemmas is what is able to change the status quo and revitalize a mission, an impulse or important thoughts, thus creating the conditions for it to increase immensely the chances of bringing it to success. Or, following Albert Einstein's postulate: ˝We cannot solve our problems with the same thinking we used when we created them˝, we should think: ˝Where does the road to success start? How do we solve or neutralize a problem? ˝ And the answer is: ˝ By taking a consistent and systematic approach, analyzing each component! And we eliminate every possibility of negative influence.˝ These thoughts apply with full force to cancer rates in general, but also to melanoma rates in particular: the murderous tempo of globalization and modernization in medicine has not yet led to the desired decrease in these rates; on the contrary, they are rising headlong and remain largely unpredictable and difficult to regulate. The conclusion is that a solution should be sought by refracting light through another prism: that of Nitrosogenesis and Pharmaco-Oncogenesis. A step-by-step and systematic approach to solving a problem requires patience, determination, and perseverance. As this perseverance is needed mainly to overcome the general ignorance, neglect, disinterest, uneducation and uncertainty of others, rather than doubt in one's own thesis, analysis, and the need for an active approach. Careful analysis of concepts such as ˝Drug Mediated Nitrosogenesis˝ and ˝Onco-pharmacogenesis/Pharmaco-oncogenesis˝ of skin cancer would certainly contribute to the elucidation of skin carcinogenesis in the context of polymedication of the contamination and polymorbidity worldwide. The FDA has already in 2019 taken this much needed first step of universal awareness and its ˝arm˝ has been taken seriously and responsibly solely by dermatologists and dermatosurgeons. It was this guild and only this guild that launched its independent, never-ending observations, logically grounded (hypo)theses, remaining to date confirmatory, unshakable, and enigmatic regarding the unit: intake of potentially contaminated medication and subsequent development of melanomas. It is this and only this branch of the medical guild that has also become the guarantor of safety and objectivity in science, and thus of safety in the fight for survival of a huge number of skin cancer patients. Contaminated oral antidiabetic drugs in the face of Metformin and Sitagliptin do not make an exception in this respect. Similarly to cutaneous melanomas occurring (and published in the scientific literature) after combined intake (or monomedication) of/ between ranitidine, valsartan, olmesartan, candesartan, telmisartan, irbesartan, losartan, enalapril, lisinopril, perindopril, hydrochlorothiazide, nifedipine, amlodipine, propafenone, bisoprolol, nebivolol, melitracen and a number of others, we inform about another rare but not unexpected clinical observation: occurrence of cutaneous melanomas after taking another class of drugs- oral antidiabetic ones. Or after the intake of nitrosamine-contaminated antidiabetic drugs. And whether this contamination is "real or potential" is left to regulators and manufacturers to decide. We accept it as `real-potential' or `potentially-real' because of the fact that neither the regulators nor the manufacturers know what it is or whether it is there or how it arose. The data shared in patients one and two in the presented scientific work are confirmatory in relation to the potential pathogenetic action of nitrosamine contaminated drugs such as 1) bisoprolol/ nebivolol/ candesartan/ hydrochlorothiazide and amlodipine, as well as 2) furosemide in the direction of cutaneous melanoma. Patient 3 in fact also represents the first formally described patient with subsequent melanoma development worldwide, having developed it following intake of potentially/actually nitrosamine-contaminated metformin and metformin/sitagliptin (both drugs are themed in the FDA's Potentially Contaminated Drug Bulletin: 1) metformin, multiple times between 2020-21, due to its contamination with NDMA and 2) sitagliptin, as of September 2022, due to its contamination with NTTP). It should not be seen as surprising to anyone that the intake of relatively similar carcinogens/nitrosamines or NDSRIs, but as an unofficial component of heterogeneous drugs, produces a relatively monomorphic clinical picture- that of cutaneous melanoma. Or to put it metaphorically: ˝The wolf changes its hair, but not its mood˝. A carcinogen remains a carcinogen, regardless of whether it is ingested in a lemonade, a tablet, a sandwich, or a bonbon. Similarly to the intake of nitrosamines in food. Future studies should address the important tasks/dilemmas to elucidate 1) the phototoxic/photocarcinogenic effect of unmetabolized nitrosamines identified in drug formulations; 2) the phototoxic/photocarcinogenic effect of DNA adducts generated after their metabolization, and 3) the availability of specific DNA adducts in lesional/tumor tissue and blood of patients after ingestion of nitroso-containing drug formulations. This level of evidence is likely to lead to a reconsideration of the arguments for the introduction of permanent elimination regimes for nitrosamines in medicines. Metabolic reprogramming (and its relationship to UVB radiation) due to the availability of nitrosamines in cigarette smoke is also currently a proven reality. Based on the available clinicopathological correlations, we believe that nitrosamines in drugs have a similar effect and are part of the key pathway activating skin carcinogenesis under the influence of solar radiation. Intake of contaminated medication is associated with skin cancer generation and progression. It is up to regulators and manufacturers to justify the merits and benefits of the self-imposed presence of carcinogens in drugs or the benefits of such drugs. Apart from the "cancer-generating benefit", of course, which is already widely known. And let us not forget that: "A lie stops being a lie and becomes a truth the moment it is officially refuted".

MULTIPLE KERATINOCYTIC CANCERS AFTER INTAKE OF ANTIHYPERTENSIVES (LISINOPRIL/BISOPROLOL/HCT) AND ANTIARRHYTMICS (PROPAFENONE): THE IMPORTANT NEW LINKS TO THE NITROSO-CONTAMINATION AND THE METABOLIC REPROGRAMMING OF THE FUTURE CANCER CELL.

The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.

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.

LOSS OF EFFICACY OF ADALIMUMAB IN HIDRADENITIS SUPPURATIVA: FOCUS ON ALTERNATIVES.

The loss of efficacy of adalimumab, one of the most commonly used biologics for the treatment of hidradenitis suppurativa/acne inversa, is not news to the scientific community, and it should be noted that the number of cases not responding to this agent has been progressively increasing in recent years. We present a 45-year-old patient with hidradenitis suppurativa/acne inversa (Hurley II-III) with a complaint duration of 3 years who has been on adalimumab 40 mg weekly for 9 months. The lack of improvement in the clinical condition as well as the progression of the disease within the ongoing biologic therapy led to the need for repeated hospitalizations and the additional introduction of intravenous treatment with a regimen of antibiotics (Ertapenem, Metronizadol, Ceftriaxone), zinc, colchicine, and pain relievers. During these hospitalizations, a partial improvement was found, which was not durable and required the parallel administration of antibiotics, colchicine and zinc in combination with adalimumab in an outpatient regimen. Several attempts at surgical treatment/incision in non-specialized units were also made, and these too remained generally unsuccessful or with a nondurable, unsatisfactory clinical outcome. Due to the subsequent consecutive worsening of the symptomatology, the patient was admitted for evaluation of the clinical condition and optimization of treatment. Surgical treatment was performed by surgical deroofing under general anaesthesia, concurrent with discontinuation of adalimumab/antibiotic application and long-term remission was achieved. Surgical deroofing has also been shown to be an effective therapeutic option in the loss/lack of efficacy of adalimumab in patients with hidradenitis suppurativa (Hurley II-III). In the case of therapeutic resistance or worsening of symptomatology in patients with acne inversa within adalimumab therapy, other advanced alternatives such as golimumab, anakinra, etanercept are available. The efficacy of these second-line agents is also questionable due to the development of resistance to them as well, which in turn necessitates the frequent switch to third-line agents such as: Ustekinumab, Tildarkizumab, Certolizumab or Ixekizumab. The future will show to what extent this "trust" could be justified and whether in practice the surgical approach will once again displace the so-called "modern options" as the reasonable next basic and reliable alternative. The disadvantage of modern biological therapy is mainly due to the loss of efficacy/development of resistance over time, multiple side effects and frequent recurrence after discontinuation of treatment. In contrast, in the case of specific, stage-oriented, specialized surgical treatment of hidradenitis suppurativa/ acne inversa, in the form of surgical deroofing, for example, the results are long-lasting and in the case of recurrences: the latter are much more easily managed by dermatosurgery/surgery again. The effect achieved after this type of manipulation is essential for the patients' quality of life and guarantees to a large extent also prevention of the development of keratinocyte tumours in the areas affected by chronic inflammation. Precisely because of the aforementioned facts, in a serious number of patients this type of treatment could be considered as a priority. The rethinking of the guideline and the staging of surgical modalities as first-line therapy could, in a serious number of patients, have a positive effect. Swap for surgery seems to be a good alternative.

NITROSOGENESIS OF SKIN CANCER: THE NITROSAMINE CONTAMINATION IN THE CALCIUM CHANNEL BLOCKERS (AMLODIPINE), BETA BLOCKERS (BISOPROLOL), SARTANS (VALSARTAN/LOSARTAN), ACE INHIBITORS (PERINDOPRIL/ENALAPRIL), TRICYCLIC ANTIDEPRESSANTS (MELITRACEN), SSRIS (PAROXETINE), SNRIS (VENLAFAXINE) AND METFORMIN: THE MOST PROBABLE EXPLANATION FOR THE RISING SKIN CANCER INCIDENCE.

The Nitrosogenesis of skin cancer is a newly introduced concept in medical science, the significance of which is yet to be the subject of detailed analyses and discussions. Contamination of the most commonly used drugs for systemic treatment worldwide (such as Angiotensin receptor II blockers/ARBs, ACE inhibitors, Beta blockers, Thiazide diuretics, Metformin, Ranitidine, Nizatidine, tricyclic antidepressants, anticoagulants/dabigatran, Rifampicin, calcium channel blockers, SSRIs/ selective serotonin reuptake inhibitors, Varenicline) is already a fact and is more than worrying but also indicative. It is "this relationship" that has been repeatedly described in the medical literature (initially) as an association, and subsequently now increasingly as a causal relationship, a pathogenetic relationship. Observational data from clinicians over the past year increasingly speak in favour of a pathogenetic link and associate every single drug declared as contaminated with the development of heterogeneous forms of skin cancer gradually and surely. New drugs are added monthly that have not yet been declared as actually/potentially contaminated but are probably known to regulatory authorities or are in the process of being clarified. In parallel, the number of nitrosamines identified as contaminants in medicines is growing. This should not be surprising to anyone: ˝You take 3 drugs contaminated with mutagens- you subsequently develop skin cancer˝. Polymorbidity and multimedication against the background of polycontamination with nitrosamines appears to be the most serious problem at present. While until recently polymorbidity was considered to be a key factor in carcinogenesis (generator, trigger, inducer), today this dogma should be re-examined or looked at from another, radically different angle: from the angle of polycontamination to multimedication within polymorbidity. It is this that could provide a good explanation for the pandemic concerning skin cancer, for example. The development of relatively identical patterns of manifestation of skin tumors after concomitant intake of drugs declared as contaminated (drugs from the classes already mentioned above/ with radically different mechanism of action) supports unequivocally the thesis that: the nitrosogenesis of skin cancer is an undeniable fact that should be studied in detail. Studied because it could be eliminated. The analysis presented within this scientific thesis concerns 4 polymorbid patients who developed skin tumors within the framework of the multimedication they were assigned. The concomitant intake of medications declared as contaminated (in the presented patients) led to the manifestation of single or multiple skin neoplasms that were successfully treated surgically. Once again, the importance of potential/actual contamination of beta blockers, ACE inhibitors, oral antidiabetic drugs, and sartans in the generation of 1) non-melanocytic forms of skin cancer, and 2) melanoma precursor lesions or so-called dysplastic moles is established and validated. The possible contamination with nitrosamines of 1) other types of tricyclic antidepressant- Melitracen; 2) antidepressant of the selective serotonin reuptake inhibitor (SSRI) class: Paroxetine; 3) antidepressant of the serotonin and noradrenaline reuptake inhibitor (SNRIs) class: Venlafaxine, as well as of the systemic anticoagulant: apixaban is highlighted for the first time in the world literature.

NITROSOGENESIS OF CUTANEOUS MELANOMA: SIMULTANEOUSLY DEVELOPMENT OF PRIMARY CUTANEOUS THICK MELANOMA OF THE BREAST, THIN MELANOMA/DYSPLASTIC MOLE OF THE BACK DURING PARALLEL INTAKE OF BISOPROLOL, AMLODIPINE AND VALSARTAN/ HCT: NITROSAMINE POLYCONTAMINATION IN THE MULTIMEDICATION AS THE MOST POWERFUL SKIN CANCER TRIGGER.

According to the latest and modern concepts- polymorbidity and polymedication are perceived as one of the most likely triggers for the development and progression of skin cancer (and melanomas in particular). The reason for this should be sought in polycontamination with nitrosamines (in the context of polymorbidity and polymedication of affected patients). This polycontamination is expanding in scale with each passing day and this in turn allows its detailed (albeit postponed) analysis. The concept of polycontamination could be related on the one hand to: 1) the patient's medication (number of drugs affected by nitrosamine contamination), but also to: 2) the number of mutagens or so-called contaminants (nitrosamines) contained in a single drug preparation. Unfortunately, the recently introduced acceptable daily intake dose (ADI) as a concept by the regulatory institutions, does not find its much desired application due to : 1) the lack of precise indication regarding the nitrosamine concentration on the leaflet of each potentially/actually contaminated medicine ; 2) the immediately resulting impossibility to calculate the daily acceptable dose (concentration of mutagens) in each patient (within the framework of polymedication), as well as 3) the ever increasing number/type of those identified in medicines as contaminants. Thus, in practice, the daily medication intake (of several drugs belonging to the groups of drugs declared as officially contaminated) could have adverse consequences for the health of patients precisely due to the fact that: the concentration of nitrosamines in each of the drugs taken could (not) exceed the аcceptable daily intake dose, but the total cumulative intake for the day would (most likely) be - many times higher. At present, however, this calculation turns out to be more of a ˝dream˝: A delusion or a myth about a personalized medical approach. On a pragmatic level, it could be concluded that: the establishment of certain stereotypes of clinical behaviour (such as the occurrence of melanomas, for example) after the intake of a heterogeneous class of drugs (which in all likelihood contain relatively similar carcinogens/nitrosamines in terms of composition and concentration), should suggest at least a common pathogenesis. The article focuses the attention of clinicians on the issues related to the coadministration of potentially nitrosamine-contaminated drugs for high blood pressure (such as Bisoprolol, Amlodipine and Valsartan/Hydrochlorothiazide), while also emphasizing the outcomes that could result from this long-term co-administration: simultaneous appearance of thick melanoma in the left breast area, thin melanoma on the back and dysplastic nevus thoracic on the left. The Nitrosogenesis of melanoma appears to be a ˝new perspective/beam of light˝ concerning its pathogenesis, and from a radically different angle of observation. The confirmatory nature of the clinical picture (multiple melanomas) in the patient we presented could be seen as confirmatory of a number of analogous cases of multiple melanomas occurring after intake of nitrosamine contaminated antihypertensive drugs. The feasibility of personalized single-stage melanoma surgery, which was applied to the patient presented, is emphasized. The choice of a surgical resection field of 1 cm for thin melanomas with a suspected (clinically/ dermoscopically) tumour thickness of less than 1 mm proved in practice to be an adequate approach, in accordance with the standards of the newly developed innovative guideline for one step surgical removal of cutaneous melanomas (OSMS).

SENTINEL LYMPH NODE- A POSSIBLE GUARANTEE OF RECURRENCE-FREE SURVIVAL.

Dilemmas in the diagnosis and treatment of cutaneous melanoma, concerning the prognosis of patients, are far from finding an adequate or optimal solution at the moment. The issues are multifaceted and encompass a number of key points such as : 1) the choice of resection field, 2) the choice between a one-stage and a two-stage model of surgical removal of the tumor lesion, 3) the removal (or not) of the so-called sentinel lymph node, 4) the time intervals between the two surgical sessions, 5) the need or not for reciprocity between the clinically measured and the histologically established postoperatively resection field, and a number of others. The likelihood that the key to successful treatment/no recurrence of cutaneous melanoma lies in one or more of the above points is high. We present and analyze two patients with histopathologically established intermediate-thickness cutaneous melanomas, treated : 1) one of them: with a two-stage approach according to the generally accepted AJCC/EJC recommendations, and the other with 2) a single-stage procedure/ one step melanoma surgery (OSMS) with a resection margin of surgical security of 2 cm and no detection/removal of the so-called draining lymph node (at his request). The first patient developed progression and lethality within 2 years, and the second patient remained progression-free 6 years later. Conclusions based on these observations, although speculative, could be as follows: Strict adherence to the guidelines does not insure patients against progression and lethality (patient 1), but an individualized/ personalised/modified approach, as well as deviations from the official recommendations of the generally accepted guidelines (AJCC/EJC) - could ensure (sometimes) the absence of such (progression) (patient 2). In practice, the reason for the successful treatment of cutaneous melanomas and the lack of progression, could also be due to (or associated with) the differences in the therapeutic approaches applied by clinicians. These could be seen as a good starting point for deeper analysis. The reason for the lack of progression could probably be sought in the fusion of the surgical sessions or in the application of the one step melanoma surgery (OSMS). In practice, the total resection field in one-stage and two-stage melanoma surgery is the same, but in the one-step melanoma surgery (OSMS) approach it is achieved within only one surgical session. This fusion of surgical sessions provides a number of advantages for patients that are currently not well studied from a scientific/prognostic point of view. Another key, even strange point, is the non-performance of a sentinel/draining lymph node. According to common beliefs, detection and removal of the draining lymph node is advisable, but it has more diagnostic, clarifying rather than a therapeutic value. The lack of its localization and removal in the described patient could also be related/associated with the lack of progression (although unlikely): and this fact is evident not only in the data presented in this publication, but also in other cases described in the scientific literature. And would probably benefit from further careful analysis. The lack of progression in intermediate-thickness melanomas in certain patients could be related to the following 2 interesting, concurrent, and currently unclear events: 1) the consolidation of the 2-in-1 surgical sessions (i.e., in the application of a one-step model of surgical behaviour / OSMS/ one step melanoma surgery), and 2) the failure (probably) to perform a sentinel lymph node ditection and removal. Whether this is a sporadic finding-or whether there is a definite correlation-would need to be verified by observing a larger number of patients at different clinical centers. The likelihood that other factors influence the presence or absence of this progression remains quite possible.

NEIGHBOURING MELANOMAS AND DYSPLASTIC NEVUS DEVELOPING SIMULTANEOUSLY AFTER CANDESARTAN INTAKE: NITROSAMINE CONTAMINATION/ AVAILABILITY AS MAIN CAUSE FOR SKIN CANCER DEVELOPMENT AND PROGRESSION.

Although the problem with nitrosamines and their connection to the generation of skin cancer deepens, it is also thoroughly, carefully, and obligingly neglected. The probable reason for this is in all likelihood the lack of a solution or way out of this situation at the regulatory level. There is almost no sartan (on the European market/certain countries) after taking which the development of single or multiple melanomas, as well as melanomas in combination with single/multiple keratinocyte tumors, is not observed. But also, skin tumors (again melanomas) in combination with up to two other tumors - simultaneously or subsequently. These cases are immediately reported to the regional regulatory units, but unfortunately to no avail. Valsartan, irbesartan, olmesartan, and now candesartan is the main "suspect medications" for the development of melanomas, regardless of the dilemma: 1) whether the available nitrosamine remains responsible (for melanoma) as a mono/poly-contaminant (as availability or at a certain dose) or 2) is the generic substance itself also partly to blame? The literature data on the subject are contradictory, but does not exclude the involvement of any of these units in the generation and progression of melanomas. The lack of official results of possible checks for the presence (of nitrosamines) after the side effect reports were submitted to regulatory bodies further deepened the doubts of the clinicians, supporting the possible pathogenetic role of not only nitrosamines as a key link regarding the development of skin cancer. In practice, permissive regimes for the availability of carcinogens/mutagens in minimum permissible amounts, have been established? It is unclear whether this should be interpreted as a powerlessness of the regulatory authorities in the face of powerful pharmaceutical concerns? Or is it rather a lull before the start of general regulatory changes and a forthcoming "shifting of the layers"? The paradox also arises from the fact that many contaminated batches are quickly, quietly withdrawn from the market, despite being declared harmless or dangerous only for animals. We report on a patient who developed thin melanoma and neighbouring melanoma in situ after receiving candesartan, treated via one step melanoma surgery within one surgical session with a complete surgical margin of 2 cm. In parallel with the mentioned, a dysplastic nevus was observed clinically and confirmed dermatoscopically in the area of left scapula, for which surgical treatment is planned. Based on the currently available literature data, a thorough analysis of the role of nitrosamines, as a possible powerful pathogenetic factor for the occurrence and progression of melanomas, was made. The possible role of the generic substance as a cofactor in the carcinogenesis of skin cancer is also discussed.

А FLAVOUR OF DEATH: PERINDOPRIL INDUCED THICK MELANOMA AND BCC OF THE BACK. POTENTIAL ROLE OF THE GENERIC SUBSTANCE OR/-AND POSSIBLE NITROSAMINE CONTAMINATION AS SKIN CANCER KEY TRIGGERING FACTORS.

Contamination of certain drugs and foods with one of the most potent carcinogens/mutagens- nitrosamines, remains to be an issue and unresolved at present. The increased contamination of these mutagens in the most commonly used drugs in the human population doesn't ceases to baffle clinicians, critics, public scholars, and analysts of the nitrosamine saga. The introduction of permissive determinations of the presence of carcinogens in drugs only reinforces doubts about the powerlessness of regulatory authorities in the face of the influence of powerful pharmaceutical cartels. The FDA's encouraging promises of 2018 for strict control of carcinogens in sartans seems to have been permanently forgotten? By 2021, it was unthinkable that these carcinogens would be present in blood drugs and affected batches were immediately removed. Following alert checks confirming their post-existence in diabetes drugs, anti-smoking drugs, a number of antibiotics, ACE inhibitors, Sartans, thiazide diuretics, ranitidine, but probably a number of others, the decision has been taken to give the green light to their permissible availability. An availability that in all likelihood has the flavour of death. A "flavour" that has been confirmed in hundreds of international publications. Or in data from scientific papers submitted to regulatory regional units for verification and which remain sadly silent to this day. The "silent confirmation" and the lack of any adequate response in favour of public health are a sufficient further indicator of the attitude and position of the regulatory authorities. A position that should be changed. Starting from the mentioned facts and the data announced already in 2016/2017 of all-American data shared originally in American scientific journals, using their statistical estimates, we present the first case in the world literature of nodular melanoma and basal cell carcinoma occurring after taking perindopril. This intake turns out to be confirmatory one with respect to the statistics presented by Beatrice Nardone dating back to 2017. The potential pro-carcinogenic effects of both nitrosamines and the generic substance of perindopril are discussed.

THE NITROSAMINE CONTAMINATION IN BETA BLOCKERS (BISOPROLOL/METOPROLOL), ACE INHIBITORS (LISINOPRIL/PERINDOPRIL), THIAZIDES DIURETICS (HCT), CALCIUM CHANNEL BLOCKERS (AMLODIPINE/FELODIPINE), SARTANS (CANDESARTAN) AND ТHE SUBSEQUENT SKIN CANCER DEVELOPMENT AND PROGRESSION: APOCALYPSE NOW.

The problem of contamination of the most commonly used medicines with nitrosamines is worsening worldwide. According to recent literature data, this "contamination" is the cause not only of skin cancer (keratinocytic/melanoma) but also of gastrointestinal neoplasms, brain tumours, neuroblastoma, rectal carcinoma, acute lymphoblastic leukaemia, and many others. It is these clinical manifestations that are associated with/ or already directly linked to the nitrosamine content of drugs and food products used by patients in previous periods. And it is this permissive availability/contamination that could prove to be the most likely, powerful inducer of acquired mutations underlying the worldwide cancer pandemic. Of further concern is the evidence of contamination of newer classes of medications by nitrosamines- namely: beta blockers, calcium antagonists and selective serotonin reuptake inhibitors (SSRIs). In practice, mankind faces the problem of certainly over 1 billion patients taking nitrosamine-contaminated drugs: 280 million patients with depression (antidepressants), over 1 billion patients with arterial hypertension (antihypertensive drugs), over half a billion patients with type 2 diabetes mellitus (oral antidiabetic drugs/metformin/ sitagliptin), over 4 billion patients with gastritis (ranitidine), over 5 million with tuberculosis (rifampicin), and probably a number of others. The calculations are apocalyptic, since even if only 20-30% of the groups were affected, the number of patients taking these drugs would, by a rough calculation, currently amount to over 1 billion. And there are certainly other classes of drugs yet to be announced. It is for this reason that we should not be surprised that the data on the development of keratinocyte cancer after intake of nitrosamine-contaminated preparations is growing at a breakneck pace. This data indirectly but strongly confirms the importance of a newly introduced concept in the medical science : Nitrosogenesis of skin cancer. A concept, until recently unknown, incomprehensible, but at the same time frightening and gradually accepted, imposing itself and which with each passing day is gaining more and more scientific significance and "visibility", "scientific tangibility, receptivity, and acceptability." This article presents, for the first time in the world literature, patients who developed single/multiple forms of keratinocytic cancer (partly in combination with melanoma precursors-dysplastic moles) after administration of two new classes of potentially nitrosamine-contaminated antihypertensive drugs: beta blockers (bisoprolol, metoprolol) and calcium antagonists (amlodipine, felodipine). For the first time in the scientific literature, the contributory pro-carcinogenic role of another potentially nitrosamine-contaminated ACE inhibitor- lisinopril , as well as that of candesartan: in the development of keratinocytic cancer is also discussed. For the first time in the world literature, the conclusion regarding the pathogenetic relationship between the intake of potentially contaminated drugs (from different drug groups) and cancer development is based on the model of the equivalent clinical manifestation of skin tumors (rather than on controlled long-term prospective analyses). Nitrosamine contamination in these drug groups appears to be the sole and major unifying factor or causative agent for these manifestations.

METASTATIC NODULAR MELANOMA DEVELOPING ON NEVUS SPILUS DURING INTAKE OF BETA BLOCKERS (BISOPROLOL/NEBIVOLOL) AND ACE INHIBITORS (PERINDOPRIL). POTENTIAL LINKS TО THE DRUG RELATED NITROSOGENESIS/CARCINOGENESIS, DUNNING-KRUGER EFFECT AND GENETIC WEAPONS OF THE NEW GENERATION.

Drug-induced Nitrosogenesis/Carcinogenesis turns out to be a ubiquitous, pervasive, large-scale, poorly controllable concept for the academic community, which underlies the long-term, permanent modification of the human genome by contact with nitrosamines/NDSRIs, which ultimately leads to the generation of diverse cancers, but also melanoma in particular. The discovery of a (currently) unclassifiable number of nitroso derivatives/genome modifiers in the most commonly distributed drugs worldwide (in about 300 preparations according to the FDA/includes beta blockers/bisoprolol/nebivolol and ACE inhibitors/perindopril), their forced tolerability, attributed as a necessity or lack of alternative also to the present (but also to future periods), and their proven carcinogenicity (already 70 years ago), suggest a kind of creepy form of experiment to which public health is subjected worldwide. The creation of a universal nitroso-comfort of pharmaceutical companies and the regulation of a permanent intake of carcinogens in drugs for years to come, but also decades back, suggest possible cartel agreements between the regulation/distribution unit and that of production cycles. These "agreements" are becoming increasingly evident and in all likelihood position nitrosogenesis from a until recently unknown element, to a pathogenetic factor of paramount importance. Melanoma could be viewed precisely as the controlled end gene-modified product of drug-mediated nitrosogenesis/carcinogenesis, proven to be a locoregional (but not only) phenomenon hundreds if not thousands of times. The dilemma stays: Are the nitrosamines in drugs genetic weapons, ethnic bioweapons for silent war ? The nitrosogenesis concerning melanoma leads to the logical conclusion that cancer is in fact a largely controlled set event or, according to others, a forced necessity of evolutionary globalization processes to purge the population in certain regions. In favor of this statement indicative are namely: 1) lack of regulatory control/results of such conducted, 2) complete information veil for the end user regarding contamination with carcinogens/nitrosamines in certain batches or all batches of drugs, 3) misinformation and lack of transparency regarding the concept of nitrosogenesis also for the academic community, as well as 4) the impunity to pharmaceutical conglomerates after criminal negligence/controlled criminogenicity proven thousands of times by the FDA/EMA leading to regulatory controlled drug mediated genocide of the human population in certain areas on a daily basis. And most important of all: 5) the lack of refusal to eliminate these drugs, i.e. - the imposition of forced tolerance at any cost. It is extremely unfortunate that the mentioned and identified grotesque/situation, its tolerance on a global scale, lead to a misjudgement of the significance of real tumor inducers within the global health map//statistics as well as melanoma. The focus of prevention is being displaced, while the incidence of cancer in general and that of melanoma is skyrocketing. Nitrosamines could be defined as the newest, modern, until recently invisible and unknown, but -controllable form of genetic weapon to modify the human genome. Because of these very facts, the likelihood that clinicians and the academic community are in the frozen and permanent state of the Dunning-Kruger effect is very real. Certain globalization regulatory elements create problems and assignments that must be solved ˝competently˝ by incompetent, fully regulatable compartments. As their state of competence depends again and entirely on ˝their incompetence˝. Until now. After the formalization of the concept of Nitrosogenesis (as a form of genetic weapon) and melanoma for example, but not only, it remains to be seen whether universal incompetence will become a guarantee of competence and the survival. Or- will it remain again at the level of globalized, criminally conditioned, appointed and regulated from above "competent incompetence". The dilemmas to regulators and manufacturers remain open : Is it competent to take drugs that contain carcinogens/nitrosamines? Is it competent for this issue to continue for decades with impunity? Is it competent for regulators not to inform consumers about the presence of carcinogens/genome modifiers in medicines for decades? Is it competent for certain regions to be affected by nitrosamine contamination and not others? Is it competent not to reflect this in regional and global health bulletins on side effects? Is it competent to make thousands of times the profits from the modified genetic map business, regulated and legally initiated through the intake of carcinogens? Is it competent to have the concentration of carcinogens within polymedication exceeding many times the daily allowable doses of carcinogens and have no solution for this? Is it competent, when the intake of nitrosamines in medicines is associated with the generation of melanomas and heterogeneous cancers- to have no alternative to this or when one is available- to conceal it skillfully? Is it competent to determine carcinogenic activity based on mutagenic tests? Is it competent to be polyincompetent within a framework of mass (in)competence? We report systemically administered drugs for the treatment of high blood pressure from the group of beta blockers (bisoprolol/nebivolol) and ACE inhibitors (perindopril) that have been identified by regulators in the face of FDA as hypothetically contaminated with nitrosamines/NDSRIs with a carcinogenic potency between 4 and 5, respectively. Within this cumulative intake, (which according to the regulators was not at risk of developing cancerous forms), similar to other cases in the world literature, the patient developed a relatively short-term, metastatic nevus spilus-based nodular melanoma. The paper analyses not only the role of nitrosogenesis, but also that of two pregnancies and painful sunburns as potential cofactors for melanoma genesis. Academic attention is drawn to the potential impact of drug-mediated nitrosogenesis/carcinogenesis. Nitrosamines in the framework of polycontamination and polymedication could also be identified as one of the most effective, until recently unknown, modern generation genetic weapons for modifying the human genome and controlling cancer. Moreover, they could be controllably applied and skillfully targeted. At least until now. The officialization of carcinogens in more than 250 of the most common drugs and the clinico-pathological correlations concerning the development of cancer/melanoma in poorly controlled geographical regions represent a kind of in vivo prospective study to determine precisely the real carcinogenic role of nitrosamines to date.

NITROSOGENESIS, ANTIDEPRESSANTS AND THE SERTRALIN INDUCED NEVUS ASSOCIATED CUTANEOUS MELANOMA: THE NDMA/ NNK (NDSRIS) CONTAMINATION AS MOST POTENT MELANOMA INDUCTORS: ALEA IACTA EST.

The purposeful oblivion of the objective truth, the disregard of scientific reality, the denial of the contributions and successes of surrounding researchers, the substitution of priorities in clinical routine and the unwillingness to reason in the right direction often lead to disastrous consequences in the field of public health. Controlled projects almost never lead to a significant contribution or breakthrough in medicine that will be remembered by future generations. Another illustrative example in this regard is the link shared above to the saga of the worldwide cancer pandemic and its possible real cause: the contamination of drugs with nitrosamines/NDSRIs. The carcinogenic action of nitrosamines in rats under experimental conditions was demonstrated as early as the early 1960s (1954) by Barnes and Magee. The series of subsequent experiments in their numerous research studies was strongly indicative of a pathogenetic role of nitrosamines / dimethylnitrosamine / in the development of liver cancer and kidney cancer. Starting from the fact that contact with nitrosamines is of primary importance for the development of tumours in animals, there is practically no circumstance that would lead us to believe that the intake of the same mutagens in man would have a different carcinogenic effect from that already known to us (as was found under experimental conditions as early as 1954, but in animals). On the contrary, to this day the incidence of cancer is increasing every year and, according to global statistics, it is projected to increase by nearly 50% or 18 million new cases by 2040. The intake of (un)identified nitrosamines found in drugs as contaminants is increasing analogously to the shared breakneck cancer incidence. In addition to the number of identified carcinogens or NDSRIs, the number of affected drug classes is also progressively growing and in mid-2023 this number amounts to over 250 drugs according to the official data of the FDA bulletin of 08.04.2023. In practice, the population/patients have been in a continuous, still ongoing, multicentric prospective study since 1954. The parameters of the ˝experiment˝ are probably pre-set, crystallizing gradually over time and imposed forcefully in the form of hypnotic suggestions and directives by regulators. Encouragingly , the results of the prospective study are also available, are not one-sided and have been published in dozens of international journals as well as in part in the well-known Cancer Journal of the clinicians / Impact factor 254,7. The bad news is that in most of these observations and results, there is no correlation of what is shared between, say, 1) mandatory alternative-free intake of mutagen-contaminated drugs and 2) the breakneck development of heterogeneous cancers/including melanomas, and the scientific vision of the studies is currently rather one-sided. Cancer incidence is skyrocketing (according to Globocan/Cancer Journal for the Clinicians), and not a single worldwide study has commented on its potential link to actual contamination of the most commonly used drugs worldwide with nitrosamines/NDSRIs. For the past 5 years, the team of the Bulgarian Society of Dermatological Surgery has been committed to formalizing the final results of these prospective nationwide observational studies and providing full transparency on the relationship between the intake of actual/potential nitrosamine-contaminated drugs and the development of skin cancer. Over 95% of newly reported skin cancers during this period (2016-2023) were associated with prior intake of drugs listed in the 2023 FDA as potentially nitrosamine/NDSRIs contaminated or carcinogens. Melanoma is one of the most significant patterns of tumor arising after contact of the human body with nitrosamines. Whether the drugs affected by the contamination are from the group of sartans, beta blockers, hydrochlorothiazide, calcium antagonists, ACE inhibitors or antidepressants- the ultimate side effect remains the same and is known to the scientific community as or by the frightening and loud name : melanoma. We report the occurrence of another case of nevus associated cutaneous melanoma and multiple dysplastic nevi after taking the antidepressant Sertraline. A drug declared according to the official FDA bulletin of 08.04.2023 as potentially contaminated with class 2 nitrosamines/ NDSRIs: having similar to completely identical carcinogenic potency as that of NDMA and NNK. Or reciprocal to that in valsartan, irbesartan, olmesartan, repeatedly described already as possible melanoma inducers. According to the literature search, this is also the first case in the world of Sertraline-induced nevus associated cutaneous melanoma, and we share the view/ thesis that the real inducer of the tumor is in fact the impurities in the medication in the form of contaminants or nitrosamines: the so-called NDSRIs. The nitrosogenesis of skin cancer is a more than significant concept that has been cleverly concealed by the scientific community until recently. The reason for this concealment could be sought in the paramount importance or central role that the nitrosogenesis occupies at the base of the "pyramid" guaranteeing billions of dollars of monthly revenue to the regulators of globalism.

NITROSOGENESIS LESSONS FROM DERMATOLOGISTS-NITROSAMINES/ NDSRIS CONTAMINATION OF THE POLIMEDICATION IN POLIMORBID PATIENTS AS THE MOST POWERFUL SKIN CANCER INDUCTOR: DOUBLE HATCHET FLAP FOR SCC OF THE SCALP OCCURRING DURING TREATMENT WITH VALSARTAN/ HYDROCHLOROTHIAZIDE AND LERCANIDIPINE.

Nitrosogenesis remains to be a topic that is and, in all likelihood, will be relevant in the near and distant future. The reason for this actuality is mainly due to the official data of the regulatory authorities in the face of the FDA, starting back in 2018 with the announcement of the contamination of Valsartan with nitrosamines. This issue only became more profound in April 2023, when again the FDA declared over 250 of the most widely distributed drugs worldwide as actually or potentially contaminated with ˝hypothetical˝ carcinogens. Unfortunately, according to the literature, it is the intake of ˝hypothetical carcinogens˝ that is associated with the development of real carcinomas, including cutaneous tumours. Additionally, the type of carcinogens that could ˝hypothetically˝ be found in these drugs (in the regulatory agency recommendations) has been added to the list, and they are categorized as having a ˝hypothetical carcinogenic potency˝ between 1 to 5 according to the FDA regulation as to pharmaceutical companies from August 2023. Reference values have also been established for each carcinogen. Interestingly, in certain geographic regions such as Eastern Europe, for example, in certain institutions, over periods of 10 years or more, over 98.9% of cases of actual cutaneous tumours (keratinocytic, melanocytic, etc.), could be linked/associated primarily (not hypothetically) to polymedication, which according to official FDA data from April 2023, could be defined as actually/potentially contaminated with up to several ˝hypothetical˝ carcinogens simultaneously. The lack of official data on the contamination of these batches of drugs (with nitrosamines/ NDSRIs) remain even for the period 2018-2023 more than worrying and are one indirect evidence of their real rather than hypothetical availability. Nonetheless, the 2023 FDA data cast considerable doubt as to whether, within the polymorbidity and contamination of polymedication, the allowable daily doses of carcinogens are being substantially exceeded. An open question for regulators remains: Did the giant Pfizer withdraw its high blood pressure drugs in 2022 (hydrochlorothiazide, quinapril) due to the presence of ˝hypothetical carcinogens˝? In practice, Pfizer appears to be one of the few or only companies to have openly stated the reason for withdrawing their preparations due to contamination with real carcinogens and thus protect end users. With this official preventive act, the Giant Pfizer gained the trust of patients worldwide. Another and even more serious dilemma remains whether this is a controlled contamination of certain batches of medicines in certain geographical regions? Indicative therefore are recently published data on the absence of contamination of all batches of a certain class of medicines in certain geographical regions. The genesis of the 'sporadicity' and the 'selectivity' of contamination remain for the time being unresolved and open new and novel questions. We present an 82-year-old patient with arterial hypertension taking hydrochlorothiazide, valsartan and lercanidipine for 3 years who developed a short-term squamous cell carcinoma of the scalp after taking them (1,5- 2 years later) , operated successfully by double hatchet flap. The pathogenesis of the skin tumor/keratinocytic cancer is commented in the context of nitrosogenesis and the officially announced contamination by the FDA with ˝hypothetical carcinogens˝ leading once again to the appearance of a real squamous cell carcinoma of the skin. The polycontamination of multimedication within polymorbidity appears to be problematic. It is thanks to the official FDA data that the strength of these interrelationships is beginning to become clearer although not at the desired speed of clinicians and end users. Discovering the logical relationship between databases (concerning the incidence of skin cancer, but not only) from different periods should only be relative or consistent with current bulletins of regulators and contaminated polymedication. This is what guarantees that the objective truth will be brought to the surface and ensure, through the possible rapid elimination of the contaminants: 1) better survival for patients and 2) better quality of life.

NITROSAMINES IN COMMONLY PRESCRIBED ANTIHYPERTENSIVES AND THE (UN)CONTROLLED DRUG-INDUCED SKIN CANCER: SIMULTANEOUS DEVELOPMENT OF CUTANEOUS MELANOMA AND MULTIPLE BCC AFTER CONCOMITANT ADMINISTRATION OF BISOPROLOL AND FUROSEMIDE.

The era of nitrosogenesis is the era that is conditioned by the permanent and prolonged intake of carcinogens/mutagens, also known as nitrosamines/NDSRIs in the context of polymedication/polycontamination in polymorbid patients. Until recently, the favoured and universally accepted thesis by the scientific community that polymorbidity determines the risk of developing cancer has been shown to be weakly substantiated and superseded by the more modern notion that: it is the polycontamination with carcinogens in the context of concomitant medication/ polymorbidity that determines to a large extent the risk of developing heterogeneous cancers, including skin cancer: keratinocytic and melanocytic. The FDA is the organization that first pulled back the curtain on the backstage back in 2018 on this topic. It was not until 2023 that the FDA again catalogued over 250 drugs that are affected by contamination with carcinogens/mutagens/NDSRIs having varying carcinogenic potencies graded between 1 to 5. The expectations of clinicians and patients globally at the moment remain hopeful that the diplomatic recommendations of regulators will soon be replaced by more restrictive regimes and sanctions. The reason for the need to clarify this issue quickly is due to the following circumstances: 1) The reassuring calls and analyses of the regulators that the minimum intake of carcinogens ( nitrosamines or intake within reference values) , could not become a threat to the health of patients even after 70 years of intake, appear to be rather inconsistent; 2) Lack of any official data on any drug batch that has at least been declared by the FDA/EMA (if declared at all) as potentially contaminated; 3) Another not insignificant reason is that a number of scientific publications are indicative of exactly the opposite: short-term concomitant intake of polycontaminated drugs leads to short-term cancer development while shortening cumulative survival and quality of life for those affected. Only the transparency of the results of checks carried out on the presence of carcinogens in drug batches can guarantee peace of mind, and this in turn can be guaranteed by the regulatory authorities. 4) In parallel, the number of clinical data indicating an association between the intake of potentially nitrosamine-contaminated drugs (mainly for high blood pressure, but not only) and - in particular - keratinocytic and/or melanocytic skin cancer is growing avalanche-like. The dramatic increase in skin cancer in general/ worldwide is in absolute contradiction to the continuous explanations that the most important factor in the generation of skin cancer is ultraviolet light and sunburn: the incidence of skin cancer is increasing despite the widespread intensive use of sunscreen protection creams, the lack of any sun exposure in certain groups of patients, and its occurrence in areas not exposed to solar radiation. It follows only that solar radiation is not the only and perhaps not the most important factor determining the occurrence and progression of skin cancer. We report another concomitant intake of potentially nitrosamine contaminated blood pressure medications: bisoprolol and furosemide, taken over a period of 7 years that resulted in the concurrent occurrence of a medium-thickness cutaneous melanoma and 2 basal cell carcinomas. Successful surgical treatment of the tumors was performed, and the role of concurrent administration of ˝hypothetical˝ class 4 carcinogens within the framework of polymedication, polycontamination, and polymorbidity is discussed.

NITROSAMINE CONTAMINATION WITHIN CARDIAC MULTIMEDICATION - SARTANS (VALSARTAN), CALCIUM CHANNEL BLOCKERS (AMLODIPINE AND NIFEDIPINE), AND ANTIARRHYTHMICS (PROPAFENONE) AS A SIGNIFICANT FACTOR IN THE DEVELOPMENT AND PROGRESSION OF MULTIPLE KERATINOCYTIC CANCERS: ADVANCEMENT ROTATION FLAP FOR KERATOACANTHOMA OF THE UPPER LIP AND UNDERMINING SURGERY FOR BCC OF THE SHOULDER AS AN OPTIMAL DERMATOSURGICAL APPROACH.

The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/nitrosamines, NDSRIs (classified according to the FDA regulation to the companies of 2023 to those with a carcinogenic potency between 1 and 5), are one of the most important steps to clarify the concept of skin cancer nitrosogenesis/ pathogenesis. The FDA is the first regulatory institution in the world to courageously declare that a problem exists and should be addressed. The main and currently unexplained and somewhat controversial issue lies in 1) the sporadic nature of polycontamination in different geographical regions, and 2) the lack of official data from the established international, but also regional pharmaceutical market regulators on the results of the checks conducted for nitrosamine contamination of the respective batches. It is this that leads scientists to the idea of (albeit seemingly) speculative but entirely possible controlled contamination of the production in certain geographical regions. This (hypo)thesis is supported, albeit indirectly, by the fact that: a recent regional check for possible contamination of sartans in a particular geographical region was not indicative of the presence of any nitrosamines/NDSRIs. But this fact is indicative of several extremely important things: 1) contamination is not ubiquitous, its genesis is heterogeneous; 2) contamination could be completely avoided at production level in certain geographical regions; 3) ˝controlled contamination˝ or carelessness of a heterogeneous nature should be excluded by the relevant regulators. Regular inspection and certification of medicinal products in relevant geographical regions to exclude contamination with nitrosamines/NDSRIs would be the surest method to protect public health globally. The initial parameters of the restrictive processes for the availability of nitrosamines in medicines have been established by the most powerful regulator globally in the face of the FDA, with the hope being that manufacturers will find a short-term solution to the problem. We report another patient who simultaneously developed 2 cutaneous tumors under potentially/actually nitrosamine contaminated drugs such as: beta blockers- atenolol, calcium antagonists- nifedipine/amlodipine, sartans- valsartan and antiarrhythmics- propafenone. One of the tumors was localized in the upper lip area (keratoacanthoma) and the other in the right shoulder area (basal cell carcinoma). Successful surgical treatment of the tumors was performed in the form of upper lip advancement rotation flap and elliptical excision of the second lesion. The evolution/growth rate of the tumors in relation to the potential mutagens/carcinogens heterogeneous in their potency contained in the drugs is commented.