Medical Institute of the Ministry of the Interior, Sofia
Recent publications
The toxicokinetics of nitrosamines remain a mystery to this day, though it appears that the role of nitrosamines in potentiating the generation of mutations required for the onset of skin cancer continues to be a significant concern. Nitrosamines are mutagens, genotoxic substances, and mediators of phototoxicity/ carcinogenicity, whose long-term daily usage, in the context of polypharmacy, can result in the parallel appearance of heterogeneous forms of skin cancer: keratinocytic and melanocytic. But a number of clinical observations suggest that it is the nitrosamines that potentiate the multiple occurrences of skin cancer over the years, or recurrences of skin cancer localized in areas exposed to solar radiation. This article reports the occurrences of keratoacanthoma and multiple actinic keratoses in a patient on systemic therapy with telmisartan and tamsulosin-medications that contain Nitrosamines/ NDSRIs. Successful surgical treatment by modificated advancement flap and cryotherapy was performed. The role of nitrosamines as mediators of phototoxicity in the context of drug-mediated Photo-Nitrosogenesis/ Nitrosocarcinogenesis is discussed. Contamination of certain classes of drugs with nitrosamines is proving to be more than a serious problem. This problem is fueled on the one hand by the fact that nitrosamines are 1) photocarcinogens (known for decades), but on the other hand, they are also 2) mutagens/carcinogens, genotoxic substances (according to the FDA classification). The phototoxic effect according to current data is not calculated by the tests provided by the regulators (at least so far), which in practice leads to a miscalculation of the total, cumulative carcinogenic effect in the context of the intake of a contaminated mono or polymedication. The tests could be seen as either largely static, according to some clinical observations-even as categorically insufficient in terms of defining the concept of carcinogenicity in real-world settings (such as the intake of carcinogens with drugs, for example). The processes of carcinogenesis are dynamic, multifactorial and could hardly be characterized by this kind of tests. New literature evidence finds a disconnect precisely in the determination of carcinogenic activity by assays proposed by regulators such as the Ames test (in bacteria) and the CPCA test in rodents. An open dilemma remains: since there is no concordance between the mutagenicity test in bacteria (Ames) with that in rodents (CPCA) , what should be their significance in humans? For this reason, the application of the above-mentioned tests might be seriously limited in the future. We present a patient with multiple actinic keratoses and an epithelial skin tumor in the scalp area that developed during therapy with Tamsulosin and Telmisartan. We comment on the role of drug-mediated Photo-Nitrosocarcinogenesis/ Oncopharmacogenesis in the background of potential/actual carcinogen contamination.
Rotation advancement flaps are a challenge for dermatosurgery and in particular the severe clinical cases, mainly affecting skin tumors in the facial area or the so-called ˝high risk areas˝. The proximity of these areas to important vital structures (such as nerves and blood vessels) also determines the need for more precision when performing this type of manipulation. Teamwork and preoperative planning are crucial and provide a number of advantages in terms of the timely achievement of the therapeutic endpoints. We present two cases of patients with squamous cell carcinomas in the periocular and periorbital areas treated by rotation advancement flaps. The problems that may arise within these interventions and the prerequisites for the latter to be successful are discussed.
Cutaneous cylindromas are rare, slow-growing adnexal tumors commonly found on the capillitium or face. When located on the capillitium, they can cluster together, forming a headgearlike structure that gives the characteristic “turban” appearance. Brooke-Spiegler syndrome, an autosomal dominant condition, is typically benign, though malignant transformation can occur. We present a 61-year-old male with a 30-year history of mushroom-like formations, clinically and histologically confirmed as cylindromas, affecting approximately half of the hairy part of the capillitium. In addition, an erythematous-livid plaque with ulceration and crusting was observed on both left and right lower legs. The patient was suspected of having a sporadic, non-inherited form of Brooke-Spiegler syndrome. Surgical excision of the mushroom-like lesions was recommended. In cases of non-inherited forms of BrookeSpiegler syndrome, early detection and preventative measures are critical. A brief discussion focusing on the management of the condition is provided, emphasizing whether true sporadic cases of Brooke-Spiegler syndrome exist or if they represent another clinically “silent” form of the condition.
Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade cutaneous sarcoma typically found on the proximal extremities and the trunk, characterized by infiltrative growth and low risk of metastasis. High rates of local recurrence or relatively large tumor sizes can significantly complicate therapeutic management, particularly when 1) surgical intervention is not adequately performed and /or 2 access to newer medications is limited or their high cost imposes a financial burden on patients. We present the case of a 63-year-old male with a histologically confirmed dermatofibrosarcoma protuberans, measuring 6 cm in diameter, located on the right dorsal region, accompanied by several confluent multifocal nodules situated infralaterally to the primary formation. Wide surgical excision with 5 mm margins in all directions was performed, achieving clean resection margins in all directions and short term recidive-free outcome. This report also provides a brief overview of the therapeutic options available for DFSP, emphasizing the surgical approach, which remains the gold standard for treatment.
Modern skin cancer pathogenesis includes new concepts such as nitroso photocarcinogenesis and nitroso-mediated photosensitivity. The above 2 new concepts are in all likelihood also modeled/determined by photocarcinogens known as nitrosamines and/or NDSRIs available as contaminants in many drugs worldwide. The phototoxicity of nitrosamines is a known nonspecific property of them, for which evidence exists as far back as 1972. Current data from 2023/2024 are completely supportive of nitrosamines identified in drugs, with genotoxicity and phototoxicity proven once again. Regulators' data on polycontamination of a drug with up to several nitrosamines at the same time are of concern. The carcinogens/mutagens in question could also act as bi-/ polycarcinogens depending on whether they are metabolized or not. Permanent combined intake of potentially/actually nitrosamine-contaminated drugs appears to be key in the subsequent development of multiple cutaneous tumours, according to new findings in the literature. The localization of these tumours in areas exposed to intense solar radiation could also be seen as indirectly pointing to the presence of certain photosensitisers in the human body. Some of these nitrosamines are photocarcinogens and human carcinogens at the same time. The identification and specification of each of these genotoxic photosensitizers in drugs has yet to be further investigated in detail. The FDA identifies them currently as substances with carcinogenic potency. The clinicopathologic correlations published to date within the intake of potentially contaminated drugs are indicative of 1) the need to redefine skin cancer pathogenesis and 2) the subsequent possible introduction of complete elimination regimens against nitrosamines. We inform about another polymedication intake in a patient with arterial hypertension and diabetes mellitus, which includes the following medications: gliclazide 60 mg once daily and metformin hydrochloride 850 mg once daily, both since 24 years ; sotalol hydrochloride 80 mg since 2 years; bisoprolol fumarate 5 mg since 17 years; candesartan cilexetil/hydrochlorothiazide 16 mg/ 12.5 mg since 2 years; and lercanidipine hydrochloride 20 mg also since 2 years. Within this intake, it is notable that 1) all 6 of these drugs appear in the databases for possible availability as nitroso compounds, and that 2) this is the seventh consecutive keratinocyte tumor treated surgically (in this period). In the presented patient, surgical treatment was performed using a shark pedicle island flap for BCC of the nose, which is an ideal option for tumors with location in the alar or periralararea. An optimal postoperative outcome was achieved. This article focuses on the possible role of drug-mediated photo nitrosogenesis/ carcinogenesis of skin cancer by briefly reviewing and analyzing the available literature to date.
Mechanical asphyxia is a severe condition caused by a physical blockage that impedes breathing in the upper airways, trachea, and lungs. We present a case of a 39-year-old man who died suddenly at home while getting ready for work. He had previously experienced shortness of breath and a sore throat. Despite consulting a pulmonologist, who ruled out lung diseases, no other specialist evaluations were conducted. We performed a comprehensive forensic investigation, including collecting medical history and criminological data, a forensic autopsy, and subsequent toxicological and histological analyses. The autopsy revealed a benign laryngeal lesion that completely blocked the upper airways. The cause of death was determined to be acute obstruction, leading to mechanical asphyxia. This case highlights the importance of comprehensive and timely medical evaluations to prevent serious life-threatening complications.
Colorectal cancer (CRC) is a leading cause of mortality worldwide. Its incidence holds a major position among the most common life-threatening diseases. Hence, the early identification and precise characterization of disease activity based on proper biomarkers are of utmost importance for therapeutic strategy and patient survival. The identification of new biomarkers for colorectal cancer or disease-specific levels/combinations of biomarkers will significantly contribute to precise diagnosis and improved personalized treatment of patients. Therefore, the present study aims to identify colorectal cancer-specific immunological biomarkers. The plasma levels of several cytokines (interleukin-1β /IL-1β/, IL-2, IL-4, IL-10, IL-12, IL-15, TGFβ and IFNγ) of 20 patients with colorectal cancer and 21 healthy individuals were determined by ELISA. The expression of several types of glycoproteins on the surface of peripheral blood leukocytes isolated from CRC patients and healthy volunteers was evaluated by flow cytometry. Correlations between cytokine levels and cell surface glycoprotein expression were analyzed. The obtained results demonstrated significantly elevated levels of CD80, CD86, CD279 and CD274 expressing leukocyte populations in the cancer patient group, while the numbers of NK cells and CD8- and CD25-positive cells were decreased. Based on these data and the correlations with cytokine levels, it can be concluded that CD25, CD80, CD86, CD274 and CD279 glycoproteins combined with specific plasma levels of IL-1β, IL-2, IL-15 and TGFβ could represent potential biomarkers for colorectal cancer.
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. PubMed Disclaimer
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- Riviroxaban 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.
Lyme borreliosis is a frequently encountered tick-borne infection worldwide, caused by a spirochete from the Borrelia burgdorferi genoscpecies. In most cases, the initial sign of Lyme disease is the pathognomonic symptom - erythema migrans rash appearing at the site of the thick bite. Оther described cutaneous manifestations besides erythema migrans ‒ such as erythema nodosum (an acute nodular septal panniculitis), papular urticaria, granuloma annulare, psoriatic changes, lichen striatus et atrophicans, Henoch-Schönlein purpura, and morphea ‒ could potentially present as an initial/first sign of acute Borrelia burgdorferi infection. Serological testing for Lyme disease is only reliable after the initial stages of the disease. Additional PCR or serological examinations such as ELISA, immunoblot, indirect immunofluorescence examination could be performed. The diverse cutaneous manifestations of Lyme disease can lead to delays or ineffectiveness in treatment, as these symptoms may not be promptly identified as signs of the infection. Therefore, a comprehensive evaluation of the three key aspects - clinical findings, serology, and histology - is essential and should be considered collectively. We present a 78-year-old female with an acute form of Borrelia infection following a thick bite, manifesting as erythema nodosum on the lower extremities. Serology confirmed the presence of Borrelia infection, and the histological findings were indicative of erythema nodosum. The patient initially received anti-inflammatory and antibiotic medications. Reverse development of the nodules was observed after therapy with ceftriaxone, methylprednisolone, esomeprazole, and local dressings with povidone-iodine. For outpatient care, her regimen consisted of systemic reduction of the corticosteroid therapy, esomeprazole, and doxycycline. Due to the potential triggering of erythema nodosum by valsartan, it was recommended switching to an alternative medication. The rarity of erythema nodosum as an initial or first sign of acute Borrelia infection is being discussed.
Autoerotic death, as a subtype of mechanical asphyxia, refers to a person's fatal outcome while engaging in solitary sexual activity using various devices and methods to reduce oxygen supply and induce cerebral hypoxia, leading to increased sexual gratification. These asphyxial deaths are accidental and sporadic. In cases of sexual asphyxia, especially when strangulation methods such as hanging or ligature are used, thorough crime scene investigation is crucial to determine the type of asphyxia and the manner of death. Inadequate information about specific crime scene findings can lead to significant errors in determining the manner of death and the type of strangulation, potentially leading to cases being mistaken for ligature strangulation in a homicidal manner or hanging in a suicidal manner.
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/Pharmacooncogenesis˝ 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 ʺreal or potentialʺ 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 ʺcancer-generating benefitʺ, of course, which is already widely known. And let us not forget that : ʺA lie stops being a lie and becomes a truth the moment it is officially refuted.ʺ
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 mutagencontaminated 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 concentrationsregarding 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 Pharmacooncogenesis of skin cancer is determined by exogenously mediated Nitrosogenesis or the permissive availability for certain nitrosamines in drugs worldwide.
Onco-pharmacogenesis or pharmaco-oncogenesis of skin cancer is a concept , which could also be considered as an ʺend productʺ 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 ʺmutationallyʺ, 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 ʻparentsʼ 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 shortterm nodular melanoma with a subsequent fatal outcome. Wecomment on the role of drug-mediated nitrosogenesis and its relationship to photocarcinogenesis and onco-pharmacogenesis.
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-NitrosoCarcinogenesis/ 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-NitrosoCarcinogenesis of keratinocyte cancer in the context of OncoPharmacogenesis. 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
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
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.
This study aims to identify laboratory and genetic markers important for COVID-19 severity to improve patient assessment and treatment. COVID-19 patients were divided into two groups based on disease severity. Clinical, laboratory (complete blood count, complete biochemical parameters - lactate dehydrogenase (LDH), serum ferritin), and genetic markers ( OAS1 rs4767027) were analyzed. A total of 61 COVID-19 patients and 48 negative controls were investigated. Group I showed more often lymphopenia – 3.16 (1.39–3.89) vs 5.61(4.21–7.98), p-0.027 and thrombocytopenia – 165 (75–256) vs 212 (198–349), p-0.031, higher LDH (621 ± 218 U/L vs 312 ± 110 U/L), p-0.014. OAS1 rs4767027 genotype and allele frequencies did not differ significantly from worldwide population frequencies. Lymphopenia and thrombocytopenia are likely associated with immune inflammation and COVID-19 severity. While increased OAS1 transcript levels are correlated with reduced risk of infection, they can contribute to NLRP3 inflammasome activation once the infection has been established.
Poor air quality in urban cities has led to the replacement of motorized vehicles with active means of transportation such as cycling. Unfortunately, while developing and constructing bike infrastructure, officials fail to address air quality problems associated with bikers, and most dedicated cycling lanes are built alongside high-traffic highways. Because of their greater ventilation rate, bikers face significant health hazards. To safeguard a city’s citizens’ sustainable quality of life, it’s vital to understand how to identify and measure PM exposure, especially in potentially dangerous places. This work presents a software tool based on experimental data for optimizing and evaluating bicycle routes by assessing the overall quantity of particulate matter intake in terms of rider physiological reaction. The tool uses a modified path-finding method, including traffic and environmental data from fixed and mobile sensors. The final result is an optimized path for cyclists with minimum PM inhalation value.
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