Lidija Kandolf-Sekulović

Immunomodulatory effects of low‐intensity near‐infrared laser irradiation on contact hypersensitivity reaction

Background/Purpose: Contact hypersensitivity (CHS) reaction is a useful model for studying the skin immune system and inflammatory reactions in the skin. In this study, an experimental model of CHS reaction was employed to assess immunomodulatory effects of near‐infrared (near‐IR) low‐intensity laser (LIL) irradiation, which is used as adjuvant therapy in dermatology, physical medicine, rheumatology, etc., because of its declared anti‐inflammatory, biostimulative and analgesic effects.

Melanoma risk is associated with vitamin D receptor gene polymorphisms.

Previous studies have reported that vitamin D receptor (VDR) gene polymorphisms are associated with the occurrence of various cancers, including melanoma. The aim of the current study was to investigate the association of VDR gene polymorphisms with melanoma risk, clinicopathological characteristics, and vitamin D levels. The study group included 117 patients (84 patients with superficial spreading melanoma and 33 patients with nodular melanoma). The control group included 122 sex-matched and age-matched healthy-blood donors of the same ethnicity. VDR gene polymorphisms FokI, EcoRV, TaqI, and ApaI were genotyped by real-time PCR. In 60 patients, the total 25-hydroxyvitamin D levels were evaluated in serum samples by direct chemiluminescence. Associations among parameters were considered to be significant if the P value was less than 0.05. Significant differences in the frequencies of VDR genotypes were observed between cases and the control group for FokI and TaqI polymorphisms (P<0.0001; P=0.005, respectively). Heterozygous Ff as well as mutant FF genotypes of the FokI polymorphism were associated with increased melanoma risk compared with the wild-type form [odds ratio (OR)=3.035, P=0.003; OR=9.276, P<0.0001, respectively]. A significantly increased melanoma risk was observed for the heterozygous Tt (OR=2.302, P=0.011) and the mutated variant tt (OR=3.697, P=0.003) of the TaqI polymorphism in comparison with the wild-type genotype. None of the polymorphisms studied was associated with clinicopathological characteristics and vitamin D serum level. Our results suggest that FokI and TaqI polymorphisms in the VDR gene may be considered as potential biomarkers for melanoma susceptibility. Low vitamin D levels in melanoma patients indicate the need for vitamin D supplementation.

A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma

Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3(-), CD19(-), CD56(-)), HLA-DR(-/low), CD11b(+) and CD33(+). Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) < 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI.

Melanoma in South-East Europe: epidemiological data from the central cancer registry and clinicopathological characteristics from the hospital-based registry in Serbia

Background  Melanoma in South‐East Europe shows varying incidence from 1.7 per 100,000 in Albania to 14.5 per 100,000 in Slovenia, but more detailed data from this region are scarce. In this study, we report epidemiological and clinicopathological characteristics of melanoma in central Serbia.

National Guidelines for the Treatment of Atopic Dermatitis

1Clinic of Dermatovenereology, Clinical Center of Serbia, Department of Dermatovenereology, School of Medicine, University of Belgrade, Belgrade, Serbia 2Institute for Child and Youth Health Care of Vojvodina, Faculty of Medicine, University of Novi Sad, Serbia 3Clinic of Skin and Venereal Diseases, Military Medical Academy, Department of Dermatovenereology, School of Medicine, University of Belgrade, Belgrade, Serbia 4Department of Dermatovenereology, Clinic of Skin and Venereal Diseases, Clinical Center Niš, School of Medicine, University of Niš, Niš, Serbia

Dress Syndrome - A Case Report

Abstract The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse drug-induced reaction that occurs most commonly after exposure to drugs, most frequently anticonvulsants, sulfa derivates, antidepressants, nonsteroidal anti-inflammatory drugs, and antimicrobials. We present a 61-year-old male, with a generalized maculopapular exanthema on the trunk, face, extremities, palms, soles, palate, and fever (38°C). His medical history was notable for generalized epilepsy, treated with carbamazepine during 1 month. The diagnosis of DRESS syndrome was confirmed by specific RegiSCAR criteria. In our case, skin eruptions were successfully treated with oral methylprednisolone, cephalexin, and topical corticosteroid ointment. In conclusion, although the mechanisms of this syndrome are not completely understood, numerous cases were reported in children and adults. This syndrome should be considered in every patient with skin eruption, fever, eosinophilia, liver and hematological abnormalities. Prompt recognition, supportive therapy and initiation of corticosteroids may prevent systemic manifestations.

Serbian Association of Dermatovenereologists’ Guidelines for the Diagnosis and Treatment of Psoriasis

1Clinic of Dermatovenereology, School of Medicine, Military Medical Academy, Belgrade, Republic of Serbia 2Clinic of Dermatovenereology, Clinical Center of Niš, Faculty of Medicine, University of Niš, Republic of Serbia 3Clinic of Dermatovenereology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Republic of Serbia 4Clinic of Dermatovenereology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Republic of Serbia

Porphyria Cutanea Tarda – a Case Report

Abstract Porphyria cutanea tarda is a metabolic disorder that results from a reduced enzymatic activity of uroporphyrinogen decarboxylase. It is the commonest chronic porphyria. Two types of this disease have been reported up to now: acquired (Type 1, 80%) and inherited (Type 2, 20%) an autosomal dominant pattern with low clinical penetrance. Both types are associated with haemochromatosis, alcohol abuse, estrogens, iron overload, hepatitis C virus infection, and halogenated aromatic hydrocarbons causing deficiency of the uroporphyrinogen decarboxylase enzyme in the liver. In this case report we described a 23-year-old woman with increased hair growth on the face and neck, who visited an outpatient dermatology clinic for laser hair removal due to excessive hair growth on the face and neck during the last eight years (Figures 1, 2). Four laser treatments were carried out with incomplete effects. After the fourth laser hair removal treatment, a small sore on the tip of the nose was observed. The patient used oral contraceptive pills during the past 8 months. No additional medications were taken. The diagnosis of porphyria cutanea tarda was confirmed by specific biochemical analyses, since increased excretion of uroporphyrin and coproporphyrin were detected. After discontinuation of drospirenone and ethinyl estradiol (YazÒ tablets) a gradual clinical and laboratory improvement was noticed suggesting a causative role of this drug. There are many published reports discussing and describing estrogens as contraceptive agents, hormone supplements for postmenopausal replacement therapy in females, and adjunctive hormonal therapy in males with prostatic carcinoma, being the probable trigger of porphyria cutanea tarda. However, the mechanisms by which estrogens exert their effects on disease expression have not yet been fully clarified. Conclusion: this case report points to the importance of hypertrichosis as the first manifestation of porphyria cutanea tarda, since it may be a long lasting sign before the onset of other clinical symptoms of the disese Sažetak Uvod: Porfirija kutanea tarda (PCT) metabolički je poremećaj koji nastaje kao rezultat smanjene aktivnosti uroporfirinogen dekarboksilaze. Opisuju se dva tipa PCT: stečeni, tzv. izolovani ili tip I, koji se javlja češće, kod oko 80% svih obolelih i nasledni, familijarni ili tip II koji se nasleđuje dominantno ali sa malom penetracijom inkriminisanog gena. Oba tipa se javljaju povezano sa određenim, tzv. faktorima rizika ili deklanširajućim faktorima, kao što su: alkohol, estrogeni, prezasićenost gvožđem, infekcija virusom hepatitisa C, izloženost halogenim aromatičnim ugljovodonicima koji svi uzrokuju smanjenje enzima uroporfirinogen dekarboksilaze (UROD) u jetri. U PCT je utvrđen visok nivo molekularne heterogenosti s obzirom da je kod pacijenata sa PCT tip II do danas utvrđeno više od 105 različitih mutacija gena odgovornog za sintezu UROD enzima (gen mapiran na hromozomskoj regiji 1p34). Ipak, rastuća incidencija PCT kod žena se pripisuje upotrebi estrogena kako u obliku tableta za kontracepciju tako i u okviru suplementarne hormonske terapije. Prikaz slučaja: U radu je prikazan slučaj osobe ženskog pola, stare 23 godine, kod koje su zbog hirzutizma na licu i vratu koji je bio prisutan u poslednjih osam godina, sprovedena četiri tretmana aleksandritnim laserom. Posle četiri tretmana, manifestovala se ranica na vrhu nosa. Nakon detaljno uzete anamneze, pacijentkinja je navela da su joj se na koži lica u periodu 7−19. godine povremeno javljali vodeni plikčići, i to na koži lica i šaka. Promene su se javljale naočito u vezi s povećanom i produženom ekspozicijom suncu, a spontano su nestajale ostavljajući blage ožiljke. U 15. godini života primetila je povećanu kosmatost na licu i na vratu, kao i tamnu boju mokraće. Poslednje dve godine pre nego što je došla na pregled kod nas, pacijentkinja se javila gastroenterologu zbog povremenih tupih bolova u predelu gornjeg abdomena koji su bili praćeni trostrukim povećenjem serumskih transaminaza, povećanim nivoom bakra u urinu i serumu i povećanim nivoom feritina u serumu. Ultrasonografski pregled gornjeg abdomena je otkrio samo dva konkrementa u žučnoj kesici. Anamneza u smislu uzimanja drugih lekova, potrošnje alkohola ili preležanog virusnog hepatitisa bila je negativna. Porodična anamneza, u smislu prisustva porfirije i povećane kosmatosti (hipertrihoze) kod srodnika, bila je negativna. Laboratorijski nalazi koji su odstupali od uobičajenih fizioloških vrednosti bili su: povišena vrednost asparataminotransferaze i alaninaminotransferaze, feritina u serumu; povišene vrednosti bakra u 24-časovnom urinu; 60 puta povećan nivo porfirina i nivo koproporfirina u 24-časovnom urinu. Histopatološki pregled bioptiranog uzorka obolele kože sa nadlanice odgovarao je ranim lezijama kod PCT, a histopatološki pregled bioptiranog uzorka jetre je pored blagog periportalnog zapaljenskog mononuklearnog infiltrata otkrio depozite gvožđa u periportalnom makrofagnom prostoru kao i u malim grupama periportalno lokalizovanih hepatocita. Pacijentkinja je bila na terapiji oralnim kontraceptivima tokom poslednjih 8 meseci. Nije bilo upotrebe drugih lekova. Nakon isključivanja drospirenona i etinilestradiola (Yaz tbl.), primećeno je postepeno kliničko i laboratorijsko poboljšanje koje je ukazivalo na kauzalnu ulogu leka. Dijagnoza PCT postavljena je na osnovu kliničkog, laboratorijskog i histopatološkog pregleda. Lečenje je započeto ukidanjem oralnog kontraceptiva i niskim dozama antimalarika hidroksihlorokvina (200 mg 2 x nedeljno) i periodičnim flebotomijama (300−500 ml u početku uz konsultaciju hematologa). Kliničko poboljšanje bilo je evidentno 4 nedelje nakon započinjanja lečenja i manifestovalo se sledećim: prestanak pojave novih lezija; svetlija boja mokraće; smanjenje uroporfirina i koproporfirina u 24-časovnom urinu. Sve vreme tokom naredne tri godine, kada je pacijentkinja redovno klinički i laboratorijski kontrolisana, nije bilo recidiva tj. pojava novih promena na koži i laboratorijskih odstupanja. Diskusija: Treba naglasiti da negativna porodična anamneza ne isključuje postojanje tipa II PCT, s obzirom na nisku penetrantnost mutacije PCT gena u ovom autozomno-dominantno nasledom obliku bolesti. Tako su pojedini autori definisali tip III PCT u kome oboleli imaju normalan nivo UROD enzimske aktivnosti u eritrocitima a imaju istovremeno obolele srodnike u porodici. Biohemijski PCT karakterišu povišene vrednosti porfirina (u serumu i urinu) i to prvenstveno zbog povećane akumulacije uroporfirina u jetri. Uroporfirini predstavljaju supstrat na čiju oksidaciju utiče UROD enzim, a koji u PCT cirkuliše u povećanim količinama u plazmi i urinu. Kod klinički manifestne PCT, aktivnost UROD enzima mora biti manja od 25% (po nekima manja i od 20%) od normalne aktivnosti, stoga 50% enzimska aktivnost koja je prisutna kod oboleleih od tipa II PCT može predstavljati samo predisponirajući faktor, ali je nedovoljno niska da bi izazvala simptome PCT. Stoga je neophodno prisustvo drugih genetskih i spoljašnjih faktora koji bi doprineli povećanoj prijemčivosti jedne osobe za obolevanje kako od tipa I tako i od tipa II PCT. Treba znati da je nizak nivo enzimske aktivnosti UROD enzima (manje od 25% od normalnih vrednosti) u klinički manifestnoj PCT, posledica oksidacije uroporfirinogena u uroporfometen koji deluje kao kompetitivni inhibitor UROD enzimu u jetri. Ovaj enzimski proces je zavisan od gvožđa. Serumski nivo gvožđa i feritina je povećan, ali može biti i na gornjoj granici normalih vrednosti. Bitno je da PCT postaje klinički manifestna samo ukoliko postoji povećana aklumulacija gvožđa u jetri. Za razliku od jetre, nivo gvoža u serumu može biti povećan kod samo 50% obolelih. Iako se određivanje nivoa UROD aktivnosti u eritrocitima smatra tehnikom skrininga za diferencijaciju tipa I od tipa II PCT, ova metoda nije dovoljno pouzdana zato što pojedini pacijenti sa tipom II mogu imati smanjenu UROD aktivnost koja se preklapa sa najmanjom vrednosti (intermedijerni nivo) UROD aktivnosti kod osoba sa tipom I PCT. Zbog toga je potrebno dodatno molekularno genetsko ispitivanje. Ovo ispitivanje nije indikovano samo kod onih osoba koje imaju intermedijerni nivo UROD aktivnosti u eritrocitima. Ovo ispitivanje treba sprovoditi i u cilju postavljanja egzaktne dijagnoze kod pacijenata koji nemaju obolele srodnike, a imaju mutacije na UROD genu. Nažalost, mi nismo bili u mogućnosti da sprovedemo genetsko ispitivanje.Postoji mnogo radova u kojima se navodi da estrogeni mogu biti okidači kod PCT. Ipak, mehanizam kojim estrogeni utiču na ispoljavanje bolesti nisu u potpunosti razjašnjeni. Iako dietilstilbestrol i estrogen izazivaju povećanu sintezu aminolevulonske kiseline u jetri, kojom se ne može objasniti ekskrecija porfirina karakteristična za PCT. Štaviše, većina pacijenata koja uzima estrogene ne pokazuje klinička niti biohemijska odstupanja karakteristična za PCT. Zaključak: Ovim radom želimo da naglasimo značaj hipertrihoze, kao prve manifestacije PCT jer to može biti prvi i jedini klinički znak, koji tokom dugog vremenskog perioda prethodi pojavi drugih kliničkih znakova i simptoma

Cutaneous Adverse Drug Reactions / Dematološka neželjena dejstva lekova

Abstract Adverse drug reactions may be defined as undesirable clinical manifestations resulting from administration of a particular drug; this includes reactions due to overdose, predictable side effects, and unanticipated adverse manifestations. Adverse drug effects on the skin are among the most frequent reactions and, according to a study, account for approximately 14% of all adverse drug reactions. However, the incidence of cutaneous adverse effects in general population is unknown. Systemic drug administration results in various cutaneous adverse reactions, and medications used in the treatment of skin diseases themselves have their own adverse effects. Adverse drug reactions include a wide range of effects, from harmless exanthema of short duration, urticaria to systemic cutaneous reactions such as drug rash with eosinophilia and systemic symptoms (DRESS) or toxic epidermal necrolysis. Exanthematous eruptions and urticaria are the two most common forms of cutaneous drug reactions. Less common include fixed eruptions, lichenoid, pustular, bullous and vasculitis reactions. The most severe cutaneous and mucosal adverse drug reactions are epidermal necrolysis, which is usually drug-induced, DRESS syndrome, and acute generalized exanthematous pustulosis. Therefore, the diagnostic of adverse drug reactions requires a detailed history of drug intake and development of skin disorders, excellent knowledge of clinical presentations for a wide range of drug-induced skin reactions as well as of the very medications being taken by patients. In addition to details on drug intake, it is necessary to learn about taking herbal and alternative preparations, which may also cause adverse reactions. A drug started within 6 weeks of the development of disorders is considered the most common cause of adverse reaction, as well as drugs taken periodically but regularly. Once a reaction has occurred, it is important to prevent future similar reactions with the same drug or a cross-reacting medication. Early withdrawal of all potentially responsible drugs is essential, particularly in case of severe drug reactions. Sažetak Definicija: Neželjena dejstva lekova mogu se definisati kao nepoželjna klinička manifestacija, to jest posledica primene određenog leka što uključuje reakcije usled predoziranja lekom, predvidljive neželjene efekte i neočekivane neželjene manifestacije. Neželjena dejstva lekova na koži jedna su od najčešćih reakcija i, prema jednoj studiji, obuhvataju oko 14% svih neželjenih reakcija na lekove. Kliničke manifestacije: Neželjene reakcije na lekove obuhvataju širok spektar manifestacija, od bezazlenih egzantema kratkog trajanja, preko urtikarije do sistemskih reakcija koje se manifestuju i na koži, poput sindroma egzantema izazvanog lekom s eozinofilijom i sistemskim simptomima - DRESS sindrom (eng. drug induced rash with eosinophilia and systemic symptoms) ili toksične epidermalne nekrolize. Dve najčešće forme neželjenih reakcija na koži koje izazivaju lekovi su egzantemi i urtikarija. Ređe forme neželjenih reakcija na koži koje izazivaju lekovi su fiksne erupcije, lihenoidne, pustulozne, bulozne i vaskulitis reakcije. Najteže neželjene reakcije lekova na koži i sluzokožama jesu toksična epidermalna nekroliza koja je gotovo uvek izazvana lekom, DRESS sindrom i akutna generalizovana egzantematozna pustuloza. Dijagnoza: Postavljanje dijagnoze neželjene reakcije na lek stoga zahteva detaljne anamnestičke podatke o hronologiji uzimanja lekova i pojave promena na koži, dobro poznavanje kliničke slike velikog spektra različitih reakcija koje lekovi izazivaju na koži, ali i dobro poznavanje samih lekova koje pacijent uzima. S obzirom da biljni preparat i preparat alternativne medicine mogu takođe izazvati neželjene reakcije na koži, neophodno je saznati i podatke o njihovom uzimanju. Smatra se da je lek koji je počeo da se uzima u periodu od šest nedelja od nastanka promena najčešći uzročnik neželjene reakcije, kao i lekovi koji se povremeno ali redovno uzimaju. Lečenje: Kad nastane reakcija, važno je kod pacijenta sprečiti buduće slične reakcije na isti lek ili ukrštenu reakciju lekova. Rano povlačenje svih potencijalno odgovornih lekova od suštinske je važnosti, posebno u slučaju ozbiljnih reakcija na lekove.

Neurofibromatosis type I (von Recklinghausen’s disease): A Report of Three Cases / Neurofibromatoza tip I (von Recklinghausenova bolest): prikaz tri slučaja

Abstract Neurofibromatosis type I (NF1) is an autosomal dominant, multisystemic disease that usually affects the skin, nervous system and bones. Diagnosis is made by matching at least two of the following 7 diagnostic criteria: six or more caféau- lait macules over 15 mm in diameter, two or more neurofibromas, axillary and/or inguinal freckles, optic glioma, two or more Lisch’s nodules (iris hamartoma), changes in the bones in the form of sphenoid dysplasia, thinning of the cortex of long bones and existence of neurofibromatosis in the first degree relatives. We report three patients, two men and a woman aged 18 to 33 years, in whom the first changes occurred at puberty, and there was no positive family history in any of them. All three patients had café-au-lait spots over 15 mm in diameter and numerous localized neurofibromas on the skin of the trunk and extremities that were histologically verified. In two patients, ophthalmic examinations recorded Lisch’s nodules in the iris. In one of the patients, MRI of the head, revealed presence of oval lesions with diameters of 10-15 mm, which may correspond to neurofibromas, and in the other patient fibrous dysplasia of the femur and tibia were observed. Psychological testing in one patient revealed IQ at the lower limits of average (IQ 68). After the diagnosis of neurofibromatosis type I, the patients were given advice about the disease and a plan for the monitoring and control of possible symptoms, and also the possibility of genetic testing during pregnancy. A multidisciplinary approach is required for diagnosing and monitoring of patients with neurofibromatosis type 1. Sažetak Uvod: Neurofibromatoza tip I (NF1) je autozomno dominantno, nasledno neurogeno, multisistemsko oboljenje koje najčešće zahvata kožu, nervni sistem i kosti. Dijagnoza ovog oboljenja se postavlja ukoliko su ispunjena najmanje dva od sledećih 7 dijagnostičkih kriterijuma: šest ili više café au lait makula promera preko 15 mm, dva ili više neurofibroma, aksilarne i/ili ingvinalne makule, optički gliom, dva ili više Lisch-ovih nodula (hamartromi dužice), promene na kostima u vidu sfenoidne displazije, istanjenje korteksa dugih kostiju sa ili bez pseudoartroze i postojanje neurofibromatoze kod rođaka prvog stepena. Prikaz bolesnika: Prikazujemo tri bolesnika, dva muškarca i ženu starosti od 18 do 33 godine kod kojih je, nakon učinjenog kliničkog ispitivanja postavljena dijagnoza neurofibromatoze tipa I. Kod sva tri bolesnika prve promene u vidu svetlosmeđih mrlja i sitnih mekih čvorića na koži javili su se u dobu puberteta. Sva tri pacijenta imala su café-au-lait makule promera preko 15 mm i brojne neurofibrome lokalizovane na koži trupa i ekstremiteta koji su patohistološki verifikovani. Kod dva pacijenta oftalmološkim pregledom evidentirani su Lischovi noduli na dužici, dok je kod jednog pacijenta pregled pomoću nuklearne magnetne rezonancije glave ukazao na endokranijalno prisustvo ovalnih lezija dijametara od 10-15 mm koji mogu odgovarati neurofibromima, a rendrengrafijom na oba femura i obe tibije uočena fibrozna displazija. Lečenje: Terapija neurofibromatoze tipa I je simptomatska i predominantno hirurška uz adekvatno praćenje i multidisciplinarni pristup bolesniku i odgovarajuće genetsko savetovanje.