Marijan Novakovic

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.

Ibuprofen-induced extensive toxic epidermal necrolysis - a multidisciplinary therapeutic approach in a single case.

Dear Sir, Toxic epidermal necrolysis (TEN) or Lyell’s syndrome is a life-threatening (up to 90% mortality rate), extensive cutaneous, drug-induced adverse event1. Similar skin damage/defects -but usually without a fatal outcome- are observed following drug administration in Stevens-Johnson’s syndrome (SJS; milder form) and TEN/SJS (intermediate type). In these conditions the epidermis can be detached from the underlying structures (dermis) over the whole body surface. Mucous membranes may also be affected. The precise aetiopathogenesis of TEN is still unclear. Some toxic metabolites, inflammatory mediators or modifiers, as well as cytotoxic T lymphocytes, regulatory T cells and dermal dendrocytes could induce apoptosis or necrosis of epithelial cells1–3. The human leucocyte antigen (HLA) system also plays an important role in the pathogenesis of TEN, since some drugs may bind directly to the HLA-complex and create self-reactivity due to the drug-modified HLA-peptide repertoire. This event is mediated by cytotoxic T lymphocytes and/ or natural killer cells after their interaction with cells expressing the HLA-complex3. We report here the case of a 21-year old female with extensive erythema, necrosis, and exfoliating bullous detachment of the epidermis and mucous membranes (conjunctival, oral and genital; affected skin area=80%; Figure 1A and 1B). Initially, she had an influenza-like prodrome after taking ibuprofen to treat a headache and dysmenorrhea. She was admitted to the Clinic for Plastic Surgery of MMA (Belgrade, Serbia) and on presentation she was febrile (39.3 °C) with a characteristic positive Nikolsky’s sign. Laboratory analyses were as follows: haemoglobin, 121 g/L; white blood cell count, 6.77×109/L (neutrophils 80%, lymphocytes 25%, eosinophils 4%, monocytes 1%), platelet count, 466×109/L; elevated levels of C-reactive protein, aspartate aminotransferase and alanine aminotransferase (330 mg/L, 80 IU/L and 145 IU/L, respectively), and low concentrations of total proteins (50 g/L) and albumin (22 g/L). The results of coagulation studies and tests for viral infections were normal. Skin biopsy demonstrated prominent cell death with basal vacuolar changes and lymphocyte infiltrates, obscuring the dermo-epidermal junction (Figure 1C), which confirmed the clinical diagnosis of TEN. Figure 1 A) and B) Female patient with TEN: extensive erythema, necrosis, and critical muco-cutaneous lesions with intense exfoliation. C) Cell destruction with lymphocyte infiltrates and distraction of the dermo-epidermal junction. D) Therapeutic apheresis - ... The first-line treatment was immediate withdrawal of theculprit drug, elimination of the drug and its metabolites, and fluid resuscitation with crystalloid infusions (1 mL/kg of body weight per hour) via a central venous catheter, adjusted on the bases of the arterial blood pressure (>65 mmHg), central venous pressure (≤10 mmHg) and urine output (diuresis rate). The patient was isolated (using aseptic techniques and state) and local dermatological and ocular topical treatment were applied continuously. Nutrition was provided enterally via a nasogastric tube. In the early treatment of this patient, we performed our originally designed multimodal therapeutic apheresis -plasma exchange (PE) combined with leucapheresis- using COBE®-Spectra apheresis-sets (Terumo BCT, Lakewood, CO, USA) and a sterile connected multibag system. Multimodal therapeutic apheresis simultaneously provides rapid improvements in more than one blood abnormality and aids the patient’s recovery from a live-threatening emergency to a clinical condition with a potentially positive outcome4,5. The rationale for initial plasma exchange in this case was to eliminate/decrease the level of residual ibuprofen and its metabolites, critical cytokines (such as tumour necrosis factor-α, interferon-γ), and drug-induced inflammatory mediators (perforin, granzyme B released from cytotoxic T lymphocytes and granulysin secreted by cytotoxic T lymphocytes and natural killer cells) from the circulation (urgent plasma depuration). Plasma exchange was performed on three consecutive days by processing an average of 5900±952 mL of the patient’s whole blood. A total of 5.4-fold the plasma volume was exchanged and replaced by albumin in normal saline (Figure 1D). The basic goal of the leucapheresis-treatment was to reduce the circulating lymphocyte count in the patient’s blood to obtain an immunomodulatory effect. The patient’s subsequent systemic treatment included broad-spectrum antibiotics (chosen on the basis of the skin microbial findings), intravenous immunoglobulins (dose 1.0 g/kg of body weight per day for 3 consecutive days; infused over 6 hours) and corticosteroids (dose 0.5 mg/kg of body weight)1,2. This young female patient recovered completely after 1 month of intensive systemic and topical treatment. In conclusion, this multidisciplinary management -fluid resuscitation, urgent plasma depuration and immunomodulation (multimodal therapeutic apheresis), as well as topical and systemic medications (antibiotics, intravenous immunoglobulins and corticosteroids)- undoubtedly prevented septicaemia and multisystem organ failure, the major cause of death in severe TEN.

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.

Skin vascularisation field by the ascending branch of the peroneal artery ramus perforans

BACKGROUND/AIM Soft tissue defects in the distal third of the lower leg are persistent and constitute a major problem in the reconstructive surgery. This study presents an analysis of the anatomical vascularization filed of ascending branch of the peroneal artery ramus perforans (PARS). The aim of this study was to assess reliability of the distal flap on the antero-lateral aspect of a lower leg distal third. METHODS Direct gentiana violet injection into the interosseal perforator of ten fresh cadaveric lower legs with subsequent corrosion acrylic preparation was performed to reveal vascularization filed of the ascending branch of the PARP. Height, length, diameter and communication of perforating branch and its subsequent smaller ascending and descending branches were determined. The CAMIA software was used. RESULTS Our results show that the PARP is always present. Its origin from the peroneal artery is at the medial height of 66 mm when measured from the inferior border of the lateral malleolus. Medium length of ramus perforans is 51.7mm. After transition through the interosseous membrane, ramus perforans divides into ascending and descending branches. The diameter proximal to the level of bifurcation is 1.37 mm (variation 1.0-1.8 mm), and the diameter of the ascending branch distal to the level of bifurcation is 1 mm. Using CAMIA software, the medium length, width and area of the vascularization filed labeled with gentian violet were calculated to be 164 mm (variation 125-210 mm), 66 mm (57-77 mm), and 10,305 mm2 (6,385 mm2-14,341 mm2), respectively. CONCLUSION Our results support the use of fasciocutaneous distal flap, vascularized by the ascending branch of the PARP for reconstruction of soft tissue defects in the distal third of the lower limb, malleolar regions and dorsum.