Othon Papadopoulos

Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma

PURPOSE A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous (IV) therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and relapse-free survival (RFS) in comparison with observation. Analysis of the hazard curves for RFS and overall survival (OS) in E1684 revealed separation of the high-dose and observation arms, suggesting that the induction phase may represent a critical component of this regimen, although this has not been tested prospectively. PATIENTS AND METHODS We conducted a prospective randomized study of IV induction therapy versus a full year of high-dose IFN, with primary end points of RFS and OS for patients with stage IIB, IIC, and III melanoma, within 56 days of curative surgery. Patients were randomly assigned to receive IFN-alpha-2b 15 x 10(6) U/m2 IV x 5/7 days weekly x 4 weeks (arm A) versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat dose) administered subcutaneously three times a week for 48 weeks (arm B). RESULTS Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A, n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI, 58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P = .9) and the median OS was 64.4 months versus 65.3 months (P = .49). Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. CONCLUSION There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment.

Autologous transplantation of adipose-derived stem cells enhances skin graft survival and wound healing in diabetic rats.

BackgroundDiabetes can lead to impaired wound healing and skin grafts used surgically for diabetic wounds are often complicated with necrosis, although different therapies have been proposed. Adipose-derived stem cells (ASCs) participate in tissue repair processes and may have a role during impaired wound healing. In this study, autologous transplantation of ASCs was used to determine if it increases angiogenesis and skin graft survival and enhances wound healing in diabetic rats. MethodsAdipose-derived stem cells were successfully isolated and cultured. A full-thickness skin graft model was used to determine the effects of locally administered ASCs in 10 rats rendered diabetic (group 1), whereas 10 others served as controls (group 2). Histological examination of skin grafts followed after 1 week. Additionally, immunohistochemical staining intensity of vascular endothelial growth factor (VEGF) and transforming growth factor &bgr;3 (TGF-&bgr;3) was assessed in all grafts. ResultsThe gross and histological results showed significantly increased survival, angiogenesis, and epithelialization. Mean area of graft necrosis was significantly less in group 1 than in group 2 (7.49% vs 39.67%, P < 0.001). Statistically significant increase of capillary density, collagen intensity, VEGF, and TGF-&bgr;3 expression was noted in group 1 compared with group 2. ConclusionsThese findings suggest that autologous ASC transplantation can enhance skin graft survival in diabetic rats through differentiation, vasculogenesis, and secretion of growth factors such as VEGF and TGF-&bgr;3. This might represent a novel therapeutic approach in skin graft surgery for diabetic wounds.

Improvement of skin-graft survival after autologous transplantation of adipose-derived stem cells in rats

BACKGROUND Skin grafts are frequently used for a variety of indications in plastic and reconstructive surgery. Their necrosis is a common complication, while different therapies have been proposed. Currently, adipose-derived stem cells (ASCs) hold great promise for their angiogenic potential and role during tissue repair. In this study, autologous transplantation of ASCs was used in skin grafts in rats to determine if it increases angiogenesis, skin-graft survival and wound healing. METHODS ASCs were isolated, cultured, labelled with fluorescent dye and injected under full-thickness skin grafts in 10 rats (group 1), while 10 others served as controls (group 2). Skin grafts were analysed after 1 week. Collagens framework was assessed with Massons trichrome stain and angiogenesis with von Willebrand factor (vWF) immunohistochemistry. In addition, immunohistochemical staining intensity of vascular endothelial growth factor (VEGF) and transforming growth factor b3 (TGFb3) was assessed in all grafts. RESULTS Mean area of graft necrosis was significantly less in group 1 than in group 2 (6.12% vs. 32.62%, p<0.01). Statistically significant increase of microvessel density, collagen density, VEGF and TGFb3 expression was noted in group 1 compared with group 2 (all: p<0.01). CONCLUSIONS These findings suggest that autologous ASCs transplantation increases full-thickness skin-graft survival and shows promise for use in skin-graft surgery. This might be both due to in situ differentiation of ASCs into endothelial cells and increased secretion by ASCs of growth factors, such as VEGF and TGFb3 that enhance angiogenesis and wound healing.

Blood perfusion of the free anterolateral thigh perforator flap: its beneficial effect in the reconstruction of infected wounds in the lower extremity.

BackgroundIn a prospective study, we evaluated the blood perfusion and the blood flow of anterolateral thigh (ALT) flap by both near-infrared spectroscopy and color Doppler ultrasonography. Moreover, we assessed the ability of the perforator flap to reconstruct infected wounds of the lower extremity in 11 patients.MethodsNear-infrared spectroscopy showed excellent oxygen saturation, and Doppler ultrasonography documented excellent blood flow and decreased vascular resistance in the ALT flap postoperatively.ResultsAll flaps were successful and all wounds healed uneventfully within 2 weeks without any signs of recurrences or persistent infection. All patients achieved acceptable gait function after rehabilitation.ConclusionsApart from the mandatory role of thorough debridement, our results indicate that the ALT flap offers rich blood supply to the recipient area, thus contributing to the sterilization and healing of an infected wound within a short time period.

High-frequency p16INK4A promoter methylation is associated with histone methyltransferase SETDB1 expression in sporadic cutaneous melanoma

Epigenetic mechanisms participate in melanoma development and progression. The effect of histone modifications and their catalysing enzymes over euchromatic promoter DNA methylation in melanoma remains unclear. This study investigated the potential association of p16INK4A promoter methylation with histone methyltransferase SETDB1 expression in Greek patients with sporadic melanoma and their correlation with clinicopathological characteristics. Promoter methylation was detected by methylation‐specific PCR in 100 peripheral blood samples and 58 melanoma tissues from the same patients. Cell proliferation (Ki‐67 index), p16INK4A and SETDB1 expression were evaluated by immunohistochemistry. High‐frequency promoter methylation (25.86%) was observed in tissue samples and correlated with increased cell proliferation (P = 0.0514). p16INK4A promoter methylation was higher in vertical growth‐phase (60%) melanomas than in radial (40%, P = 0.063) and those displaying epidermal involvement (P = 0.046). Importantly, p16INK4A methylation correlated with increased melanoma thickness according to Breslow index (P = 0.0495) and marginally with increased Clark level (I/II vs III/IV/V, P = 0.070). Low (1–30%) p16INK4A expression was detected at the majority (19 of 54) of melanoma cases (35.19%), being marginally correlated with tumor lymphocytic infiltration (P = 0.078). SETDB1 nuclear immunoreactivity was observed in 47 of 57 (82.46%) cases, whereas 27 of 57 (47.37%) showed cytoplasmic immunoexpression. Cytoplasmic SETDB1 expression correlated with higher frequency of p16INK4A methylation and p16INK4A expression (P = 0.033, P = 0.011, respectively). Increased nuclear SETDB1 levels were associated with higher mitotic count (0–5/mm2 vs >5/mm2, P = 0.0869), advanced Clark level (III‐V, P = 0.0380), epidermal involvement (P = 0.0331) and the non‐chronic sun exposure‐associated melanoma type (P = 0.0664). Our data demonstrate for the first time the association of histone methyltransferase SETDB1 with frequent methylation of the euchromatic p16INK4A promoter and several prognostic parameters in melanomas.

Management of external ear keloids using form-pressure therapy

Keloids are a frequent finding after physical trauma. Keloids of the pinna (helix and antihelix) as a complication of ear‐piercing are the most difficult cases. Clinicians have tended to avoid the surgical approach, preferring local conservative treatment with corticosteroids or other treatments. We report use of intrakeloid resection and a form‐pressure device to treat pinna keloids and avoid recurrence. The purpose is to maintain the form of the folds of the pinna. The recommendation for this therapy is to maintain the pressure at 24–30 mmHg, and the duration of the form‐pressure therapy in our patients was about 25 weeks.

A study of a single variant allele (rs1426654) of the pigmentation-related gene SLC24A5 in Greek subjects.

Abstract:  The SLC24A5 gene, the human orthologue of the zebrafish golden gene, has been shown to play a key role in human pigmentation. In this study, we investigate the prevalence of the variant allele rs1426654 in a selected sample of Greek subjects. Allele‐specific polymerase chain reaction was performed in peripheral blood samples from 158 attendants of a dermatology outpatient service. The results were correlated with pigmentary traits and MC1R genotype. The vast majority of subjects (99%) were homozygous for the Thr111 allele. Only two subjects from the control group (1.26%) were heterozygous for the alanine and threonine allele. Both of these Thr111/Ala111 heterozygotes carried a single polymorphism of MC1R (one with the V92M variant and another with the V60L variant). Following reports of the rs1426654 polymorphism reaching fixation in the European population, our study of Greek subjects showed a prevalence of the Thr111 allele, even among subjects with darker skin pigmentation or phototype.

Orbitopalpebral repair after 835 excisions of malignant tumours

Repair of any defect in the eyelid depends on its size and position and the state of the surrounding tissues. Basal cell carcinoma (BCC) is the most common malignant tumour of the eyelids, and squamous cell carcinoma (SCC), mixed carcinomas or basosquamous cell carcinomas (BSC), and cutaneous melanomas (CM), also invade the eyelids and periocular zones. Reconstruction of the eyelids and associated orbital structures after resection requires a complete understanding of the anatomy. The adequacy of the reconstruction is judged by the quality of functional restoration and the aesthetic appearance. The purpose of this study was to document various, simple or complex reconstructive procedures that may be used after excision of malignant tumours of the eyelids and to assess the outcome of surgical treatment.

PEDICLED MYOCUTANEOUS AND MUSCLE FLAPS IN THE MANAGEMENT OF COMPLICATED CARDIOTHORACIC PROBLEMS

The purpose of this study was to review our experience with the management of patients with complicated cardiothoracic problems by the use of pedicled myocutaneous or muscle flaps, and discuss the various methods of reconstruction. Over the last 11 years, we have treated 54 patients with complicated cardiothoracic problems by reconstruction with pedicled myocutaneous or muscle flaps. The underlying causes were chest wall tumours (n = 13), radionecrosis of the chest wall (n = 12), deep or chronic sternal infections (n = 25), and bronchopleural fistulas (n = 4). The most commonly used muscles for reconstruction were pectoralis major and the rectus abdominis. Our results compare favourably with those reported elsewhere. We conclude that although the use of pedicled myocutaneous or muscle flaps is not free of complications, it is an effective and reliable method for the management of patients with complicated cardiothoracic problems.

Gracilis myocutaneous flap: Evaluation of potential risk factors and long‐term donor‐site morbidity

This study reviewed our experience with the gracilis myocutaneous (GMC) flap, potential risk factors for flap necrosis, and long‐term morbidity at the donor‐site. From 1993 to 2002, 29 GMC flaps were harvested from 27 patients (pedicled n = 21 and free n = 8). The overall incidence of flap necrosis was 13.79% (partial (n = 2) and total (n = 2) necrosis). Flap necrosis was correlated with body mass index >25 (P = 0.022), with smoking (P = 0.04 9) and with radiation therapy at the recipient site (P = 0.020). The long‐term morbidity at the donor‐site was low, except for scar appearance (17.24%), thigh contour deformity (58.62%), and hypoesthesia (17.24%). Significant age and gender differences were seen for ranking of scar ugliness, with females (P = 0.0061) and younger patients (age ≤55) (P = 0.046) assigned higher values. Significant age differences were seen for ranking of thigh contour deformity, with younger patients assigned higher values (P = 0.0012). In conclusion, patient overweight, smoking, and previous radiation therapy at the recipient site may be the “potential risk factors” for flap necrosis. The long‐term morbidity at the donor‐site was low, which was in agreement with previous reported studies. A larger series would be the subject of a future study.