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ABSTRACT: BACKGROUND: The treatment of tinea capitis using radiotherapy was introduced at the beginning of the twentieth century. In Israel, between 1949 and 1960, approximately 17,000 children underwent radiotherapy treatments for tinea capitis (actual numbers are probably higher due to irradiation in countries of origin as a prerequisite for immigration). Skin cancer presents a major problem for patients who underwent irradiation for the treatment of tinea capitis [aggressive biological behavior, multiple basal cell carcinomas (BCCs), up to 40 lesions in a single patient, with no predisposing condition such as Gorlin's or Bazex's syndromes]. There are ample data in the literature concerning the molecular changes in ultraviolet (UV) radiation-induced BCCs. However, similar data regarding ionizing radiation-induced BCCs are scarce. One work found higher rates of p53 and PTCH (both are tumor suppressor genes whose alterations are associated with BCC formation and frequency, but not biological behavior) abnormalities in post ionizing radiation BCCs. The absence of documented differences in gene expression that would account for a different biological behavior of radiotherapy-related BCCs, coupled with the aggressive and recurrent nature of these lesions, has propelled us to examine these differences by comparing gene expression in BCCs of the scalps of patients who were previously irradiated for tinea capitis in their childhood and of the scalps of patients who were not. METHODS: Tissue samples of excised scalp BCCs from seven previously irradiated patients (five male, two female) and seven not previously irradiated patients (six male, one female) were frozen upon excision and genetically analyzed using DNA microarray chips. RESULTS: No correlation was found between previous ionizing irradiation and gene expression. CONCLUSIONS: The negative results of this study, coupled with the observation of aggressive biological behavior of BCCs in previously irradiated patients merit further attention. Other explanations for the aggressive biological behavior of radiotherapy-induced BCCs come to mind. One such explanation could be that the difference between the groups lies not in the tumor itself, but in the host, who is more susceptible to the local destruction caused by the tumor due to changes in the surrounding tissue (e.g., impaired blood supply due to radiation, structural damage in seemingly healthy skin). This hypothesis will be the focus of further research. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Aesthetic Plastic Surgery 10/2012; · 1.41 Impact Factor
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ABSTRACT: The treatment of burn victims constitutes a considerable challenge both to the clinician in regard to mundane treatment and to health systems in regard to structural organization. The state of Israel is in dire need of competent burn care capabilities for political, geographical, and demographic reasons. Israel currently has five designated burn units but no burn center. A review of the recent literature suggests that larger burn centers can convey lower mortality rates and better functional outcomes for severe burn patients in comparison to smaller burn units. The objective of this study is to assess Israel's burn care alignment needs and capabilities based on Israel's burn patient and burn unit data. In addition, the authors aim to compare the burn care alignment capabilities with those of the country's European and American counterparts. Data of all the burn patients hospitalized in Israel's level 1 trauma centers' burn units between the years 1998 and 2005 according to the Israeli Trauma Registry were analyzed. Simultaneously, data regarding the setup and arrangement of each burn unit were obtained from each burn unit director via phone. Between the years 1998 and 2005, 974 adult patients with burns of the second degree or higher spanning 20% TBSA and more were hospitalized in the five hospitals that operate a functional specialized burn unit. The average hospitalization period was 32.4 days while the mortality rate was 21.1%. Currently, Israel's five burn units report possessing 27 burn beds and 14 burn intensive care unit beds. Due to the continuous risk for terror attacks and military campaigns and due to Israel's inability to refer excess burn patients to neighboring countries, Israel desperately needs efficient burn care capabilities. Israel currently trails both the United States and Europe in regard to burn beds and burn centers per population. The annual quantity and severity of burn patients in Israel largely exceeds the amount needed to justify an establishment of a burn center by the current American Burn Association guidelines, while the literature provides vast amount of evidence proving burn centers' efficacy in improving outcome, shortening hospitalization periods, and reducing costs. Taking all these elements into consideration, it might be prudent to establish a national burn center in Israel to promote burn care standards and disaster planning up to international standards.
Journal of burn care & research: official publication of the American Burn Association 03/2012; 33(4):510-7. · 1.37 Impact Factor
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Michal Mauda-Havakuk,
Naomi Litichever,
Ellad Chernichovski,
Odelia Nakar,
Eyal Winkler,
Ram Mazkereth, Arie Orenstein,
Eran Bar-Meir,
Philippe Ravassard,
Irit Meivar-Levy,
Sarah Ferber
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ABSTRACT: Cellular differentiation and lineage commitment have previously been considered irreversible processes. However, recent studies have indicated that differentiated adult cells can be reprogrammed to pluripotency and, in some cases, directly into alternate committed lineages. However, although pluripotent cells can be induced in numerous somatic cell sources, it was thought that inducing alternate committed lineages is primarily only possible in cells of developmentally related tissues. Here, we challenge this view and analyze whether direct adult cell reprogramming to alternate committed lineages can cross the boundaries of distinct developmental germ layers.
We ectopically expressed non-integrating pancreatic differentiation factors in ectoderm-derived human keratinocytes to determine whether these factors could directly induce endoderm-derived pancreatic lineage and β-cell-like function. We found that PDX-1 and to a lesser extent other pancreatic transcription factors, could rapidly and specifically activate pancreatic lineage and β-cell-like functional characteristics in ectoderm-derived human keratinocytes. Human keratinocytes transdifferentiated along the β cell lineage produced processed and secreted insulin in response to elevated glucose concentrations. Using irreversible lineage tracing for KRT-5 promoter activity, we present supporting evidence that insulin-positive cells induced by ectopic PDX-1 expression are generated in ectoderm derived keratinocytes.
These findings constitute the first demonstration of human ectoderm cells to endoderm derived pancreatic cells transdifferentiation. The study represents a proof of concept which suggests that transcription factors induced reprogramming is wider and more general developmental process than initially considered. These results expanded the arsenal of adult cells that can be used as a cell source for generating functional endocrine pancreatic cells. Directly reprogramming somatic cells into alternate desired tissues has important implications in developing patient-specific, regenerative medicine approaches.
PLoS ONE 01/2011; 6(10):e26298. · 4.09 Impact Factor
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Galya Lerman,
Camila Avivi,
Corine Mardoukh,
Aviv Barzilai,
Ariel Tessone,
Ben Gradus,
Felix Pavlotsky,
Iris Barshack,
Sylvie Polak-Charcon, Arie Orenstein,
Eran Hornstein,
Yechezkel Sidi,
Dror Avni
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ABSTRACT: Psoriasis is a complex disease at the cellular, genomic and genetic levels. The role of microRNAs in skin development was shown in a keratinocyte-specific Dicer knockout mouse model. Considering that two main characteristics of psoriasis are keratinocytes hyperproliferation and abnormal skin differentiation, we hypothesized that aberrant microRNA expression contributes to the psoriatic phenotype. Here, we describe the differential expression of miRNAs in psoriatic involved and uninvolved skin as compared to normal skin, revealing an additional aspect of this complex disorder.
Expression arrays were used to compare microRNA expression in normal skin versus psoriatic involved and uninvolved skin. Fourteen differentially expressed microRNAs were identified, including hsa-miR-99a, hsa-miR-150, hsa-miR-423 and hsa-miR-197. The expression of these microRNAs was reevaluated by qPCR. IGF-1R, which is involved in skin development and the pathogenesis of psoriasis, is a predicted target of hsa-miR-99a. In an in situ hybridization assay, we found that IGF-1R and miR-99a are reciprocally expressed in the epidermis. Using a reporter assay, we found that IGF-1R is targeted by hsa-miR-99a. Moreover, over expression of miR-99a in primary keratinocytes down-regulates the expression of the endogenous IGF-1R protein. Over expression of miR-99a also inhibits keratinocyte proliferation and increases Keratin 10 expression. These findings suggest that overexpression of hsa-miR-99a in keratinocytes drives them towards differentiation. In primary keratinocytes grown in high Ca(++), miR-99a expression increases over time. Finally, we found that IGF1 increases the expression of miR-99a.
We identified several microRNAs that are expressed differentially in normal and psoriatic skin. One of these miRNAs is miR-99a that regulates the expression of IGF-1R. Moreover, miR-99a seems to play a role in the differentiation of keratinocytes. We suggest that miR-99a is one of the regulators of the IGF-1R signaling pathway in keratinocytes. Activation of IGF1 signaling results in elevation of miR-99a which represses the expression of IGF-1R.
PLoS ONE 01/2011; 6(6):e20916. · 4.09 Impact Factor
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ABSTRACT: The newly reconstructed nipple is extremely sensitive to mechanical pressure and shearing forces, which can cause flap necrosis and sloughing of the skin, eventually promoting infection. Current available dressing solutions are cumbersome, inefficient, displeasing, or otherwise not readily obtainable.
In this study, 10 patients with newly reconstructed nipples were instructed to use breastfeeding nipple shields as the sole means of nipple dressing after the reconstruction procedure.
No complications were observed overall. Patients reported full adherence to the postoperative dressing regimen as well as ease of use, availability, low costs, and pleasing aesthetic appearance under garments.
Silicone breastfeeding nipple shields offer an efficient, affable, cheap, widely available, and aesthetically pleasing form of postoperative dressing for reconstructed nipples. Their use may enhance patient compliance with the dressing regimen and lower the postoperative complication rate.
Aesthetic Plastic Surgery 10/2009; 34(1):48-51. · 1.41 Impact Factor
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Gal Markel,
Rona Ortenberg,
Rachel Seidman,
Sivan Sapoznik,
Nira Koren-Morag,
Michal J Besser,
Jair Bar,
Ronnie Shapira,
Adva Kubi,
Gil Nardini,
Ariel Tessone,
Avraham J Treves,
Eyal Winkler, Arie Orenstein,
Jacob Schachter
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ABSTRACT: It was previously shown that CEACAM1 on melanoma cells strongly predicts poor outcome. Here, we show a statistically significant increase of serum CEACAM1 in 64 active melanoma patients, as compared to 48 patients with no evidence of disease and 37 healthy donors. Among active patients, higher serum CEACAM1 correlated with LDH values and with decreased survival. Multivariate analysis with neutralization of LDH showed that increased serum CEACAM1 carries a hazard ratio of 2.40. In vitro, soluble CEACAM1 was derived from CEACAM1(+), but neither from CEACAM1(-) melanoma cells nor from CEACAM1(+) lymphocytes, and directly correlated with the number of CEACAM1(+) melanoma cells. Production of soluble CEACAM1 depended on intact de novo protein synthesis and secretion machineries, but not on metalloproteinase function. An unusually high percentage of CEACAM1(+) circulating NK and T lymphocytes was demonstrated in melanoma patients. CEACAM1 inhibited killing activity in functional assays. CEACAM1 expression could not be induced on lymphocytes by serum from patients with high CEACAM1 expression. Further, expression of other NK receptors was impaired, which collectively indicate on a general abnormality. In conclusion, the systemic dysregulation of CEACAM1 in melanoma patients further denotes the role of CEACAM1 in melanoma and may provide a basis for new tumor monitoring and prognostic platforms.
Cancer Immunology and Immunotherapy 08/2009; 59(2):215-30. · 3.70 Impact Factor
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Gal Markel,
Rachel Seidman,
Michal J Besser,
Naama Zabari,
Rona Ortenberg,
Ronnie Shapira,
Avraham J Treves,
Ron Loewenthal, Arie Orenstein,
Arnon Nagler,
Jacob Schachter
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ABSTRACT: NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands.
We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2D(high) or NK30(high) donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies.
NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities.
PLoS ONE 02/2009; 4(5):e5597. · 4.09 Impact Factor
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ABSTRACT: An efficient immune response against tumours depends on a well-orchestrated function of integrated components, but is finally exerted by effector tumour-infiltrating lymphocytes (TIL). We have previously reported that homophilic CEACAM1 interactions inhibit the specific killing and interferon-gamma (IFN-gamma) release activities of natural killer cells and TIL. In this study a model for the investigation of melanoma cells surviving long coincubation with antigen-specific TIL is reported. It is demonstrated that the surviving melanoma cells increase their surface CEACAM1 expression, which in turn confers enhanced resistance against fresh TIL. Furthermore, it is shown that this is an active process, driven by specific immune recognition and is at least partially mediated by lymphocyte-derived IFN-gamma. Similar results were observed with antigen-restricted TIL, either autologous or allogeneic, as well as with natural killer cells. The enhanced CEACAM1 expression depends, however, on the presence of IFN-gamma and sharply drops within 48 hr. This may be a mechanism that allows tumour cells to transiently develop a more resistant phenotype upon recognition by specific lymphocytes. Therefore, this work substantiates the melanoma-promoting role of CEACAM1 and marks it as an attractive target for novel immunotherapeutic interventions.
Immunology 07/2008; 126(2):186-200. · 3.32 Impact Factor
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ABSTRACT: Colorectal carcinoma is one of the more prevalent, highly malignant human tumors, occurring in about 7% of the population. However, if diagnosed and treated in its early stages, colon cancer is curable. In our study, we used a mouse xenograft model to investigate the capability of a fluorescent conjugate of a novel synthetic somatostatin (SST) analog to improve detection of human colorectal tumors that are characterized by over-expressed SST receptors. Human HT-29 colon carcinomas were induced in nude mice. After administration of the fluorescent SST conjugate, in vivo low- and high-magnification fluorescence microscopy, as well as high-resolution spectrally resolved imaging were performed, and the time-dependent biodistribution was determined quantitatively (using fiber-optic spectroscopy). Administration of the conjugate (at concentrations of 6 mg/kg body weight) enabled targeting small (1-5 mm diameter) tumors with high sensitivity and selectivity. Toxicity studies at dosages up to 1,000 mg/kg body weight did not reveal any drug related abnormalities. In conclusion, the SST conjugate significantly enhanced the detection of HT-29 colon tumors by fluorescence imaging because of a 5- to 8-fold increase in the contrast between malignant and normal tissues.
International Journal of Cancer 06/2008; 122(9):2044-9. · 5.44 Impact Factor
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Burns: journal of the International Society for Burn Injuries 05/2008; 35(2):294-6. · 1.95 Impact Factor
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Dermatologic Surgery 03/2008; 34(2):240-2. · 1.80 Impact Factor
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ABSTRACT: When studying water diffusion in biological systems, any specific signal attenuation curve may be reproduced by a broad range of mathematical functions. Our goals were to quantify the diffusion and T(2) relaxation properties of water in a simple biological system and to study the changes that occur in osmotically stressed cells. Human breast cancer cells were incubated in isotonic or hypotonic osmotic buffers. Diffusion-weighted and T(2)-weighted magnetic resonance images were acquired during sedimentation over 12 h. Diffusion-weighted imaging (DWI) data were analyzed with a biexponential fit, the Kärger model for exchange between two freely diffusing populations and the Price-modified Kärger model accounting for restricted diffusion in spherical geometry. We found that only the Price model provided an accurate quantitative description for water diffusion in both cell systems, independent of acquisition parameters, over the entire density range. Model-derived cell radii, intracellular volume fractions and transmembrane water exchange times were in good agreement with results calculated from light microscopy and with model-free exchange times. T(2) data indicated two populations in fast exchange, with volume fractions clearly different from DWI populations. Hypotonic stress led to higher slow apparent diffusion coefficient, longer T(2) and lower membrane permeability. The tortuosity in a hypotonic cell suspension complied with the Wang model for spherical geometry. Quantitative characterization of biological systems is obtainable by DWI, using appropriate modeling, accounting for water restriction and exchange between compartments.
Magnetic Resonance Imaging 02/2008; 26(1):88-102. · 1.99 Impact Factor
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Dermatologic Surgery 01/2008; 33 Suppl 2:S199-206; discussion S206. · 1.80 Impact Factor
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ABSTRACT: Early detection of malignant melanoma of the skin is the most important factor in patient survival. Naked-eye diagnostic sensitivity and specificity are low. Patients with multiple nevi are at high risk to develop melanomas and the clinical follow-up of such patients is difficult, resulting in missed melanomas on the one hand and unnecessary biopsies on the other.
To describe the set-up of a special clinic aimed at early detection of melanoma and follow-up of high risk patients and preliminary results from 20 months of operation.
We established a pigmented lesions clinic based on a digital photography studio enabling documentation and comparison over time of full body photography and dermoscopy.
In the first 20 months of work, 895 patients were seen, 206 of them for follow-up visits. A total of 29,254 photos were taken. Altogether, 236 lesions were suspicious (either clinically or dermoscopically) and the patients were advised to excise them. Seven melanomas were found in this initial examination (which did not include long-term follow-up).
With multimode photographic cutaneous surveillance, early detection of melanoma in high risk patients has been reported. Our clinic utilizes the same techniques and diagnostic algorithm as other leading clinics throughout the world, thus enabling us to deliver better follow-up for those patients.
The Israel Medical Association journal: IMAJ 11/2007; 9(10):708-12. · 1.02 Impact Factor
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ABSTRACT: We report the use of expanded reverse abdominoplasty in three female patients with postburn scars involving the entire epigastric region in which the inframammary folds were effaced, resulting in distortion of breast contour. In two of the patients, tissue expanders were used, and subsequently, reverse abdominoplasty was performed, thus re-creating the inframammary fold. The third patient reported to be pregnant after expanders were placed; therefore, smaller volumes of inflation for tissue expansion were necessary. We believe that this procedure is an optimal solution, both aesthetically and functionally, in respect to other reconstructive techniques in female patients with normal skin inferior to epigastric burns. The surgical technique and results are discussed.
Journal of burn care & research: official publication of the American Burn Association 10/2007; 28(6):849-53. · 1.37 Impact Factor
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ABSTRACT: Burns are a major public health problem, with long hospitalization stay in both intensive care units and general wards. In Israel about 5% of all hospitalized injuries are burn injuries. There are no long-term epidemiological studies on burn injuries in adults in Israel.
To identify risk factors for burn injuries and provide a starting point for the establishment of an effective prevention plan.
We analyzed the demographic, etiologic and clinical data of 5000 burn patients admitted to the five major hospitals with burn units in Israel during a 7 year period (1997-2003). Data were obtained from the records of the Israeli National Trauma Registry. The differences between various groups were evaluated using the chi-square test.
Male gender was twice as frequent as female gender in burn patients (68.0% vs. 31.9%), and non-Jewish ethnicity was more common when considering their proportion in the total population (62.3% vs. 36.8%). Second and third-degree burns with body surface areas less than 10% constituted the largest group (around 50%). The largest age group was 0-1 years, constituting 22.2% of the cases. Inhalation injury was uncommon (1.9%). The most common etiologies were hot liquids (45.8%) and open fire (27.5%). Children less than 10 years old were burnt mainly by hot liquids while the main cause of burns for adults > 20 years old was an open flame. The majority of burns occurred at home (58%); around 15% were work related. The mean duration of hospitalization was 13.7 days (SD 17.7); 15.5% were in an intensive care unit with a mean duration of 12.1 days (SD 17.1). Surgical procedures became more common during the period of the study (from 13.4% in 1998 to 26.59% in 2002, average 19.8%). The mortality rate was 4.4%. We found a strong correlation between burn degree and total body surface area and mortality (0.25% mortality for 2nd to 3rd-degree burns with less than 10% TBSA, 5.4% for 2nd to 3rd-degree burns with 20-39% TBSA, and 96.6% for burns > 90% TBSA). The worst prognosis was for those over the age of 70 (mortality rate 35.3%) and the best prognosis was for the 0-1 year group (survival rate 99.6%).
The groups at highest risk were children 0-1 years old, males and non-Jews (the incidence rate among non-Jews was 1.5 times higher than their share in the general population). Those with the highest mortality rate were victims of burns > 90% TBSA and patients older than 70. Most burns occurred at home.
The Israel Medical Association journal: IMAJ 10/2007; 9(9):659-62. · 1.02 Impact Factor
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Dermatologic Surgery 08/2007; 33(7):880-1. · 1.80 Impact Factor
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ABSTRACT: An ingrowing toenail is an excessive lateral nail growth into the nail fold. It acts as a foreign body and exerts a local pressure sore-like effect, which may result in inflammation and granulation. Several treatment modalities exist, including chemical ablation and different surgical procedures. Here we describe and compare a simple and effective method of partial matricectomy using the CO2 laser (group A) versus a similar method with the addition of lateral nail fold vaporization (group B).
Outcome evaluation of a modified laser treatment modality for ingrowing toenails and determination of the role of lateral fold vaporization in reducing the recurrence of symptoms.
Forty patients (mean age 32.45 years) were treated with CO2 laser ablation of toenails between 1999 and 2005 by four physicians. One physician implemented a method that includes lateral nail fold vaporization and resection of the nail segment with its nail bed from 1999 to 2005. Three physicians implemented a similar technique but without lateral fold vaporization between 1999 and 2003, and added lateral fold vaporization to the performed procedure starting in 2004.
The recurrence rate was 37.5% in group A and 6.2% in group B. The overall average disease-free follow-up period was 42.2 months.
The use of CO2 laser in the treatment of ingrowing toenails offers an effective modality. We demonstrate the importance of lateral fold vaporization with the CO2 laser both in improving efficacy and in decreasing recurrence rates over a long follow-up period.
Journal of Cosmetic and Laser Therapy 07/2007; 9(2):97-100. · 0.98 Impact Factor
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ABSTRACT: Cheilitis is a precancerous skin lesion most often affecting the lower lip. We describe a technique in which this disorder can be treated using Er:YAG laser vaporization. The Er:YAG laser wavelength at 2940 nm lies in a very strong water absorption peak; tissue interaction results mainly in vaporization with minimal heat conduction to adjacent tissue.
To evaluate the efficacy and outcome of a new modality in the treatment of actinic cheilitis with the Er:YAG laser.
Between 2002 and 2005, 12 patients with actinic cheilitis were treated at our institute with the Er:YAG laser. All patients were cured with no recurrence to date, and none suffered postoperative complications.
Patients were men and women aged between 37 and 71 years. The healing duration varied from 7 to 30 days (mean 22.33+/-6.91 days) and the follow-up ranged from 8 months to 3 years (mean 23.16+/-9.48 months). No recurrences were detected in our study.
Using the Er:YAG laser provides accurate tissue ablation, giving a very satisfactory cosmetic result, with a short healing period, no lip deformity and no sensation loss.
Journal of Cosmetic and Laser Therapy 04/2007; 9(1):23-5. · 0.98 Impact Factor
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ABSTRACT: Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor presenting as a painless subcutaneous mass in the extremities first reported in 1998. We report the first case of a MIFS tumor in the groin.
We have performed seven immunohistochemical stains that were not applied before on MIFS.
The first case of a MIFS tumor in the groin.
MIFS must be considered in the differential diagnosis of a painless mass not only in the distal extremities but also in the groin. The diagnosis of this tumor is difficult and can be missed if not considered because of the unusual location. Due to high recurrence rates and one case of documented metastases, the recommended treatment is wide excision.
Journal of Cutaneous Pathology 04/2007; 34(3):276-80. · 1.56 Impact Factor
