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We describe the case of a patient with systemic amyloidosis that manifested as generalized alopecia. Amyloidosis was documented by means of skin biopsy and urine immunoelectrophoresis.

Extensive attention has been directed to lymphedema involving the extremities. However, there has been relatively limited study of the cutaneous lymphatics of the head and neck. In this review of head and neck lymphatics, we capsulize the history of the lymphatics, the anatomy of the cutaneous lymphatics, lymphatic function and physiology, and imaging modalities used to define this intricate vascular system. To appreciate the clinical challenges associated with head and neck lymphatic dysfunction, we also provide an overview of disease processes of the cutaneous lymphatics and their treatment, theories on the etiology of lymphedema, and future directions to better understand lymphatic function and disease. Knowledge of the cutaneous lymphatics of the head and neck are critical to the clinical evaluation of patients, who present with this debilitating condition and to our understanding of its pathogenesis and appropriate management.

Human herpesviruses (HHVs) have frequently been suspected as etiologic agents or cofactors in cutaneous disease. However, clearly established associations are rare. Investigations into an etiologic association between HHVs and cutaneous disease are complicated by the ubiquity and nearly universal prevalence of some herpesviruses. This article summarizes the associations between cutaneous disease and HHV-6, HHV-7, and HHV-8. In addition to a personal library of references, the PubMed database of biomedical literature was searched using the following Medical Subject Heading terms: HHV-6, HHV-7, and HHV-8, each in conjunction with cutaneous manifestations, virology, epidemiology, dermatopathology, and therapeutics, between 1998 and March 2011. Free-text searches with known or suspected disease associations were added for broader coverage. The results have been summarized to provide a practical review for the physician likely to encounter cutaneous diseases.

Porphyria cutanea tarda (PCT) is a vesiculobulIous disorder often associated with estrogens, hepatitis C virus (HCV), alcoholism, hereditary hemochromatosis (HH), and human immunodeficiency virus. Hepcidin, a peptide hormone produced by the liver, has been associated with iron metabolism in 3 common precipitating factors for PCT: HCV, HH, and alcohol consumption. We present the case of a patient with erosions and noninflammatory bullae on his hands and forearms who received a diagnosis of PCT. On further examination, the patient was found to be positive for 3 precipitating factors: HCV, an HH gene mutation, and alcohol use. For patients with PCT, it is important to perform phenotypic screening for HCV and HH. Targeting hepcidin with replacement therapy to decrease iron may be a treatment of not only HCV, HH, and alcoholic cirrhosis, but also PCT.

The purpose of this review is to provide insight and clarification in the quandary of classification and delineate clinical and histological features and pathophysiology of paraneoplastic pemphigus. This is a paraneoplastic disease of epithelial autoimmunity and adhesion originally described by Dr. Anhalt in 1990. Paraneoplastic pemphigus represents only one manifestation of the heterogeneous autoimmune syndrome in which patients, in addition to small airways occlusion, may display a spectrum of at least five clinical variants of the mucocutaneous disease [i.e. pemphigus-like, pemphigoid-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like, termed paraneoplastic autoimmune multiorgan syndrome (PAMS)]. There is a need for the expanded, inclusive classification of diverse mucocutaneous and respiratory presentations of PAMS. Multiple specific effectors of humoral and cellular autoimmunity mediating epithelial damage have been identified. An update of advances in clinical and basic research on PAMS and in management and overall prognosis of PAMS is provided.

Objective To review the results of skin biopsies and patient-provided specimens from patients whose assessment was consistent with delusional infestation, including delusions of parasitosis. Design Retrospective medical record review. Setting Mayo Clinic, Rochester, Minnesota. Patients The study population comprised all patients who were seen at Mayo Clinic and had a diagnosis of delusional skin infestation, including delusions of parasitosis, between 2001 and 2007, and who underwent biopsies as part of their dermatologic evaluations or brought samples to their clinical consultations. Main Outcome Measures The results of examination of these biopsy and patient-provided specimens. Results A total of 108 patients met inclusion criteria for this study: 80 received biopsies, 80 had self-procured skin specimens, and 52 patients received biopsies and provided specimens. No biopsy specimen (0 of 80) provided evidence to support skin infestation. The most common interpretations in the 80 biopsy specimens were dermatitis in 49 of 80 (61%); excoriation, ulceration, or erosion in 38 (48%); and nonspecific dermal inflammation in 25 (31%). Patient-provided specimens were most frequently assessed by the physician (generally a dermatologist) evaluating the patient, although 20 of the 80 samples (25%) were submitted for pathologic evaluation. Of these 80 specimens, 10 (13%) contained insects. All but 1 of the insects were noninfesting varieties; 1 (1%) was a pubic louse. The remaining findings consisted of cutaneous debris, environmental detritus, or plant material. Conclusion In patients with suspected delusional infestation, neither skin biopsies nor examination of patient-provided specimens provided objective evidence of skin infestation.

BACKGROUND: Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post-transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors' knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high-risk for NMSC. METHODS: The study was designed as a prospective, randomized, double-blind, placebo-controlled clinical trial. To test the possible skin cancer-preventing effect of a 2-year treatment with acitretin, 70 nontransplantation patients aged ≥18 years who had a history of ≥2 NMSCs within 5 years of trial onset were randomized to receive either placebo or acitretin 25 mg orally 5 days per week. The primary outcome measure was the rate of new NMSC development. RESULTS: Seventy patients were randomized to receive either acitretin alone (N = 35) or placebo (N = 35). During the 2-year treatment period, the patients who received acitretin did not have a statistically significant reduction in the rate of new primary NMSCs (odds ratio, 0.41; 95% confidence interval, 0.15-1.13; 54% vs 74%; P = .13). However, using the incidence of new NMSC, the time to new NMSC, and total NMSC counts, an umbrella test indicated a significant trend that favored the use of acitretin (chi-square statistic, 3.94; P = .047). The patients who received acitretin reported significantly more mucositis and skin toxicities compared with the patients who received placebo. CONCLUSIONS: Although there was not a statistically significant benefit observed with the use of acitretin, this may have been the result of low statistical power. Cancer 2012;. © 2011 American Cancer Society.

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.

Background At our institution, hospitalization for intensive treatment (combining wet dressings and topical corticosteroids) is a primary intervention for severe pediatric atopic dermatitis. Prior reports of this treatment are limited. Objective We sought to review the efficacy of wet dressings for pediatric atopic dermatitis. Methods We reviewed records of pediatric patients hospitalized from January 1, 1980, through April 20, 2010, who received intensive topical treatments for atopic dermatitis. Results In total, 218 pediatric patients had widespread atopic dermatitis severe enough to warrant hospitalization, despite prior outpatient topical treatments and other interventions such as immunomodulating agents, phototherapy, dietary manipulation, or contact allergen avoidance. Mean (SD) age was 5.97 (4.91) years (range, 2 months-17 years); 141 patients (65%) were female. There were 266 hospitalizations: 192 patients (72%) had one admission, 15 (6%) had two admissions, and 11 (4%) had 3 or more admissions. Mean (SD) duration of hospitalization was 3.61 (2.23) days (range, 1-16 days). Upon discharge, all patients showed improvement. In 239 of 266 hospitalizations, patient records showed quantification of improvement (global assessment): 121 (45%) had 75% to 100% improvement, 102 (38%) had 50% to 75% improvement, and 16 (6%) had 25% to 50% improvement. Limitations This was a retrospective study. Conclusion Intensive inpatient treatment (with wet dressings and topical corticosteroids) was highly effective in controlling severe and recalcitrant atopic dermatitis. Intensive topical treatment, although underused, is an effective first-line approach for patients with severe atopic dermatitis.

A 71-year-old woman presented with exquisitely tender mucosal erosions, a diffuse polymorphous eruption, and night sweats. Workup revealed multiple myeloma with a monoclonal IgG-kappa paraprotein in the serum. Her severe oral involvement was suggestive of paraneoplastic pemphigus, but direct and indirect immunofluorescence tests were negative. A skin biopsy showed spongiosis and a sparse perivascular lymphocytic infiltrate, with occasional CD8-positive lymphocytes in the epidermis. Her lesions improved with intravenous immune globulin. Immunohistochemical staining on the formalin-fixed biopsy specimen was strongly positive for IgG and IgG-kappa in an epidermal "chicken-wire" pattern, but negative for IgG-lambda. Her pulmonary tissue stained negative for IgG-kappa, suggesting clinical relevance of the myeloma paraprotein in her epidermis. To our knowledge, this is the first report of a multiple myeloma patient with such an eruption.

EPIDEMIOLOGY- PATHOGENESIS.- DISEASE ENTITIES.- Non-Melanoma Skin Cancer.-Melanocytic Tumors.- Cuteanous Lymphomas.- Others.- THERAPIES.

Background: Diagnosis of cutaneous lymphoma in the absence of systemic lymphoma may be difficult. Reactive lymphoid lesions can mimic lymphoma clinically and histologically and have been designated pseudolymphomas. Objective: Our purpose was to analyze lymphoid gene rearrangements in cutaneous lymphoproliferative lesions and to correlate these findings with the histologic, immunophenotypic, and clinical profile. Methods: We examined 21 cases of lymphoproliferative lesions that developed in skin and performed molecular rearrangement analysis of T-cell receptor and immunoglobulin genes. We examined identical tissues by histologic and immunophenotypic criteria and conducted follow-up clinical evaluation of all patients. Results: Clonal rearrangements of immunoglobulin (seven cases) or T-cell receptor (two cases) gene were detected in 9 of 21 patients. No specific histologic or immunophenotypic feature was consistently associated with a clonal lymphoid gene rearrangement. Systemic lymphoma developed in one patient in whom a clonal rearrangement within the immunoglobulin gene was identified. Conclusion: Gene rearrangement analysis may be helpful in differentiating primary cutaneous lymphoma from pseudolymphoma. The chronic clinical course of patients with clonal lymphoid gene rearrangements supports a lack of correlation between clonality and biologic aggressiveness.

Within the space of the last 5 years, application of the revolutionary in vitro method of deoxyribonucleic acid (DNA) amplification known as the polymerase chain reaction (PCR), has become ubiquitous. The rapidly increasing number of clinical and research articles utilizing this technology, both in the dermatologic and general medical literature, requires one to have at least a basic understanding of how the PCR is conducted, what it has to offer, and the potential shortcomings. Such knowledge will hopefully allow a more critical appraisal of an increasingly complex literature. This review aims to describe the methodology and medical applications of this powerful technique with special consideration to the increasing role PCR may have on dermatologic research and practice.

Keratinocytes were established in serum-free culture medium from lesional and nonlesional skin of a patient with vitiligo (skin type III) and from an age-matched healthy control subject. Both differentiating and undifferentiated cells were examined for the presence of beta 2-adrenoceptors in culture medium containing either low (0.1 x 10(-3) M) or high (1.5 x 10(-3) M) calcium concentrations. Binding experiments were performed with saturating levels of radiolabeled (--)-[3H] CGP 12177, a nonselective beta-adrenergic antagonist. Controls for nonspecific binding were determined by the addition of the beta-adrenergic antagonist, propranolol (5 mumol), before the introduction of (--)-[3H] CGP 12177 to cell cultures. Undifferentiated keratinocytes yielded the highest expression of beta 2-adrenoceptors, whereas differentiating keratinocytes grown in medium with a low calcium concentration (0.1 x 10(-3) M) had a significantly lower expression of receptors with the exception of vitiliginous cells, which retained high densities of receptors, similar to undifferentiated cells. In addition, these vitiliginous keratinocytes showed a defect in 45calcium uptake. In contrast, differentiated keratinocytes from all three cell strains, grown in medium containing a high calcium concentration (1.5 x 10(-3) M) revealed a significantly lower receptor density compared to undifferentiated cells. This finding identified the importance of the extracellular calcium concentration in the expression of beta 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Certain scalp hair shafts from 2 of 10 cases of pili annulati examined by scanning electron microscopy exhibited an unusual weathering pattern. The majority of affected hair shafts showed minor surface abnormalities at regular intervals (nodes) associated with the underlying spaces. However, in a few examples, there was marked damage to the cuticle at the nodes exposing the underlying cortex; in severe cases there was cracking of both cuticle and cortex. These damaged nodes were also associated with trichorrhexis nodosa-like breaks of the hair shaft. This study shows that the nodes in pili annulati may have some inherent weakness that could result in breaks in the hair shaft exposed to physical trauma.

A 71-year-old woman presented with exquisitely tender mucosal erosions, a diffuse polymorphous eruption, and night sweats. Workup revealed multiple myeloma with a monoclonal IgG-kappa paraprotein in the serum. Her severe oral involvement was suggestive of paraneoplastic pemphigus, but direct and indirect immunofluorescence tests were negative. A skin biopsy showed spongiosis and a sparse perivascular lymphocytic infiltrate, with occasional CD8-positive lymphocytes in the epidermis. Her lesions improved with intravenous immune globulin. Immunohistochemical staining on the formalin-fixed biopsy specimen was strongly positive for IgG and IgG-kappa in an epidermal "chicken-wire" pattern, but negative for IgG-lambda. Her pulmonary tissue stained negative for IgG-kappa, suggesting clinical relevance of the myeloma paraprotein in her epidermis. To our knowledge, this is the first report of a multiple myeloma patient with such an eruption.

Lipid rafts are cholesterol-rich cell signaling platforms, and their physiological role can be explored by cholesterol depletion. To characterize transcriptional changes ongoing after lipid raft disruption in epidermal keratinocytes, a cell type that synthesizes its cholesterol in situ, we performed whole-genome expression profiling. Microarray results show that over 3,000 genes are differentially regulated. In particular, IL-8, urokinase-like plasminogen activator receptor, and metalloproteinases are highly upregulated after cholesterol extraction. Quantitative reverse transcriptase PCR validation and protein release measurements demonstrate the physiological relevance of microarray data. Major enriched terms and functions, determined by Ingenuity Pathways Analysis, identify cholesterol biosynthesis as a major function, illustrating the specificity of keratinocyte response toward cholesterol depletion. Moreover, the inflammatory skin disorder atopic dermatitis (AD) is identified as the disease most closely associated with the profile of lipid raft-disrupted keratinocytes. This finding is confirmed in skin of AD patients, in whom transcript levels of major lipid raft target genes are similarly regulated in lesional atopic skin, compared with non-lesional and normal skin. Thus, lipid raft disruption evokes typical features of AD, thereby suggesting that lipid raft organization and signaling could be perturbed in atopic keratinocytes.

Background Although rare, cutaneous small-vessel vasculitis (CSVV) secondary to solid organ malignancy has been documented. Objective We sought to better understand the frequency, clinical course, therapeutic response, and outcome of CSVV associated with solid organ malignancy. Methods We conducted a retrospective chart review of patients seen between 1996 and 2009 with diagnoses of biopsy-proven cutaneous leukocytoclastic vasculitis and solid organ malignancy separated by less than 12 months. Results Of 17 patients (mean age, 66.5 years), 10 patients (59%) were male. CSVV occurred before (3 patients; 18%), concurrent with (3 patients; 18%), and after (11 patients; 65%) diagnosis of solid organ malignancy. The most common solid organ malignancy was of the lung (n = 4; 24%). Other associated cancers were breast (n = 3); prostate (n = 2); colon (n = 2); renal (n = 2); thyroid (n = 1); bladder (n = 1); gallbladder (n = 1); and peritoneal (n = 1). Three patients had cutaneous vasculitis in association with malignancy recurrence despite having no cutaneous vasculitis associated with their primary malignancy. Vasculitis remission with use of immunosuppressive agents alone occurred in 9 patients (53%). Eleven patients (65%) were alive at last follow-up (mean follow-up duration, 27 months). Limitations This was a retrospective study with a relatively small number of patients. Conclusion Solid organ malignancy should be considered as a possible cause of CSVV of unknown origin. In contrast to previous reports, our patients were more likely to respond to immunosuppressive therapies without treatment of the associated malignancy and to be alive at last follow-up.

Background Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), a common preservative in some brands of moist toilet paper (baby wipes and moist towelettes), has been reported to be a cause of allergic contact dermatitis. However, few cases have been reported in the United States. Observations We report the cases of 4 adult patients with severe perianal and perineal allergic contact dermatitis seen at our institution during a 6-month period. With patch testing, we identified allergy to MCI/MI, and we determined that all 4 patients were using moist toilet paper. The dermatitis resolved after use of the moist toilet paper was discontinued. Conclusion This study highlights that the MCI/MI in moist toilet paper can be a cause of perianal and perineal allergic contact dermatitis.

To clarify clinicopathologic features and reconcile discrepancies in previous studies of folliculotropic mycosis fungoides (FMF).A single-center retrospective clinicopathologic study and a systematic review of FMF.Tertiary referral center in the midwestern United States.Patients with clinical and histopathologic evidence of FMF seen at the tertiary referral center during a 12(1/2)-year period.Clinicopathologic features of FMF.Fifty patients (32 male [64%] and 18 female [36%]) met study criteria for the clinicopathologic review. Pruritic patches, plaques, and folliculocentric lesions (milia, cysts, and alopecia) on the head, neck, and trunk were common clinical findings. The mean time to diagnosis of FMF was 5.0 years. Diagnostic latency did not affect risk of death. One-year and 5-year overall survival rates were 96% and 62%, respectively. Frequent microscopic features were follicular mucinosis (74%) and epidermotropism (54%). Systematic review of 186 additional patients confirmed male predominance (ratio of men to women, 3.2:1.0), prevalent pruritus (73%), frequent follicular mucinosis (69%) and epidermotropism (37%) microscopically, and common head, neck, and trunk involvement. Combined data demonstrated that 6% of patients with FMF had concurrent non-mycosis fungoides hematologic malignant neoplasms and that the 5-year overall survival rate was 62% to 64%.Folliculotropic mycosis fungoides has distinct clinical and microscopic features and is associated with a poor 5-year overall survival rate.

Sezary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

Malignant cutaneous tumors characterized by bands, cords, nests, islands, or buds of basaloid cells.

Ménétrier's disease is an uncommon disorder of unknown etiology characterized by enlarged gastric folds with foveolar hyperplasia and cystic dilatation of gastric glands. Biochemical features that are seen frequently include hypoproteinemia, hypochlorhydria, and increased gastric mucus. Because transforming growth factor alpha (TGF alpha) is an epithelial cell mitogen that inhibits gastric acid secretion and increases gastric mucin content, we hypothesized that its altered expression might be involved in the pathogenesis of this disease. Therefore, we characterized TGF alpha immunoreactivity in the gastric mucosa of 4 patients with Ménétrier's disease. In contrast to the normal pattern of TGF alpha immunostaining in which TGF alpha appears most concentrated in parietal cells, there was intense staining in the majority of mucous cells in the gastric mucosa of patients with Ménétrier's disease. In one patient from whom sufficient fresh tissue was obtained to isolate RNA, expression of TGF alpha and the epidermal growth factor receptor was higher in the gastric mucosa relative to a normal control. In addition, metallothionein-TGF alpha transgenic mice, which overexpress TGF alpha in gastric mucosa, show a number of features characteristic of Ménétrier's disease. These include foveolar hyperplasia and glandular cystic dilatation, increased gastric neutral mucin staining, and reduced basal and histamine-stimulated rates of acid production. Taken together, observations derived from the human material and correlation with data from a transgenic mouse model support an important role for TGF alpha in the pathogenesis of Ménétrier's disease.

Interleukin-6 (IL-6) is a multifunctional cytokine which has been suggested to function as an autocrine mitogen in psoriatic epidermis. We report here the results of several experiments designed to further examine this hypothesis. Blot hybridization was unable to detect 1.3 kb IL-6 transcripts in RNA extracted from normal or psoriatic epidermal (keratome) biopsies, suggesting that IL-6 expression is very low in normal and psoriatic epidermis. Therefore, qualitative and semiquantitative PCR/Southern blot analyses were performed on keratome-derived RNA, and revealed variable but significantly increased IL-6 mRNA levels in lesional psoriatic relative to normal tissue. To further examine the ability of normal human keratinocytes (NHK) to express IL-6, RNA was extracted from rapidly proliferating secondary NHK cultures. IL-6 transcripts were nearly undetectable by blotting in keratinocytes grown in low-calcium serum-free medium, but low levels could be induced by treatment with 1.8 mM CaCl2. IL-6 transcripts were strongly superinduced after cycloheximide treatment, suggesting that a labile protein regulates IL-6 mRNA levels in these cells. Finally, the mitogenic activity of IL-6 was examined in NHK under varying conditions of cell density and added growth factors. IL-6 did not stimulate high density keratinocyte growth in the presence or absence of other growth factors, but did stimulate clonal growth in epidermal growth factor (EGF)-deficient media at high concentrations (> or = 10 ng/ml). The proliferative effects of IL-6, but not of basic fibroblast growth factor, were abrogated by monoclonal antibodies directed against the EGF receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was undertaken to investigate the presence of C-type natriuretic peptide (CNP) immunoreactivity in cultured human vascular endothelial cells and in human plasma. CNP immunoreactivity was present in cultured human aortic endothelial cells by both immunohistochemical staining and by radioimmunoassay. With the utilization of gel permeation chromatography, this immunoreactivity proved to be consistent with the higher molecular weight CNP-53. CNP immunoreactivity was also present in human plasma (n = 22) at low picogram concentrations (6.5 +/- 0.2 pg/ml) by specific radioimmunoassay. This immunoreactivity was consistent with the lower molecular weight CNP-22 by gel permeation chromatography. These findings suggest that the vascular endothelium may be the site of CNP production. The isolation of different molecular forms of CNP in tissue and plasma may be consistent with a storage form of the peptide in endothelial cells CNP-53, while CNP-22 circulates in plasma. In summary, the present study is consistent with CNP being a peptide of endothelial cell origin.

Livedoid vasculitis, a hyalinizing vasculopathy, is characterized by extensive formation of microthrombi and deposition of fibrin in the middermal vessels, which result in epidermal infarction, ulceration, and formation of stellate scars. In a prospective study of nonhealing ulcers in patients with livedoid vasculitis, we found a high incidence of anticardiolipin antibodies, lupus anticoagulants, increased levels of plasminogen activator inhibitor, and low levels of endogenous tissue plasminogen activator (t-PA) activity. This procoagulant tendency and decreased fibrinolysis may provide an explanation for the occlusive vasculopathy often noted in biopsy specimens from these patients. On the basis of these findings, we proposed that fibrinolysis with recombinant t-PA would lyse microvascular thrombi, restore circulation, and promote wound healing. In six patients who had nonhealing ulcers caused by livedoid vasculitis and in whom numerous conventional therapies had failed, low-dose t-PA (10 mg) was administered intravenously during a 4-hour period daily for 14 days. Five of the six patients had dramatic improvement; almost complete healing of the ulcers occurred during hospitalization, and tissue oxygenation, as measured by transcutaneous oximetry, increased. The one treatment failure was due to rethrombosis of the microvasculature; this patient was subsequently re-treated but with concurrent anticoagulation, and her leg ulcers healed. We conclude that daily administration of a low dose of t-PA is safe and effective treatment for nonhealing ulcers due to occlusive vasculopathy.

Objectives To estimate and stratify the risk of development of nephrogenic systemic fibrosis (NSF) in well-defined at-risk subpopulations from a large single institution, and to perform a single-institution case series study of patients with biopsy-proven NSF. Design Retrospective cohort of patients exposed to gadolinium-based contrast agents (GBCAs) at a single institution during an 8-year period (January 1, 1999, to December 31, 2006), and a case series study of patients with biopsy-proven NSF. Setting A primary, secondary, and tertiary health care center that treated more than 2.2 million outpatients and had 135 000 hospital admissions in 2007. Patients A total of 94 917 patients exposed to GBCAs; patients at risk for NSF (3779 patients on hemodialysis, 1694 patients with renal transplants, and 717 patients with liver transplants, a well-defined subgroup that includes patients at risk for reduced renal function); and 61 patients with a clinical diagnosis of NSF. Main Outcome Measure Risk estimate for NSF. Results The risk of development of NSF is 1.0% for patients who undergo hemodialysis (8 of 827), 0.8% for patients with renal transplantation (4 of 527), and 0% for patients with liver transplantation at our institution (0 of 327). Conclusions Despite the limitations, this study, which reviewed a large number of patients who underwent intravascular GBCA injections, demonstrates a 77-fold higher risk of NSF among patients who undergo hemodialysis and a 69-fold higher risk in patients with renal transplantation. This increased risk is thought to be associated with poor clearance of most GBCAs.

Stromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell–derived non-Hodgkin lymphoma (NHL). In contrast, little is known about the microenvironment's role in T cell–derived NHL. B7-H1 (PD-L1, CD274), a member of the B7 family of costimulatory/coinhibitory ligands expressed by both malignant cells and stromal cells within the tumor microenvironment, has emerged as an important immune modulator capable of suppressing host immunity. Therefore, B7-H1 expression and function were analyzed in cutaneous and peripheral T-cell NHL. B7-H1 was expressed by tumor cells, monocytes, and monocyte-derived cells within the tumor microenvironment in T-cell NHL and was found to inhibit T-cell proliferation and promote the induction of FoxP3+ regulatory T cells. Collectively, the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach.

Various cytokines, including interferon alpha (IFNalpha), tumor necrosis factor alpha (TNFalpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been used as adjuvant therapy for advanced-stage melanoma with some success but with marked toxicity, which appears to be related to higher doses. We investigated the efficacy of IFNalpha, GM-CSF, and TNFalpha in various combinations to induce antitumor and immune responses in a B16F10 murine melanoma model. These studies showed that GM-CSF, IFNalpha, and TNFalpha, when injected together intratumorally, mediated significant inhibition of tumor growth. Tumor regression correlated with local tumor necrosis and significant infiltration of T cells. In addition, this injected intralesional cytokine cocktail also induced lymphadenopathy, with an increase in both CD4(+) and CD8(+) T cells in the draining lymph nodes. Furthermore, tumor-specific CD8(+) T cells were identified from draining lymph nodes. These investigations identify the combined effects of IFNalpha, GM-CSF, and TNFalpha in induction of the adaptive immune response and generation of antigen-specific T-cell reactivity. These results support potential clinical trials of the low-dose cytokine combination as adjuvant therapy for melanoma.

Background Psoriasis is a common, nonulcerative skin disorder. Observations We describe 3 men recently referred to our institution for evaluation and treatment of severe, ulcerative psoriasis that ultimately was determined to be aggressive, cytotoxic, cutaneous lymphoma. Each had a history of relatively indolent, nonulcerative patches and plaques (duration, 2-45 years) that changed to ulcerated lesions; these rapidly progressed and eventuated in death. Conclusions The clinical characteristics of the skin lesions and the histopathologic findings form a distinct and rare presentation of cutaneous lymphoma. The initial course is similar to that of mycosis fungoides but eventuates in a highly aggressive disease with fatal outcome.

Background Nephrogenic systemic fibrosis (NSF) is a rare, potentially fatal fibrosing disorder associated with renal insufficiency and gadolinium (Gd)-based contrast exposure. The cause remains unknown. To date, all efforts to investigate skin Gd concentrations in patients with NSF have been performed on paraffin-embedded samples, and Gd deposition has not been correlated with disease activity by a statistically significant analysis. Objective We sought to: (1) quantify Gd concentration in fresh tissue skin biopsy specimens; (2) quantify and compare synchronous Gd concentration of affected skin and unaffected skin in patients with NSF (n = 13) with a control group (n = 13); and (3) quantify serum Gd. Methods We used inductively coupled plasma mass spectrometry. Results In patients with NSF, the mean ratio of paired Gd concentrations of affected skin to unaffected skin was 23.1, ranging from 1.2 to 88.9. Mean serum Gd concentrations in patients with NSF were 4.8 ng/mL, which is more than 10 times the level in control patients. A statistically significant correlation existed between serum and affected skin Gd concentrations ( r 2 = .74, P Limitations Because of the feasibility of this study, the main limitation was the small sample size (n = 13 affected and 13 control). Conclusions Determination of Gd concentrations in fresh skin samples and serum using inductively coupled plasma mass spectrometry demonstrates significant differences in the amounts of Gd in involved versus nonlesional skin of patients with NSF. This supports the role of differential free Gd deposition from Gd-based contrast in the pathogenesis of NSF.

Understanding the acantholytic pathways leading to blistering in pemphigus vulgaris (PV) is a key to development of novel treatments. A novel paradigm of keratinocyte damage in PV, termed apoptolysis, links the suprabasal acantholytic and cell death pathways to basal cell shrinkage rendering a 'tombstone' appearance to PV lesions. In contrast to apoptolysis, the classic keratinocyte apoptosis mediating toxic epidermal necrolysis causes death and subsequent sloughing of the entire epidermis. Apoptolysis includes five consecutive steps. (1) Binding of autoantibodies to PV antigens. (2) Activation of EGF receptor, Src, mTOR, p38 MAPK and other signalling elements downstream of ligated antigens, elevation of intracellular calcium and launching of the cell death cascades. (3) Basal cell shrinkage due to: (i) collapse and retraction of the tonofilaments cleaved by executioner caspases; and (ii) dissociation of interdesmosomal adhesion complexes caused by phosphorylation of adhesion molecules. (4) Massive cleavage of cellular proteins by activated cell death enzymes leading to cell collapse, and tearing off desmosomes from the cell membrane stimulating secondary autoantibody production. (5) Rounding up and death of acantholytic cells. Thus, the structural damage (acantholysis) and death (apoptosis) of keratinocytes are mediated by the same cell death enzymes. Appreciation of the unifying concept of apoptolysis have several important implications: (i) linking together a number of seemingly unrelated events surrounding acantholysis; (ii) opening new avenues of investigation into the pathomechanism of pemphigus; and (iii) creating new approaches to the treatment of pemphigus based on blocking the signalling pathways and enzymatic processes that lead to blistering.

Characterization of the viscoelastic mechanical properties of skin is important for improving accurate medical examination and diagnosis of disorders involving cutaneous and subcutaneous tissues; more thoroughly understanding skin biophysical and physiological properties; identifying normal and abnormal skin aging and disease processes; developing and applying improved pharmacologic and other therapeutic interventions; as well as cosmetic applications. Several noninvasive methods have been developed for measurement of mechanical properties of skin [1]. However, most methods measure a stiffness parameter but not the material properties of skin. For example, the suction method measures the displacement of skin in response to suction. The measurement is dependent on the aperture and fixation of probes and also difficult to interpret.Copyright © 2009 by ASME

Background and objective: Constrictive bronchiolitis is a rare and potentially fatal manifestation of paraneoplastic autoimmune multi-organ syndrome (PAMS), also called paraneoplastic pemphigus. The current review aimed to assess the frequency and clinical features of constrictive bronchiolitis occurring in patients with PAMS. Methods: A computer-assisted search of medical records identified 17 patients with PAMS seen during the period 1994–2007. Medical records, radiological studies and biopsy results were reviewed. Results: There were 10 men and 7 women; the median age at diagnosis of PAMS was 60 years (range 33–72 years). Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia were the underlying neoplasms in over two-thirds of these patients. Constrictive bronchiolitis was diagnosed in three patients who had respiratory symptoms, severe airflow obstruction on pulmonary function testing and evidence of air trapping on CT scanning with no other identifiable cause for these findings. In contrast to previous reports, two of the three patients with constrictive bronchiolitis presented with skin and respiratory manifestations in the absence of a known neoplasm. Seven patients with PAMS died (41%) after a median interval of 13 months (range 1–33 months) and the deaths included two of the constrictive bronchiolitis patients who continued to worsen despite immunosuppressive therapy. Conclusions: In a minority of patients with PAMS, constrictive bronchiolitis occurs and tends to cause progressive airflow obstruction that responds poorly to immunosuppressive therapy. Constrictive bronchiolitis in these patients may be manifest prior to the discovery of the underlying neoplasm and the diagnosis of PAMS.

T-cell receptor gene rearrangement analysis is a useful technique to detect clonality and determine lineage of lymphoid neoplasms. We examined 103 patients with mycosis fungoides, Sézary syndrome, peripheral T cell lymphoma, potentially malignant lymphoproliferative disorders including pre-Sézary syndrome, large plaque parapsoriasis, lymphomatoid papulosis and follicular mucinosis, and various benign inflammatory infiltrates. A clonal rearrangement was detected in skin samples in 20 of 24 patients with mycosis fungoides and in peripheral blood samples in 19 of 21 patients with Sézary syndrome. A clonal population was also detected in seven of eight cases classified as peripheral T cell lymphoma. The potentially malignant dermatoses tended to have clonal rearrangement, with the exception of large plaque parapsoriasis, and further follow-up is needed to correlate clonality with the disease course. These studies demonstrate the value of molecular genetics as an adjunct to morphology in the examination of patients with cutaneous lymphoproliferative disease.

A comparative study of the antioxidant enzymes superoxide dismutase, catalase, glutathione reductase and thioredoxin reductase was undertaken in two families with xeroderma pigmentosum (XP) and in healthy controls of corresponding skin phototypes. Epidermal blister roofs obtained from the XP patients revealed significant decreases in catalase, thioredoxin reductase, and superoxide dismutase, but glutathione reductase was unaffected. In addition, keratinocytes established from XP patients contained a significantly higher than normal intracellular calcium concentration compared with control cells from a corresponding skin type. Keratinocytes established from an XP obligate heterozygote revealed intermediate levels of calcium between XP homozygotes and controls. Previously high intracellular calcium has been shown to compromise the redox status of keratinocytes by allosteric inhibition of the thioredoxin reductase/thioredoxin electron transfer system. In XP homozygous keratinocytes from sun-exposed epidermis, the intracellular concentration of reduced thioredoxin was decreased to 50% compared with these cells from unexposed skin. Taken together, the results from this study indicate that the epidermis in XP patients lacks effective defense against free radicals and peroxides. In addition to the well-established defect in the normal rates of unscheduled DNA repair, these findings provide an even better explanation for the multiple cutaneous neoplasms in these patients.

Current uses for gene rearrangement analysis in clinical dermatology are listed in Table 3. This technique is useful for determining the existence of clonal populations within a background of polyclonal lymphoid cells; 73'74 therefore, it is helpful in the diagnosis and staging of patients with CTCL and PTCL. 9'75 Although dual genotypes do occur, this technique is usually capable of determining lineage in a clonal lymphoid infiltrate 9'76'77 and elucidating and characterizing the etiopathogenesis of certain neoplasms. 78'79 On the basis of this review of the literature and our own experience, we conclude that gene rearrangement analysis shows great promise for monitoring response to therapy and detecting progression or relapse in patients with CTCL and PTCL. With the recent technology of PCR, it is possible to amplify specific sequences of DNA, detect molecular alterations in individual malignant T cells, and even identify exogenous retroviral gene sequences in tissues of patients with CTCL. 80 Although gene rearrangement analysis has supported or established the clonal nature of lymphomatoid papulosis, pre-Sezary syndrome, granulomatous slack skin syndrome, and follicular mucinosis, the clinical significance of these findings is not yet clear. In the case of primary cutaneous B-cell lymphoma and its benign counterpart, B-cell pseudolymphoma, further investigation will be needed to determine the clinical significance of clonal rearrangements.

13-cis-Retinoic acid is a stereospecific suicide inhibitor of thioredoxin reductase. [3H]-labeled 13-cis-retinoic acid has been used to covalently label thioredoxin reductase in human keratinocytes. The acid-soluble cytosol fraction of human keratinocytes contained three radioactive proteins labeled by the addition of high-specific-activity [3H]-13-cis-retinoic acid to cell cultures. One of these proteins was identified as cytosolic keratinocyte thioredoxin reductase by fast-protein liquid chromatography and SDS-gel radioautography. The inhibition of thioredoxin reductase by 13-cis-retinoic acid may explain the known cytostatic and teratogenic properties attributed to this retinoid.

Characterization of the viscoelastic mechanical properties of skin is important for improving accurate medical examination and diagnosis of disorders involving cutaneous and subcutaneous tissues. Several noninvasive methods have been developed for measurement of mechanical properties of skin. However, most methods measure a stiffness parameter but not the material properties of skin. A novel surface wave method has been developed by us for non-invasively estimating the elasticity of tissue. In this paper, we have extended this method for measuring viscoelastic material properties of human skin. A small force is generated by a mechanical shaker on the skin. The surface vibration of skin is measured using a laser vibrometer. Viscoelasticity of human skin at six anatomic sites are measured.

Background B-cell chronic lymphocytic leukemia (B-CLL) is a low-grade lymphoproliferative disorder with characteristic histomorphologic features and an identifiable immunophenotype. The skin can be involved in the context of known disease, but cutaneous signs are rarely the presenting findings. Objective Evaluation of unusual clinical cutaneous presentations of B-CLL. Methods We conducted a retrospective case series analysis of 3 patients with unusual cutaneous clinicopathologic presentations of B-cell chronic lymphocytic leukemia, including erythematous plaques, angiomatosis/telangiectasia, and erosive skin changes, respectively, without a previous clinical history of chronic lymphocytic lymphoma. Main outcome measures were clinical cutaneous presentations and histopathologic results in the diagnosis of underlying disease. Results In the 3 cases, lesion locations were the lower cheek, lower extremity, and penis (groin region). Histomorphologic testing showed mild to dense perivascular and periadnexal lymphoid aggregates throughout the dermis and extending into the panniculus, consistent with B-CLL. The diagnosis was confirmed with immunohistochemical studies that showed coexpression of CD5 and CD20 in the neoplastic lymphocytic infiltrate. Limitations None. Conclusion Cutaneous manifestations are an uncommon presentation of subclinical B-CLL. Cutaneous changes were the presenting features of underlying lymphoma in all 3 cases, highlighting the importance of maintaining a high index of suspicion for a lymphoproliferative process in cases with unusual or atypical clinicopathologic features. Additional investigations into the behavior of B-CLL in the skin may elucidate further the evolution of cutaneous lesions in this disease.

Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patient's unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma.