Dana L. Sachs

Practical Management of Patients With Non–Small-Cell Lung Cancer Treated With Gefitinib

PURPOSE The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non-small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non-small-cell lung cancer. METHODS This article reviews gefitinibs indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response. RESULTS We present our recommendations for the management of rash and diarrhea caused by this agent. CONCLUSION This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.

Molecular Effects of Photodynamic Therapy for Photoaging

OBJECTIVE To quantitatively examine the epidermal and dermal cellular and molecular changes that occur after photodynamic therapy of photodamaged human skin. DESIGN Serial in vivo biochemical and immunohistochemical analyses after photodynamic therapy using topical 5-aminolevulinic acid (5-ALA) and pulsed-dye laser treatment. SETTING Academic referral center, Department of Dermatology, University of Michigan, Ann Arbor. PATIENTS A volunteer sample of 25 adults, 54 to 83 years old, with clinically apparent photodamage of the forearm skin. INTERVENTIONS Three-hour application of 5-ALA followed by pulsed-dye laser therapy using non-purpura-inducing settings to focal areas of photodamaged forearms and serial biopsy specimens taken at baseline and various times after treatment. MAIN OUTCOME MEASURES Immunohistochemical analysis was used to assess levels of markers of epidermal proliferation (Ki67), epidermal injury (cytokeratin 16), and photodamage (p53), as well as various markers of dermal collagen production (including prolyl 4-hydroxylase and heat shock protein 47, and type I procollagen). Real-time reverse transcriptase-polymerase chain reaction technology was used to quantify type I and type III collagen. Type I procollagen protein was quantified with enzyme-linked immunosorbent assay. RESULTS Epidermal proliferation was stimulated as demonstrated by increases in Ki67 (more than a 5-fold increase; P < .05) and epidermal thickness (more than a 1.4-fold increase; P < .05). Epidermal injury was produced with increased cytokeratin 16 levels demonstrated (to nearly 70-fold of baseline levels; P < .05). Upregulation of collagen production was demonstrated with increases in procollagen I messenger RNA (2.65-fold; P < .05), procollagen III messenger RNA (3.32-fold; P < .05), and procollagen I protein (2.42-fold; P < .05) levels detected. The baseline epidermal p53 level correlated with cytokeratin 16 levels at acute time points, and the latter were found to correlate with peak collagen production. CONCLUSIONS Photodynamic therapy with the specific treatment regimen employed produces statistically significant quantitative cutaneous molecular changes (eg, production of types I and III collagen) that are associated with improved appearance of the skin. Baseline epidermal p53 immunostaining levels may be predictive of dermal responses to this therapy. Comparison with historical data using pulsed-dye laser therapy alone suggests that use of the photosensitizer may enhance dermal remodeling. The quantitative in vivo molecular data presented herein are in keeping with an evolving model to potentially predict the efficacy of new techniques for the treatment of photoaging.

Eccrine Sweat Glands are Major Contributors to Reepithelialization of Human Wounds

Eccrine sweat glands are skin-associated epithelial structures (appendages) that are unique to some primates including humans and are absent in the skin of most laboratory animals including rodents, rabbits, and pigs. On the basis of the known importance of other skin appendages (hair follicles, apocrine glands, and sebaceous glands) for wound repair in model animals, the present study was designed to assess the role of eccrine glands in the repair of wounded human skin. Partial-thickness wounds were generated on healthy human forearms, and epidermal repair was studied in skin biopsy samples obtained at precise times during the first week after wounding. Wound reepithelialization was assessed using immunohistochemistry and computer-assisted 3-dimensional reconstruction of in vivo wounded skin samples. Our data demonstrate a key role for eccrine sweat glands in reconstituting the epidermis after wounding in humans. More specifically, (i) eccrine sweat glands generate keratinocyte outgrowths that ultimately form new epidermis; (ii) eccrine sweat glands are the most abundant appendages in human skin, outnumbering hair follicles by a factor close to 3; and (iii) the rate of expansion of keratinocyte outgrowths from eccrine sweat glands parallels the rate of reepithelialization. This novel appreciation of the unique importance of eccrine sweat glands for epidermal repair may be exploited to improve our approaches to understanding and treating human wounds.

Histologic Classification of Tumor-Infiltrating Lymphocytes in Primary Cutaneous Malignant Melanoma A Study of Interobserver Agreement

The density and distribution of lymphocytes infiltrating the vertical growth phase of primary cutaneous melanomas has been suggested by several studies to be of prognostic significance. However, few pathologists comment on tumor-infiltrating lymphocytes (TILs), and there is the perception that the assessment of TILs is subject to great interobserver variability. We studied interobserver agreement on the categorization of TILs; 20 cases of primary cutaneous malignant melanoma with a vertical growth phase component were circulated among 3 pathologists and 3 dermatologists. For each case, TILs were classified as brisk, nonbrisk, or absent according to Clark. Only 1 pathologist (a dermatopathologist) was familiar with the classification of TILs. Observers were given written guidelines and a brief tutorial before their examination of the slides. Our results show that with little instruction, overall agreement among observers was good (kappa values, 0.6 or more), especially among pathologists (kappa values, > 0.7). Three observers had excellent agreement among each other (kappa values, > 0.75). These findings suggest that the categorization of TILs can be easily taught and can be applied with an acceptable level of reproducibility in routine diagnostic practice.

Cutaneous Reactions to Chemotherapy and their Management

International data from 2002 report 10.9 million new cases of cancer and 6.7 million cancer deaths. Chemotherapy is an essential component in the multidisciplinary management of most cancers. Cutaneous reactions to chemotherapeutics are common and may contribute significantly to the morbidity, and rarely to the mortality, of patients undergoing such treatments. Recognition and management of these reactions is important to provide optimal care.This article aims to present the most common cutaneous reactions to frequently used chemotherapies and provides management guidelines. A MEDLINE search from 1966 through June 2005 was conducted to identify reports of common cutaneous toxicities with systemic chemotherapy and their appropriate management.An analysis of our literature search is presented in review form outlining common chemotherapy-related cutaneous reactions and their management, as well as the chemotherapeutics responsible for the cutaneous toxicity. Chemotherapy-related cutaneous toxicity includes generalized rashes such as the spectrum between erythema multiforme and toxic epidermal necrolysis, and site-specific toxicity such as mucositis, alopecia, nail changes, extravasation reactions, or hand-foot syndrome. Most of the toxicity is reversible with chemotherapy dose reductions or delays. Certain toxicities can be effectively treated or prevented, allowing optimal delivery of chemotherapy (e.g. premedications to prevent hypersensitivity, prophylactic mouthwashes to prevent mucositis). Newer non-chemotherapeutic targeted therapies such as epidermal growth factor receptor inhibitors (e.g. gefitinib, cetuximab) may also be associated with cutaneous toxicity and can be distressing for patients. Recent data suggest that skin toxicity associated with these agents may correlate with efficacy.Cutaneous toxicity occurs frequently with chemotherapy and non-chemotherapeutic biologic therapies. Early recognition and treatment of the toxicity facilitates good symptom control, prevents treatment-related morbidity, and allows continuation of anti-cancer therapy.

Do primary small intestinal melanomas exist? Report of a case☆☆☆

Metastatic melanoma to the gastrointestinal tract is not uncommon with the small intestine representing the most common site of gastrointestinal metastases. The occurrence of primary melanoma of the small intestine, however, is rare. We describe a case of primary melanoma of the small intestine and establish criteria for distinction between primary and metastatic small intestinal melanoma.

Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: a possible surrogate marker of response?

Bortezomib is the first proteasome inhibitor to be approved for use in haematological malignancies. Although a rash has been described as a common adverse event associated with the drug, it has not been well characterised. Based on three phase II studies of bortezomib in patients with non‐Hodgkin lymphoma (140 assessable patients), we identified 26 patients who developed a unique erythematous maculopapular rash during treatment, six of whom underwent cutaneous biopsy. Punch biopsy in six patients revealed a perivascular lymphocytic infiltrate without evidence of lymphoma, consistent with a non‐necrotising cutaneous vasculitis. The combined overall response rate was 41%. The response in the 26 patients who developed a rash was 73%, compared with 33% in patients who did not. The odds ratio for response given the development of a rash was 4·6 (95% CI, 1·7–12·4, P = 0·001). This is the first report to characterise a vasculitic rash associated with bortezomib, and to show a relationship between development of the rash and response to treatment. Unlike classic hypersensitivity type reactions, this vasculitic rash may not necessarily prompt cessation of drug. In fact, the development of an isolated cutaneous vasculitis may portend a better clinical response to bortezomib in some patients.

Virus-associated trichodysplasia spinulosa

Virus-associated trichodysplasia spinulosa (VATS) is a cutaneous eruption of spiny papules predominantly affecting the face that is associated with a distinctive histologic picture of abnormally maturing anagen follicles with excessive inner root sheath differentiation and hyperkeratotic infundibula. Ultrastructurally, intranuclear viral particles consistent with polyoma virus are found. Only 2 patients have thus far been reported. Both had developed the eruption after a kidney transplant. We report 2 additional cases of VATS. One is an 8-year-old boy who presented with facial papules after a kidney transplant. The other is a 19-year-old man with a history of acute lymphocytic leukemia who never had a transplant. He developed a papular facial eruption as well as alopecia. Light microscopic and ultrastructural examinations revealed a spectrum in the severity of the histologic alterations as well as the number of intranuclear viral particles. This report expands the range of pathologic alterations associated with VATS and documents for the first time that it can affect patients without a solid organ transplant. The similarity of the clinical and histologic features of VATS with those previously reported by others as cyclosporine-induced “follicular dystrophy” or “pilomatrix dysplasia” raises the possibility that the described phenomena may reflect the same entity. Increased awareness of the distinct histologic picture associated with VATS will likely lead to more frequent diagnosis of this underrecognized entity.

Computer-assisted alignment and tracking of acne lesions indicate that most inflammatory lesions arise from comedones and de novo

BACKGROUND Inflammatory acne lesions are believed to derive from comedones; however, their evolution has not been rigorously studied. OBJECTIVE To examine the evolution of facial acne lesions using serial digital photographs and spatial alignment software. METHODS Six predefined lesion types, including inflammatory lesions, were counted and tracked from photographs taken every 2 weeks for 12 weeks from 25 individuals with untreated facial acne. RESULTS Closed comedones occurred most frequently (37%), followed by erythematous macules (26%), inflammatory papules (15%), open comedones (12%), pustules (2%), and nodules (1%). Inflammatory lesions were preceded by comedones (54%), normal-appearing skin (28%), erythematous macules (12%), and scars (6%). LIMITATIONS Lesions could have appeared and resolved within the 2-week intervals and some comedones may have been too small to identify on digital photographs. CONCLUSION Our results confirm the comedonal origin of the majority of inflammatory acne lesions. However, a sizeable number (28%) appear to arise from normal skin.

Molecular Analysis of Aggressive Microdermabrasion in Photoaged Skin

OBJECTIVE To investigate dermal remodeling effects of crystal-free microdermabrasion on photodamaged skin. DESIGN Biochemical analyses of human skin biopsy specimens following microdermabrasion treatment in vivo. SETTING Academic referral center. PARTICIPANTS Volunteer sample of 40 adults, aged 50 to 83 years, with clinically photodamaged forearms. Intervention Focal microdermabrasion treatment with diamond-studded handpieces of varying abrasiveness on photodamaged forearms and serial biopsies at baseline and various times after treatment. MAIN OUTCOME MEASURES Quantitative polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay were used to quantify changes in inflammatory, proliferative, and remodeling effectors of normal wound healing. Type I and type III procollagen served as the main outcome marker of dermal remodeling. RESULTS Coarse-grit microdermabrasion induces a wound healing response characterized by rapid increase in induction of cytokeratin 16 and activation of the AP-1 transcription factor in the epidermis. Early inflammation was demonstrated by induction of inflammatory cytokines, antimicrobial peptides, and neutrophil infiltration in the dermis. AP-1 activation was followed by matrix metalloproteinase-mediated degradation of extracellular matrix. Consistent with this wound-healing response, we observed significant remodeling of the dermal component of the skin, highlighted by induction of type I and type III procollagen and by induction of collagen production enhancers heat shock protein 47 and prolyl 4-hydroxylase. Dermal remodeling was not achieved when microdermabrasion was performed using a medium-grit handpiece. CONCLUSIONS Microdermabrasion using a coarse diamond-studded handpiece induces a dermal remodeling cascade similar to that seen in incisional wound healing. Optimization of these molecular effects is likely the result of more aggressive treatment with a more abrasive handpiece.