Training and accrediting international surgeons.

BACKGROUND: Formal international medical programmes (IMPs) represent an evolution away from traditional medical volunteerism, and are based on the foundation of bidirectional exchange of knowledge, experience and organizational expertise. The intent is to develop multidirectional collaborations and local capacity that is resilient in the face of limited resources. Training and accreditation of surgeons continues to be a challenge to IMPs, including the need for mutual recognition of competencies and professional certification. METHODS: MEDLINE, Embase and Google Scholar™ were searched using the following terms, alone and in combination: 'credentialing', 'education', 'global surgery', 'international medicine', 'international surgery' and 'training'. Secondary references cited by original sources were also included. The authors, all members of the American College of Academic International Medicine group, agreed advice on training and accreditation of international surgeons. RESULTS AND CONCLUSION: The following are key elements of training and accrediting international surgeons: basic framework built upon a bidirectional approach; consideration of both high-income and low- and middle-income country perspectives; sourcing funding from current sources based on existing IMPs and networks of IMPs; emphasis on predetermined cultural competencies and a common set of core surgical skills; a decentralized global system for verification and mutual recognition of medical training and certification. The global medical system of the future will require the assurance of high standards for surgical education, training and accreditation.

Production of melanocyte-specific antibodies to human melanosomal proteins: expression patterns in normal human skin and in cutaneous pigmented lesions.

Multiple factors affect skin pigmentation, including those that regulate melanocyte and/or keratinocyte function. Such factors, particularly those that operate at the level of the melanosome, are relatively well characterized in mice, but the expression and function of structural and enzymatic proteins in melanocytes in human skin are not as well known. Some years ago, we generated peptide-specific antibodies to murine melanosomal proteins that proved to be instrumental in elucidating melanocyte development and differentiation in mice, but cross-reactivity of those antibodies with the corresponding human proteins often was weak or absent. In an effort to characterize the roles of melanosomal proteins in human skin pigmentation, and to understand the underlying mechanism(s) of abnormal skin pigmentation, we have now generated polyclonal antibodies against the human melanocyte-specific markers, tyrosinase, tyrosinase-related protein (TYRP1), Dopachrome tautomerase (DCT) and Pmel17 (SILV, also known as GP100). We used these antibodies to determine the distribution and function of melanosomal proteins in normal human skin (adult and newborn) and in various cutaneous pigmented lesions, such as intradermal nevi, lentigo simplex, solar lentigines and malignant melanomas. We also examined cytokeratin expression in these same samples to assess keratinocyte distribution and function. Immunohistochemical staining reveals distinct patterns of melanocyte distribution and function in normal skin and in various types of cutaneous pigmented lesions. Those differences in the expression patterns of melanocyte markers provide important clues to the roles of melanocytes in normal and in disrupted skin pigmentation.

Automatic differentiation of melanoma from melanocytic nevi with multispectral digital dermoscopy: a feasibility study.

BACKGROUND: Differentiation of melanoma from melanocytic nevi is difficult even for skin cancer specialists. This motivates interest in computer-assisted analysis of lesion images. OBJECTIVE: Our purpose was to offer fully automatic differentiation of melanoma from dysplastic and other melanocytic nevi through multispectral digital dermoscopy. METHOD: At 4 clinical centers, images were taken of pigmented lesions suspected of being melanoma before biopsy. Ten gray-level (MelaFind) images of each lesion were acquired, each in a different portion of the visible and near-infrared spectrum. The images of 63 melanomas (33 invasive, 30 in situ) and 183 melanocytic nevi (of which 111 were dysplastic) were processed automatically through a computer expert system to separate melanomas from nevi. The expert system used either a linear or a nonlinear classifier. The "gold standard" for training and testing these classifiers was concordant diagnosis by two dermatopathologists. RESULTS: On resubstitution, 100% sensitivity was achieved at 85% specificity with a 13-parameter linear classifier and 100%/73% with a 12-parameter nonlinear classifier. Under leave-one-out cross-validation, the linear classifier gave 100%/84% (sensitivity/specificity), whereas the nonlinear classifier gave 95%/68%. Infrared image features were significant, as were features based on wavelet analysis. CONCLUSION: Automatic differentiation of invasive and in situ melanomas from melanocytic nevi is feasible, through multispectral digital dermoscopy.

Diagnosis of pigmented skin lesions aided by epiluminescence microscopy.

Early diagnosis of superficial melanoma (Clark Level I, II) remains the best approach to reduce the death rate from this malignant neoplasm. Today's well-informed patients understand the need to have changing moles evaluated. However, many benign pigmented lesions that undergo changes in appearance do not require excision. Epiluminescence microscopy can facilitate the differential diagnosis of cutaneous pigmented lesions and help determine which of these require biopsy.

Sun exposure and basal cell carcinomas in the nevoid basal cell carcinoma syndrome.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant multisystem disorder. Persons with the NBCC gene have varied susceptibility to basal cell carcinoma (BCC) development. OBJECTIVE: We examined the anatomic site-specific distribution of BCCs and the relation between sun exposure and numbers of BCCs in NBCC cases. METHODS: A questionnaire asking about lifetime sun exposure, sun behavior habits, and number of BCCs was sent to 16 families with NBCC evaluated between 1985 and 1991. The results were compared with previously published data for the general population. RESULTS: In the general population, 88% of all BCCs in women and 86% in men occurred on the face, head, neck, and arms versus 59% in women with NBCC and 65% in men with NBCC. Of BCCs in the general population 9% and 12% occurred on the trunk versus 38% and 32% of BCCs in NBCC cases, in women and men, respectively. We did not observe a strong relation between numbers of BCCs and history of lifetime sun exposure. CONCLUSION: The anatomic-site distribution of BCCs suggests that frequent sun exposure may not be essential for the development of BCCs in patients with NBCC. However, the observation that there are more tumors on sun-exposed areas suggests that exposure to the sun promotes the development of BCCs in patients with NBCC.

Clinical and laboratory adverse effects associated with long-term, low-dose isotretinoin: incidence and risk factors. The Isotretinoin-Basal Cell Carcinomas Study Group.

Adverse effects associated with the long-term low-dose regimens of retinoids used in cancer chemoprevention studies are not well described. In order to examine the clinical and laboratory adverse effects of 3 years of intervention with isotretinoin (10 mg/day) and to assess potential risk factors for developing these, we collected adverse effect data on patients participating in a randomized, placebo-controlled trial designed to evaluate the effectiveness of isotretinoin in preventing the subsequent occurrence of new basal cell carcinoma. Our results showed a significantly higher incidence of adverse mucocutaneous effects and serum triglyceride elevations in the isotretinoin group (P < 0.001). Associated risk factors included male gender, very fair skin, and elevated pretreatment triglyceride levels. The toxicity observed, although less severe and less frequent, was similar to that seen with higher doses and should be weighed with adverse skeletal effects when considering long-term treatment of patients with moderate cancer risk.

Malignant melanoma in xeroderma pigmentosum: search for a precursor lesion.

BACKGROUND: Malignant melanomas occur with increased frequency and at an early age in patients with xeroderma pigmentosum (XP). OBJECTIVE: The purpose of this study was to describe the histologic features of malignant melanomas in patients with XP and to search for a possible precursor lesion. METHODS: Clinical records and hematoxylin-eosin-stained sections of 19 malignant melanomas from seven patients with XP were examined. A search was conducted for malignant melanoma precursor lesions (melanocytic nevi and solar lentigines lateral to and contiguous with the malignant melanomas). Basal cell carcinomas removed from the same patients were used as controls. RESULTS: Malignant melanomas were characteristically found in biopsy specimens of small elevations and/or changed color foci arising in large, flat, darkly pigmented, gradually enlarging macules. Histologically, solar lentigo was lateral to and contiguous with malignant melanoma in 88% of the malignant melanomas. Transitional areas were present. A significantly lower number (22%) of contiguous solar lentigines, without transitional areas, were observed in the basal cell carcinoma controls. Most of the invasive malignant melanomas were spindle cell malignant melanomas. CONCLUSION: We propose that solar lentigo is the most common precursor lesion of malignant melanoma in patients with XP.

Chemoprevention of skin cancer in xeroderma pigmentosum.

Xeroderma pigmentosum is a rare recessive disease with sun sensitivity, increased freckling and defective DNA repair. Xeroderma pigmentosum patients have more than a 1000-fold increased risk of developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. We studied chemoprevention of new skin cancers with oral retinoids in xeroderma pigmentosum patients who had multiple skin cancers. Xeroderma pigmentosum patients were cleared of all pre-existing tumors surgically and then treated with high dose (2 mg/kg/day) oral isotretinoin (13-cis retinoic acid, Accutane) for two years and then for one year off treatment. Patients were examined at regular intervals for new tumor formation and for side effects. Five xeroderma pigmentosum patients had a total of 121 basal or squamous cell carcinomas in 2 years before treatment and only 25 tumors during 2 years of treatment. The tumor frequency increased 8.5-fold after the drug was discontinued (New Engl J Med 318: 1633-1637, 1988). Toxicity (cutaneous, triglyceride, liver-function or skeletal abnormalities) prompted subsequent use of a low dose protocol. Patients were treated initially with 0.5 mg/kg/day oral isotretinoin and the dose was increased sequentially to 1.0 or 1.5 mg/kg/day. We found that toxicity was less with the lower doses. The lowest effective, least toxic dose varied among the xeroderma pigmentosum patients.

Skeletal hyperostosis in patients receiving chronic, very-low-dose isotretinoin.

BACKGROUND AND DESIGN: We conducted a prospective roentgenographic survey of patients participating in a randomized, placebo-controlled, multicenter clinical trial that evaluated the effectiveness of chronic, very-low-dose (approximately 0.14 mg/kg per day for 3 years) isotretinoin in preventing the subsequent occurrences of new basal cell carcinoma in patients with previous basal cell carcinoma. To assess potential skeletal changes, a sample of 269 patients from among a total of 981 enrollees were randomly selected for comparative roentgenographic review. Baseline and 36-month roentgenograms of the cervical and thoracic spine of each patient were read side by side by a radiologist, masked to treatment group, who noted both the presence and extent of abnormalities at each vertebral level at baseline and the progression of existing or occurrence of new abnormalities at previously unaffected levels at 36 months. RESULTS: In comparison with the placebo group, significantly more patients in the isotretinoin group exhibited progression of existing hyperostotic abnormalities (40% vs 18%; P less than .001) and new hyperostotic involvement at previously unaffected vertebral levels (8% vs 1%; P = .015). CONCLUSION: Our findings indicate that chronic, very-low-dose isotretinoin can induce hyperostotic axial skeletal changes similar to those reported in patients taking higher doses.

Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9.

Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian fibroma and performed genetic linkage studies in five Gorlin syndrome kindreds. Eleven sporadic basal cell carcinomas and all 3 hereditary tumors had allelic loss of chromosome 9q31, and all informative kindreds showed tight linkage between the Gorlin syndrome gene and a genetic marker in this region. Loss of heterozygosity at this chromosomal location, particularly in hereditary tumors, implies that the gene is homozygously inactivated and normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies.

Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. Isotretinoin-Basal Cell Carcinoma Study Group.

BACKGROUND: High-dose isotretinoin has been reported to have a prophylactic effect on nonmelanoma skin cancer, although it is associated with significant toxicity. PURPOSE: To test the effectiveness of the long-term administration of low-dose isotretinoin in reducing the occurrence of basal cell carcinoma at a new site in patients with previously treated basal cell carcinomas and to measure the toxicity associated with this regimen, we conducted a clinical trial at eight cancer centers. METHODS: Nine hundred and eighty-one patients with two or more previously confirmed basal cell carcinomas were randomly assigned to receive either 10 mg of isotretinoin or a placebo daily. Patients were followed for 36 months and monitored at 6-month intervals for skin cancer and toxic effects. RESULTS: After 36 months of treatment, no statistically significant difference in either the cumulative percent of patients with an occurrence of basal cell carcinoma at a new site or the annual rate of basal cell carcinoma formation existed between patients receiving isotretinoin and those receiving the placebo. Elevated serum triglycerides, hyperostotic axial skeletal changes, and mucocutaneous reactions were more frequent in the group receiving isotretinoin than in the control group, and these differences were all statistically significant (P less than .001). CONCLUSION: This low-dose regimen of isotretinoin not only is ineffective in reducing the occurrence of basal cell carcinoma at new sites in patients with two or more previously treated basal cell carcinomas but also is associated with significant adverse systemic effects. IMPLICATION: The toxicity associated with the long-term administration of isotretinoin, even at the low dose used in this trial, must be weighted in planning future prevention trials.

Arthritis in patients with psoriasis treated with gamma-interferon.

We observed 3 patients with psoriasis who developed arthritis during treatment of psoriatic skin disease with intramuscular recombinant human gamma-interferon (IFN-gamma). Symptoms primarily involved the hands, feet, shoulders, and neck. One patient had acute plantar fasciitis. Routine laboratory studies were unrevealing. Patients presented with symptoms initially between the 10th and 12th weeks of treatment and the arthritis resolved after cessation of IFN-gamma. One patient was subsequently retreated with IFN-gamma for 4 weeks and had a temporary recurrence of arthritis with an associated rise and fall of his articular index.

Adrenal androgen secretion in postadolescent acne: increased adrenocortical function without hypersensitivity to adrenocorticotropin.

Basal and ACTH-stimulated plasma levels of cortisol, delta 4-androstenedione, and dehydroepiandrosterone (DHEA) were measured in a group of 11 female patients with postadolescent acne resistant to or relapsing after conventional therapy and in a group of 10 normal women without acne or hirsutism. Each patient received, in a blinded random fashion, a series of 5 1-h ACTH tests. For each test a different dose of ACTH-(1-24) was administered, ranging from 0-1 microgram/kg, given as an iv bolus. Blood samples were collected 0, 10, 30, and 60 min after ACTH bolus injection. Patients with acne had slightly higher concentrations of basal cortisol, delta 4-androstenedione, and DHEA than normal controls (P less than 0.05). After ACTH-(1-24) stimulation, the same patients had greater peak and time-integrated DHEA concentrations (P less than 0.03). The ED50 values of the cortisol dose-response curves were similar in patients and normal women (P less than 0.05), suggesting that there are no differences in the sensitivity of the adrenal cortex to ACTH between the acne patients and the controls studied. The ratio of DHEA to cortisol response was significantly elevated in women with acne compared to that in control women, suggesting some preponderance of the delta 5 pathway of steroidogenesis in acne (P less than 0.05). These findings of basal and ACTH-stimulated hypersecretion of delta 5-androgens in patients with postaldolescent acne are consistent with an increased volume of androgen-secreting tissue, rather than hypersensitivity of the adrenal zona reticularis to ACTH.

Suicidal ideation in Darier's disease.

We investigated the psychiatric history of patients with severe Darier's disease and a control group, which consisted of patients with comparably severe dermatologic disorders of keratinization. Three patients with Darier's disease reported either a suicide attempt (one patient) or a specific suicide plan (two), compared with one patient in the control group. Of 11 patients with Darier's disease, 7 had a history of suicidal thoughts, compared with 3 of 11 patients in the control group. Thus suicidal ideation is a potential problem in patients with cutaneous illnesses, particularly those with chronic disfiguring disorders such as severe Darier's disease.

Electrosurgical treatment of etretinate-resistant Darier's disease.

Two patients with symptomatic, etretinate-resistant, intertriginous Darier's disease were successfully treated with deep split-thickness skin excision using an electrosurgical unit. Healing was rapid and recurrence of disease has been minimal. The use of electrosurgery appears superior to other surgical techniques because, with the ease of hemostasis, the surgeon can more easily control the depth of excision and treat intertriginous creases.