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.

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.

Effects of retinoic acid on embryonic chick skin.

The influence of vitamin A on differentiating epithelia was examined in explants of skin from 14-day chick embryos exposed to retinoic acid (RA) in low, moderate, and high doses. The changes observed in RA-treated cultures are both dose- and time-dependent and are reversible when explants are transferred to control medium. The periderm sloughs prematurely and horizontal stratification is lost. Keratinization is inhibited and fewer desmosomes and tonofilaments are seen. Surface epidermal cells develop microvilli, bulge upwards, and detach. Golgi elements, rough endoplasmic reticulum, and polyribosomes are unusually prominent. Mucin granules form and gland-like structures develop with intercellular canaliculi characterized by tight junctions, brush borders, and dense secretory contents. On the basis of present evidence there are several possible mechanisms by which RA could alter epidermal differentiation. RA-induced gaps in the basal lamina allow direct contact between epidermal basal cells and fibroblasts and collagen fibers which could result in inappropriate dermal signals reaching the epidermis. In younger embryos the entire epidermis, including the mitotically inactive surface cells, appears to respond to RA, and this could imply an epigenetic modulation of cell phenotype. Finally, after the formation of a stratum corneum in older embryos only the relatively undifferentiated basal layer shows a metaplastic response, indicating that RA could be acting directly on the genome.

Circulating IgA immune complexes in patients with psoriasis.

The sera of 21 patients with psoriasis were examined for the presence of IgA-containing circulating immune complexes (CIC) using the Raji IgA radioimmunoassay. In addition, the Raji IgG radioimmunoassay and 125I-Clq binding assay were used to detect IgG- and IgM-containing CIC. Twenty-five patients with other hyperkeratotic skin disorders were studied as controls. Patients were studied before institution of systemic therapy with etretinate (20 patients) or 13-cis-retinoic acid (1 patient). In addition, sera of 15 of the patients treated with etretinate were studied before, during, and after therapy. The extent of pretreatment disease involvement as well as response to therapy were evaluated in a blinded fashion. Fourteen of 21 (67%) patients with psoriasis had evidence of IgA-containing CIC at some time during the course of their disease, as compared to only 1 of 25 patients with other hyperkeratotic skin disorders. In contrast, only 2 of 19 (11%) had evidence of IgG-containing CIC using the Raji IgG assay, and only 1 of 19 (5%) had evidence of IgG- or IgM-containing CIC using the 125I-Clq binding assay. A positive correlation was found between the extent of pretreatment disease involvement and the level of IgA-containing CIC by linear regression analysis (p = 0.01). There was, however, no correlation between clinical improvement and the presence or level of IgA-containing CIC in 15 patients followed during therapy. Sucrose density gradient analysis of the IgA-containing CIC found in 2 of these patients demonstrated IgA-containing CIC in the 9S to 13S region. The finding of IgA-containing CIC in a significant number of patients with psoriasis and the relative absence of IgG- or IgM-containing CIC suggest that IgA-containing CIC may play a role in psoriasis. The lack of correlation with clinical improvement, however, suggests these IgA-containing CIC are not directly related to the cutaneous manifestations of psoriasis, but may be important in the modification of immune or inflammatory responses in these patients.

Adrenal function in women with idiopathic acne.

The adrenal secretion of androgens were examined in 9 women (ages 19-39 yr) with postadolescent idiopathic acne and compared to age and sex-matched normal controls. Plasma dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), androstenedione (delta 4-delta), cortisol, 17-hydroxyprogesterone, 11-deoxycortisol, and testosterone were measured by radioimmunoassay in the basal state and during a 48 hr ACTH infusion. The mean plasma and time-integrated plasma levels of the 3 adrenal androgens in patients with acne were 15-25% higher than normal controls, but the groups were not significantly different (p greater than .05). The plasma testosterone values, on the other hand, were similar in both groups. In addition, cortisol, 11-deoxycortisol and 17-hydroxyprogesterone basal plasma values and responses to ACTH in patients with acne were similar to the normal control values. These findings suggest that adrenal androgen secretion is at most mildly elevated in patients with idiopathic acne and is unlikely to be the sole cause of acne since many patients without acne have similar hormone levels. Increased sensitivity of the sebaceous gland to androgens or increased local metabolism of androgen hormones in the skin to potent androgen metabolites may offer alternative mechanisms for the pathogenesis of this disorder.

Etretinate: effect of milk intake on absorption.

Since etretinate, an aromatic retinoid useful in the treatment of psoriasis and other skin disorders is lipid-soluble, it may be poorly absorbed in the absence of a fat load. We therefore studied serum concentrations of etretinate and its major metabolite (Ro 10-1670) after the controlled administration of etretinate. After an overnight fast, 6 Darier's disease and 4 psoriatic patients received a 1 mg/kg morning dose of etretinate with water or 1 pint of whole milk (fat load). There was a 260% increase (p less than 0.0005) in the mean of each patient's increase in the baseline-corrected peak serum concentration of etretinate after administration with milk (115 +/- 15 micrograms/dl) compared to after administration with water (32 +/- 4 micrograms/dl). Over a 24-h period there was an overall 296 +/- 26% (p less than 0.0005) increase in serum etretinate after administration with milk compared to water in 5 patients with Darier's disease. In contrast to the serum etretinate, there was a 17% mean decrease (p less than 0.025) in the corrected peak serum concentration of Ro 10-1670 in all 10 patients after administration of etretinate with milk compared to water. The net result of these alterations is that the mean corrected serum concentration of etretinate is higher than Ro 10-1670 at all time points measured after milk administration. In contrast, after administration of etretinate with water the major retinoid in the serum is Ro 10-1670. Establishing the clinical significance of these alterations may require controlled clinical trials.

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.

Normal pressure hydrocephalus. Recognition and relationship to neurological abnormalities in Cockayne's syndrome.

Normal pressure hydrocephalus (NPH) in adults is a well-known cause of dementia. We describe NPH in children having the recessively inherited Cockayne's syndrome (CS). Cockayne's syndrome is characterized by cachectic dwarfism, neurological dysfunction, and cutaneous sunlight sensitivity. We noted that the NPH-associated triad of dementia, gait disturbance, and incontinence developed in CS patients. Computerized tomography of the brain in our four CS patients showed hydrocephalic enlargement of the brain ventricles greatest in the older patients. There was no evidence of cortical atrophy except in the one patient who had CS with xeroderma pigmentosum. Lumbar puncture and radionuclide cisternography in the two patients tested showed normal CSF pressure, with complete blockade to flow of radionuclide above the tentorium cerebelli, ventricular reflux, and delayed absorption. Studies of NPH in CS may elucidate the pathophysiology of NPH and methods to alter its sequelae.

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.

Abnormal retinal function associated with fenretinide, a synthetic retinoid.

Five patients with basal cell carcinoma received fenretinide. Two patients while receiving the drug had evidence of abnormal rod photoreceptor function that reversed rapidly on cessation of therapy. We speculate that fenretinide may interfere with the binding of vitamin A to opsin or with the transport of vitamin A.

Hypopharyngeal and laryngeal involvement with Darier disease.

The presence of mucosal Darier disease (keratosis follicularis) was evaluated clinically and histologically in four consecutive patients with moderate to extensive cutaneous manifestations of this disease. Fiberoptic endoscopy demonstrated hypopharyngeal or laryngeal involvement or both in each patient. A dearth of corps ronds and grains in these anatomical regions was observed histologically. The routine evaluation of mucosal involvement in Darier disease should result in a higher incidence of hypopharyngeal and laryngeal lesions than is currently known. Furthermore, the recognition of hypopharyngeal and laryngeal involvement with Darier disease must be emphasized because of the clinical similarity to leukoplakia and squamous cell carcinoma.

Cornifying Darier disease--a unique variant. II. Surgical treatment.

A case of severe cornifying Darier disease (keratosis follicularis) was successfully treated by deep dermal excision of diseased skin and subsequent dermabrasion, resulting in a remission lasting more than four years to date. Persistent loss of the papillary dermis was observed in the surgically treated, disease-free areas.

Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study.

Twenty men with nodulocystic acne were treated with oral isotretinoin (13-cis-retinoic acid) for four months. Plasma lipids and lipoprotein determinations were obtained before and during treatment to quantitate the effects of oral isotretinoin on lipid metabolism. Maximum isotretinoin-induced elevations in plasma triglyceride and cholesterol levels were 67% and 16%, respectively. Additional maximal changes included very-low-density lipoprotein cholesterol increases of 56%, low-density lipoprotein cholesterol increases of 22%, and high-density lipoprotein decreases of 10% from pretreatment values. Chronic increases in plasma cholesterol levels, increases in low-density lipoprotein cholesterol levels, and decreases in high-density lipoprotein cholesterol levels may predispose subjects to premature atherosclerosis. Because of the potential for unmasking an occult lipid or lipoprotein disorder, the plasma lipid and lipoprotein profiles of subjects receiving isotretinoin should be carefully monitored.

Cornifying Darier disease--a unique variant. I. Report of a case.

A unique variant of Darier disease is described in which a patient was disabled by large, painful, cutaneous horns present on all extremities. The cornified lesions were distinguished by the presence of numerous corps ronds in the basal portion of the greatly hyperkeratotic stratum corneum, hypertrophic dermal villi containing enlarged capillaries, vacuolar dilatation of rough endoplasmic reticulum in sublacunar basal cells, unusually numerous Odland bodies in spinous cells adjacent to lacunae, and persistent attachment of tonofilaments to disrupted desmosomes. Complete separation of tonofilaments from intact desmosomes was not observed. Scanning electron microscopy revealed varied surface morphological appearances of corps ronds and of the epidermal cells covering the elongated dermal villi. The surface cells of cutaneous horns showed little tendency to desquamate.

Etretinate. Persistent serum levels after long-term therapy.

In 47 patients who received long-term etretinate therapy, we measured serum etretinate concentrations from one to 244 weeks after the discontinuation of therapy. The earliest posttreatment, nondetectable serum concentration of etretinate was observed at five weeks after treatment. Detectable serum concentrations (0.05 to 1.2 micrograms/dL) were observed more than two years (108, 111, 131, 136, and 150 weeks) following the discontinuation of therapy. Sequential serum concentrations obtained on eight individual patients were used to determine half-lives for this late-phase elimination. The median half-life for the 12 curves obtained was 12.5 weeks (range, 5.3 to 24.8 weeks). Since etretinate is stored in fat, we compared each patient's deviation from ideal body weight as a measure of excess body fat with various pharmacokinetic factors of etretinate elimination. Overweight patients tended to have slower elimination, maintain higher serum concentrations, and clear etretinate later.

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.

Successful treatment of Darier's disease by partial-thickness removal of skin.

Excision of partial-thickness skin has resulted in definitive improvement in 3 patients with widespread Darier's disease. More than 3 years after surgery, the formerly pruritic and inflammatory areas which were malodorous and had pustular crusts with intertriginous vegetating growths, are now asymptomatic and apparently free of disease. The technical details of the procedure are described, and the results are interpreted in light of our ideas of the pathogenesis of the disease.

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.