Highlights of the Canadian Dermatological Society Meeting - Whistler BC, July 2-6 1995
Published Web Location
https://doi.org/10.5070/D37nv1v11hMain Content
(9) Highlights from the Annual Meeting Canadian Dermatological Association at Whistler BC, July 2-6 1995.
by Kevin Smith M.D.*
Dermatology Online Journal, July 1995
Volume 1, Number 1
Highlights from the Annual Meeting Canadian Dermatological Association at Whistler BC, July 2-6 1995.
This was attended by about 150 [out of 450] Canadian dermatologist and their families, and a few American and Australian dermatologists who have learned what a good meeting it is. It was remarked that this was like the old AAD meetings at Palmer House in Chicago 40 years ago. Some of the kids [and a few of the parents] had a ball on the trapeze set up by a circus group, rollerblading, and hiking on Whistler Mountain were a number of bears were seen. A good time was had by all.
J. Uitto pointed out that various forms of E. bullosa affect about 50,000 people in the US [males=females, all races affected], and presented a masterful survey of the molecular biology of E.B. and the prospects for gene therapy, which will first be tried on limited areas like the finger webs which have high value and are at high risk. DNA-based prenatal testing using genetic linkage markers at 10 weeks gestation by chorionic villus sampling or at 12 weeks gestation by amniocentesis, with a report in 48 hours, is becoming practical. Blood from the parents and from an affected sibling is needed.
M. Gilbert found a village in Quebec composed of 3 heavily inbred families with a high incidence of psoriasis with a homogenous phenotype and is mapping a second psoriasis gene. This does not seem to be related to the interleukin-2 gene on 17q which has previously been associated with psoriasis. Final results may be available by Christmas. It is hoped that identification of the gene may allow the creation of a transgeneic animal model for that type of psoriasis and lead to more specific therapy. Dr. Charles Dicken from Mayo Clinic Rochester MN noted that researchers at his institution might be interested in creating the transgeneic model if the gene is isolated. In a telling comment on the state of medicine and medical research in Canada, it was pointed out that the initial work was done at the personal expense of the researchers, but fortunately funding was obtained with the assistance of Leo Laboratories [who make Dovonex] and the Canadian Dermatology Foundation to complete the analysis of the blood samples from the 350 inhabitants of the village.
M. Hope from INEX Corp. described advance in the use of non-viral vectors in gene therapy using a transmembrane carrier system [TCS]. A TCS consists of [1] cationic lipid [importent to bind and encapsulate DNA and to interact with the NEGATIVE charge of the cell membrane to create a non-bilayer event leading to fusion [fusion can be assayed using fluoresence], [2] polymer for stability and to regulate degradation rate [short chains come off fast, long chains lead to TCS that circulate for hours], [3] ligands for site specificity, [4] fusogenic factors to facilitate target cell access by endoytosis. Fusogenic factors can be [1] fusogenic lipids [which are non-immunogenic], [2] fusogenic proteins, [3] fusogenic peptides [less immunogenic than proteins], and/or [4] fusogenic polymers.
Liposomes, by contrast with TCS, are composed of cationic lipids and are cleared from serum very rapidly [~ 15 minutes] and any DNA they contain is rapidly degraded by circulating nucleases. TCS generally have a diameter of 100 nM, COMPLETELY enclose and protect DNA, and allow the addition of ligands, etc. 3 mcg of DNA in TCS was more effective that 50 mcg of free DNA in a model system. A model system using vincristine demonstrated delivery to target sites 3 orders of magnitude greater than with free VCR. This partially related to the much longer circulating time of TCS. Delivery can also be targetted to sites of inflammation, with delivery 40X > to adjacent normal tissue.
He pointed out that while both TCS and retroviruses, adenoviruses and adeno-associated viruses can give transient expression of the target gene, integration of the gene into the genome, and efficient transfection, TCS has the potential added advantages of [1] allowing unrestricted lengths of DNA to be used, [2] unlimited DNA dose, [3] low toxicity, [4] low- or non-immunogenic to facilitate repeat dosing, [5] straightforward manufacturing process with standard quality control and quality assurance, [6] simple systemic administration or intratracheal administration for lung diseases like CF, [7] potential for targeting by adding attachment proteins or carbohydrate complexes to the TCS surface, [8] 50 nM TCS may be delivered transdermally if the keratin layer is stripped or disrupted, for example delivery of tyrosinase to hair follicles.
S. Jablonska discussed the synergistic anticancer effects of retinoids and vitamin-D derivatives, with emphasis on the interaction with IL-12 and inhibition of tumor-induced angiogenesis, similar to the results found with trans-RA, 9-cis and 13-cis-RA and alpha-IFN.
D. Berg discussed experiments in the use of ALA in the pre-op assessment of skin cancer. ALA seems to be either preferentially taken up or metabolized by skin cancer cells [PBG - URO - COPRO - PROTOporphyrin] and has the advantage of causing a much shorter period of photosensitivity than hematoporphyrin deriviative [HPD]. Treated tissue emits red 630 nM when illuminated by blue 420 nM. ALA may also get into skin cancer preferentially because keratin in those areas is disrupted, or it may just show up better due to the thickness and bulk of the tumor. It would be useful to predict tumor size so that the patient would know what to expect, and to plan reconstructive surgery with possible involvement of ENT, PLS and OPTH.
20% ALA was applied for 12 hours pre-op in 12 patients. Unfortunately false negatives with scars and sclerosing BCC, and false positives with AKs and in areas Rx with 5-FU reduced the reliability of this technique.
D. Rosenthal and a panel composed of Frank Anderson [a hepatologist], James Kelly [hepatic pathologist] and Howard Stein [rheumatologist] discussed the safe use of methotrexate, and suggested that there be a "cooling of period" of perhaps a week between the discussion and the prescription of methotrexate. Folic acid [eg. 10 mg once a week] is widely used with MTX to reduce GI, liver and blood problems. Folic acid does not seem to reduce the effectiveness of MTX as a therapy for psoriasis or arthritis. Folic acid can mask the signs of B12 deficiency.
No good surrogate for liver biopsy has been developed yet. In the absence of a specific indication it was thought that it is becoming unreasonable to insist on a liver biopsy prior to starting MTX, in particular considering that perhaps 1/3 patients stop MTX within a few months for a variety of reasons. The liver pathologist stated flatly that in the absense of other indications a pre-treatment liver biopsy is NEVER justified, except as part of a prospective clinical trial with consent. The Roenigk classification of liver biopsies [Gr 1 - 4] was criticized because it was developed many years ago for use in primary biliary cirrhosis studies, where portal inflammation is the major feature, and so is not the best tool for assessing MTX toxicity which tends to produce centrilobular changes.
A biopsy at a total dose of 1.5 grams may still be reasonable. Some people with fibrosis have been continued on MTX and the fibrosis has been noted to improve on repeat biopsy, so it may not be necessary [medically] to stop MTX if fibrosis is seen. Dermatologica 1987;175:178-182. Some of the patients who IMPROVED on continued MTX may have previously been on arsenic or vitamin A, so the results of that European study may not apply in North America. Certain liver diseases like primary biliary cirrhosis and sclerosing cholangitis are sometimes TREATED with methotrexate.
It was suggested that a lot of the people who have trouble with MTX may turn out to have Hep-C or one of the other Hep viruses like G-V [which are also flaviviruses], and the occasional one has hemochromatosis, so it might be reasonable to screen for those things. It was suggested that old liver biopsy specimens from patients who had problems on MTX be analysed for Hep-C, etc using polymerase chain reaction to give us a quick answer to that question. Hep-C affects 0.6% - 1.2% of the population. Alpha-IFN for Hep-C can exacerbate psoriasis.
The rheumatologist pointed out that antimalarials seem to REDUCE liver enzymes, perhaps by stabilizing lysozomes.
The hepatologist remarked that the patients who got into trouble with MTX all had elevated LFT and/or reduced albumin. Obesity and diabetes did not seem to be independent risk factors. Pre-MTX blood work should include AST, bili, alk phos, albumin, Hep B & C, and perhaps ferritin [to R/O hemochromatosis], along with creatinine in the elderly and others with possible reduced renal function. It was noted that serum protein electrophoresis gives a more accurate measure of albumin than a simple "serum albumin".
The ALT and GGT are TOO sensitive and if you order those you will spend a lot of resources chasing false positives and stopping therapy inappropriately. The Alk phos does not reflect liver disease. Bottom line: to follow patients on MTX don't order multiple LFT: just check the AST. Biopsy if the AST remains elevated > 1.5x normal for 6 months, or if the albumin is < 3.3. Grade 3A fibrosis was said by some NOT to be a contraindication to continued MTX. It was noted that the AST is sometimes elevated for the first 2-3 months of therapy, then it settles down for reasons which are not known, so MTX does NOT have to be stopped if the AST is only elevated for a few months. If it stays elevated you should rule out hemochromatosis and Wilson's disease [check the ceruloplasmin] before going to a liver Bx.
Biopsies using a biopty [yes, that's how its spelled] gun and an 18 ga TruCut needle under ultrasound control seems to be very safe, and liver Bx in Vancouver is often done by ultrasonographers rather than GI docs.
It is important to monitor serum creatinine, in particular with older folks, and to remember that a "normal" creatinine can mean a 50% reduction in renal function if the patient happens to be a frail old person.
Maureen Rogers reported 2 families with congenital flat 1 - 3 cm mats of telangectasia and associated intracranial AVMs, and suggested that ultrasound is a better way to evaluate the skin lesions, which are also AVMs and produce spectacular and prolonged pulsatile bleeding when biopsied.
Gayle Fischer described a 21 month old boy who had constipation and episodic erythema restricted to the right cheek and starting within 20 seconds of eating. The same response was caused by putting a bit of salt on the tongue. Dx: von Freyes syndrome, caused by mixing of the sympathetic and parasympathetic branches of the auriculotemporal nerve, and can be bilateral. von Freyes can be congenital or associated with birth injury. Often no cause is identified, and it sometimes resolves after a few years without treatment. Other manifestations can include "jaw winking" or "crocodile tears". The constipation resolved when the kid was taken off the severely restrictive diet someone had put him on for "food allergies", once the true nature of his problem was explained. Another triumph for dermatology.
B. Kraftchik reports that she takes the child and a parent back to the sauna at her house when it is necessary to conduct a starch-iodine test for sweating disorders. [Bernice - does this make your sauna a business expense?]
Jack Adam listed a number of pro-inflammatory agents including lithium, leukotrienes, TNF, progesterone, iodides and in some circustances retinoids. Anti-granulomatous drugs include CIPRO and TCN which inhibit protein kinase-C, and clofazimine.
Eileen Murray reported a 36 week trial of 0.1% isotretinoin gel for UV damage. There was NO systemic uptake of isotretinoin, and this was well tolerated and somewhat effective. S. Jablonsaka remarked that in Europe topical isotretinoin has turned out to be less irritating that tretinoin, but also less effective in the mangement of sun damage.
Dr. Shore from Hopkins reported that prolonged [<1 week] continuous occlusion with a waterproof dressing held in place with Mastisol was very helpful and sometimes produced long term remissions in psoriasis, LP, DLE, hand eczema, keloids, postinflammatory hyperpigmentation and GA. Medium potency corticosteroids like Lidex were often applied before the dressing was put on, with a 3 cm margin so it would stick to the Mastisol on normal skin. Dermovate can be used on thick lesions. A dressing custom designed for this type of therapy is being marketed as Topiclude by Ferndale Medical Products in Canada.
Dr. Powell reported several pediatric cases of dermatofibrosarcoma ATROPHICANS [a variant of DFSP] were reported, and illustrated with photographs. Nodules may form after a number of years if the lesion is observed rather than biopsied and treated. Lesions may appear after trauma. Clinically the lesions look like morphea or a granulomatous process like GA. The diagnosis was not suspected prior to biopsy. Bottom line: if you would biopsy a lesion in an adult, you should biopsy that lesion in a kid. Just because the patient is a child is no excuse not to do a biopsy. CD-34 is a good marker for dermatofibroma vs. DFSP.
S. Hofstader demonstrated topical nitrogen mustard as an effective treatment for histiocytosis-X in an adult, with good photos.
C. Dicken gave an excellent discussion of a number of cases of trigeminal trophic syndrome causing self-mutilation of the central face and occasionally the forehead - with excellent clinical photos from the Mayo Clinic.
H. Lui reported benzoporphyrin derivative [BPD] is useful in therapy of skin cancer, without the prolonged photosensitivity of HPD [5 days post-Rx with BPD vs. up to 8 weeks with HPD or PhotoPhrin]. There is RAPID BPD uptake into the tumor, and rapid clearance from normal skin. BPD is activated by the LONG wavelength 690 nM light, which penetrates more deeply into the treated area. 80% complete remission for BCC/SCC with a single Rx of iv BPD then 690 nM light. Metastatic lesions had a 60% complete response. Patients preferred this Rx to surgery.
A. Krol described partial responses of 10 cases of congenital hemangiomas to ketotifen [Zaditen, Sandoz], and noted that this seems to inhibit basic fibroblast growth factor, which drops as the hemangioma involutes. It is useful to start Rx early.
A horrendous case of Mucha-Haberman disease in a child was reported - the kid had to be intubated for 2 months and also had hemophagocytosis on bone marrow Bx. Did not respond to prednisone or erythromycin but eventually got better on his own without any specific treatment, and only a bit of residual scarring. Several similar cases have been seen, and the consensus was that this was at the far end of the Mucha-Haberman spectrum.
send vitiligo/AA/CMV papers to M. Lassonde
G. Searles reported CD8 positive T-cell lymphoma presenting as generalized granulomatous lesions. The biopsy looked like sarcoid, and the patient turned out to have common variable immunodeficiency. The patient was treated with IV imunoglobulin.
M. Lassonde reported that famciclovir was as effective as acyclovir for Herpes zoster and for the prevention of posst-herpetic neuralgia, and has the advantage of tid dosing. Famciclovir is also more effective against CMV than acyclovir, raising the possiblity that Famciclovir would be useful in AA and vitiligo, where CMV has recently been found by PCR [must try this on some of my patients when I get back to Niagara Falls].
K. Arndt gave a very useful overview of the medical literature, and some suggestions for coping with the volume of new material. Personally, if I could only have ONE JOURNAL I'd ask for his Medical and Surgical Dermatology, which is a collection of abstracts from the world's literature. In particular I hope he has his contributors look at the journals which are NOT included in the on-line indexes, because this is their only chance to reach a broader audience.
Kevin Smith
* as archived from RxDerm-L 16 July 1995
All contents copyright (C), 1995. Dermatology Online Journal University of California Davis