(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
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