Occupational non-melanoma skin cancer.

Non-melanoma skin cancer is historically known to be associated with certain professions. Reporting is mandatory in Denmark when occupational exposure is suspected. In a retrospective register-based study of all cases of suspected occupational non-melanoma skin cancer reported to the Directorate of National Labour Inspection and the National Board of Industrial Injuries in Denmark in the period January 1, 1984 to December 31, 1994, we assessed the extent to which occupational exposures today are of importance in the occurrence of non-melanoma skin cancer. A total of 74 individuals (11 women and 63 men) aged 32-82 years (median 58 years) had been reported. Of these, 15 cases (20%) were approved as being occupational, 37 (50%) were rejected and 22 (30%) were either shelved or could not be further clarified. Most commonly approved were exposures such as asphalt, tar, and the like, and ionizing radiation, and localization on the arms or multiple tumours. Unexpected occupational exposure could not be identified but continued reporting is recommended in order to follow this in the future.

DNA repair capacity: inconsistency between effect of over-expression of five NER genes and the correlation to mRNA levels in primary lymphocytes.

We have previously shown that high DNA repair capacity protects psoriasis patients against chemically induced basal cell carcinoma [Dybdahl et al. Mutat. Res. 433 (1999) 15-22]. We have used the same study persons to investigate the correlation between expression of eight genes involved in nucleotide excision repair and DNA repair capacity. mRNA levels of XPA, XPB, XPC, XPD, XPF, XPG, CSB and ERCC1 in primary lymphocytes from 33 individuals were quantified by dot-blots and normalized to beta-actin. ERCC1 and XPD mRNA quantities were highly correlated (r=0.89; P<10(-11)) while XPA, XPB, XPC, XPG, XPFand CSB mRNAs were moderately correlated (r=0.2-0.7). Thus, the mRNA expressions seem to fall in at least two groups. There was a three to sevenfold variation in the expression levels of the mRNAs. This is in contrast to the more than a hundredfold variation in mRNA levels reported in cancer patients.DNA repair capacity was measured in a host cell reactivation assay, where primary lymphocytes were transfected with an UV-irradiated plasmid encoding firefly-luciferase. Only ERCC1 and XPD mRNA levels correlated with the DNA repair capacity (P<0.03). In order to see if ERCC1 or XPD activity was limiting for DNA repair, we cotransfected with plasmids encoding NER genes, thus over-expressing either XPB, XPC, XPD, CSB or ERCC1 in the host cell reactivation assay. Only XPB over-expression increased DNA repair capacity. Thus, there is no indication that neither XPD nor ERCC1 limits the DNA repair capacity. However, our results indicate that ERCC1 and XPD mRNA levels may be used as a proxy for DNA repair capacity in lymphocytes.

Psoriasis patients with basal cell carcinoma have more repair-mediated DNA strand-breaks after UVC damage in lymphocytes than psoriasis patients without basal cell carcinoma.

We have investigated the formation of strand-breaks following UVC irradiation in lymphocytes from psoriasis patients with or without basal cell carcinoma (BCC). Isolated lymphocytes were irradiated with UVC light at a dose of 3.6 J/m(2), and the level of DNA strand-breaks were measured 25 min after the irradiation by the alkaline comet assay. The generation of strand-breaks following UVC irradiation indicates DNA-repair-mediated incisions, as UVC light does not generate strand-breaks per se. We found that psoriasis patients with BCC had more DNA-repair incisions than non-cancer patients. The incision level correlated to two polymorphisms of the XPD gene. At present, it is not clear if the association is a primary effect that is related to differences of the XPD protein. Genes encoding for other repair proteins, namely XRCC1, ERCC1, and LIG1 are located close to the XPD gene, and it is possible that the association is due to a cosegregation with a polymorphism in one of these genes.

Malignant tumours and psoriasis: climatotherapy at the Dead Sea.

In this retrospective, nation-wide cohort study, the risk of cancer was assessed for 1738 Danish patients with psoriasis subjected to climatotherapy at the Dead Sea during 1972-93, by linkage to the Danish Cancer Registry. The overall risk of cancer in patients treated at the Dead Sea (standardized incidence ratio, SIR = 1.59) was higher than that expected in the general population, owing to an excess risk of non-melanoma skin cancer (NMSC) [SIR = 4.2 for basal cell carcinoma (BCC) and 10.7 for squamous cell carcinoma (SCC)]. In addition, the distribution of NMSC among body sites, age groups and sexes was unusual in those treated at the Dead Sea, favouring NMSC in young individuals and at multiple sites (SIR = 10.7 for BCC and 57.2 for SCC), multiple BCCs being particularly common among young women. Thus, people subjected to climatotherapy at the Dead Sea for psoriasis constitute a high-risk group for NMSC, SCC in particular, but not for malignant diseases in general. The study design precludes conclusions on whether climatotherapy plays a specific part in skin carcinogenesis which is different from other sources of ultraviolet (UV) radiation, as climatotherapy is inevitably confounded by excess UV exposure.

A double blind, placebo controlled study of intracavernosal vasoactive intestinal polypeptide and phenotolamine mesylate in a novel auto-injector for the treatment of non-psychogenic erectile dysfunction.

Three hundred and four patients with non-psychogenic erectile dysfunction (ED) completed a dose assessment phase with intracavernosal injection utilizing 25 micrograms vasoactive intestinal polypeptide (VIP) combined with phentolamine mesylate 1.0 mg (VIP/P-1) or 2.0 mg (VIP/P-2) in an auto-injector for a response rate of 83.9%. In a sub-group of 183 patients who withdrew from one or more previous ED therapies, 82% responded with an erection suitable for intercourse. One hundred and ninety-five patients were subsequently treated in a placebo controlled phase. 75.1% responded to VIP/P-1, 12% to placebo (P < 0.001); 66.5% responded to VIP/P-2, 10.3% to placebo (P < 0.001), with the median duration of erection of 54 min. The principal adverse event was transient facial flushing in 2770 injections (33.9%). There was no pain post injection and two episodes of priapism (0.05%). Only nine patients withdrew because of adverse events. Over 85% and 95% of patients were satisfied with the drug and auto-injector, respectively. Over 81% of patients and 76% of partners reported an improved quality of life.

Malignant tumours and psoriasis: a follow-up study.

This nationwide follow-up study concerns the pattern of malignant tumours in a cohort of patients with psoriasis, at an average of 9.3 years after discharge from hospital. The study confirms that the significantly increased risk of cancer in these patients, amounting to 1.4 times that in the general population, is mainly due to cancer of the skin and lung in both sexes and cancer of the pharynx and larynx in men. Non-melanoma skin cancer is the most common malignancy, occurring in 196 of 795 patients with cancer: standardized incidence ratio (SIR, the ratio of observed to expected cancers) 2.4 for men and 2.6 for women. This means an overall lifetime risk (up to the age of 75 years) of 14.1%. In particular, squamous cell carcinoma (SCC) by itself (n = 45, SIR 3.9 for men and 4.7 for women), cancer in multiple sites (SIR 5.9 for basal cell carcinoma (BCC) and 11.7 for (SCC) and SCC on the lower extremities (SIR 18.0) are frequent. Women run the highest risk of BCC in the age range 20-40 years, while men in the age range 30-60 years run a particularly high risk of SCC. When monitoring patients extensively treated for psoriasis, this aberrant pattern of cancer should be taken into account.

Treating men with predominantly nonpsychogenic erectile dysfunction with intracavernosal vasoactive intestinal polypeptide and phentolamine mesylate in a novel auto-injector system: a multicentre double-blind placebo-controlled study.

OBJECTIVE: To study the effect of intracorporeal injection (IC) of vasoactive intestinal polypeptide (VIP) and phentolamine mesylate (PM) on men with erectile dysfunction (ED) of nonpsychogenic aetiology. PATIENTS AND METHODS: The study comprised 236 men with primarily nonpsychogenic ED attending sexual dysfunction clinics at eight institutions. In an initial dose-assessment phase, the men were given IC injections of 25 micrograms VIP combined with PM 1.0 mg (VIP/P-1) or 2.0 mg (VIP/P-2) in a prefilled, single-use auto-injector. The main aetiologies of ED were arteriogenic (38), diabetes mellitus (DM) (39), neurogenic (35), mixed (90), and venous leakage (30). In a placebo-controlled phase, 171 patients were subsequently treated and self-administered up to 12 injections over a 6-month interval. RESULTS: In the dose-assessment phase there was an overall response rate of 82%, with responses by aetiology as follows: arteriogenic (82%), DM (85%), neurogenic (86%), mixed (80%), and venous leakage (77%). In a subgroup of 159 patients who withdrew from previous IC therapies for ED, 64% responded with an erection suitable for intercourse. Of the 171 patients treated in the placebo-controlled phase, 75% responded to VIP/P-1 and 12% to placebo (P<0.001); 66% responded to VIP/P-2 and 18% to placebo (P<0. 001), with a median duration of erection of 56 min. The principal adverse event was transient facial flushing accompanying 40% of 1711 injections. There was no pain after injection and one episode of priapism (0.06%); only seven patients withdrew because of adverse events. Over 88% and 92% of patients were satisfied with the drug and auto-injector, respectively. More than 85% of patients and 77% of partners reported an improved quality of life. CONCLUSION: The combination of VIP and PM at the dose used is a safe and effective means of treating male ED of primarily nonpsychogenic aetiology.

Low DNA repair is a risk factor in skin carcinogenesis: a study of basal cell carcinoma in psoriasis patients.

We have studied DNA repair in patients with psoriasis aiming at investigating the importance of repair in chemically induced cancer. An increased risk of non-melanoma skin cancer has been observed in psoriasis patients extensively treated with tar, methotrexate and photochemotherapy (psoralen + UVA). We measured the DNA repair capacity (DRC) by a host cell reactivation (HCR) assay in lymphocytes from psoriasis patients with and without basal cell cancer and non-psoriatic persons with and without basal cell cancer (4 x 20 study persons). Among psoriasis patients we observed a significant lower DRC in patients with skin cancer compared to patients without skin cancer (P = 0.015; Mann-Whitney, one-sided). Using the median of the healthy control group (group 4) as a cutoff value to divide the psoriasis patients into groups of high and low repair, we found that individuals who had a low repair capacity had a 6.4-fold increased skin cancer risk compared to individuals with high repair (95% confidence interval (CI), 1.44-28.5). The level of DNA repair was correlated with the age at which the psoriasis patients got their first skin cancer. The lower the level of DNA repair, the earlier the psoriasis patients had their first skin tumor (P = 0.070 Spearman; one-sided). Psoriasis patients without BCC had marginally higher repair than healthy controls (P = 0.11, Mann-Whitney, two-sided). We found no difference between BCC patients without psoriasis and healthy controls. In conclusion, these findings suggest a protective role of DNA repair in a predominantly chemically induced cancer.

Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma.

The XPD protein has a dual function, both in nucleotide excision repair and in basal transcription. We have studied the role of two nucleotide substitutions in the XPD gene, one in exon 23 leading to an amino acid substitution (Lys751Gln) and one silent in exon 6 in relation to basal cell carcinoma (BCC). Both are two-allele polymorphisms, with the nucleobases A and C at the given positions. We genotyped psoriasis patients with and without BCC and nonpsoriatic persons with and without BCC (4 x 20 persons). The choice to study psoriasis patients was motivated by their high genotoxic exposure via treatment and their high relative rate of early BCC. Subjects carrying two A alleles (AA genotype) in exon 23 were at 4.3-fold higher risk of BCC than subjects with two C alleles (95% CI, 0.79-23.57). In addition, the mean age at first skin tumor for BCC cases with the AA genotype was significantly lower than the mean age for BCC cases with the AC or CC genotype (P = 0.012). Thus, the variant C-allele of exon 23 may be protective. The exon 6 genotype was associated with the risk of BCC among the psoriasis patients; psoriatics carrying two A alleles in exon 6 were at 5.3-fold higher risk of BCC than psoriatics with two C alleles (95% CI, 0.78-36.31). For the psoriatics, the mean age at onset of BCC for cases with the AA genotype was marginally lower than the mean age for cases with genotype AC or CC (P = 0.060). Our results raise the possibility that the polymorphisms in the XPD gene may be contributing factors in the risk of BCC development. They are, therefore, important candidates for future studies in susceptibility to cancer.

[Unnecessary medical interventions. A questionnaire study among physicians and laymen]. / Uopfordret laegelig indgriben. En spørgeskemaundersøgelse blandt laeger og laegpersoner.

The aim of the study was to survey attitudes among medical doctors and lay people to unsolicited medical intervention. The design of the study was an anonymous questionnaire study including three scenarios implying ethical considerations. A total of 445 medical doctors working within different areas received the questionnaire, as did 75 medical students and 600 lay people. The results showed a response rate of 67%, highest among medical doctors and students. The lay people had significantly higher expectations concerning the medical intervention in two out of three scenarios compared to medical doctors and students. The participants were offered the opportunity to comment on the questionnaire. The conclusion of the Danish survey is that there is a significantly different approach to unsolicited medical intervention among lay people compared to medical doctors and students. Medical doctors are less disposed to perform unsolicited intervention compared with the wishes/expectations of the lay people. More open attitudes and information as well as better communication is recommended.

Seasonal variation of DNA damage and repair in patients with non-melanoma skin cancer and referents with and without psoriasis.

Quadruples of skin cancer patients with and without psoriasis and referents with and without psoriasis (4 x 20 study persons) were identified and examined for DNA damage by single cell gel electrophoresis (comet-assay) and DNA-repair by UV-induced unscheduled DNA synthesis (UDS) in mononuclear blood cells (lymphocytes and monocytes). DNA damage (strand breaks and alkaline labile sites) as assessed by the comet assay and DNA repair as assessed by UDS were significantly associated with the season in which blood sampling took place. This variation might be explained by an increased exposure to solar radiation. When the comet tail moment data were stratified by sampling period, an interaction between psoriasis and skin cancer was detected, with patients with psoriasis and skin cancer exhibiting more DNA damage. Patients with psoriasis and skin cancer also had lower UDS compared to healthy study persons, suggesting that the more DNA damage may be caused by a lower rate of DNA repair. In all study persons, the extent of UDS correlated positively with the amount of DNA damage determined by the comet assay.

Oral terbinafine in toenail dermatophytosis. A double-blind, placebo-controlled multicenter study with 12 months' follow-up.

The treatment of onychomycosis has previously often been protracted and unsuccessful. Terbinafine has been shown to be effective in short-term regimens. In this double-blind, placebo-controlled study, 148 patients with toenail dermatophytosis were randomized to treatment with either 250 mg terbinafine daily or placebo for 3 months. An additional treatment was given for 3 months to patients whose infection had not responded. The patients were followed clinically and mycologically through 12 months. After 3 months 82% of the terbinafine-treated group, versus 5% of the placebo group, showed significant improvement, i.e. negative culture and growth of unaffected nail more than 2 mm (p = < 0.0001). After 12 months clinical and mycological cure was seen in 40% of the patients treated with terbinafine for 3 or 6 months, while 67-81% were clinically cured, but with positive microscopy. Side-effects occurred in 13.5% of the terbinafine group, versus 5.4% of the placebo group, and were mild. 250 mg terbinafine daily for 3 months was significantly more effective than placebo. The efficacy did not appear to improve with additional treatment for 3 months.

An increased incidence of rejection episodes. One of the causes of worse kidney transplantation survival in black recipients.

OBJECTIVE: To evaluate the cause of worse kidney allograft survival in black recipients, which has been the source of considerable interest and debate. DESIGN: Three hundred ninety-two consecutive renal allografts (O HLA mismatch grafts excluded) were reviewed. Of the recipients, 57% were black, 27% received living donor grafts, and 86% received their first transplant. All recipients underwent an oral cyclosporine induction protocol with triple drug maintenance. Crude graft survival, the risk of rejection, and the need for dialysis were determined using donor and recipient demographic and immunologic variables. RESULTS: Graft survival was 84%, 67%, and 50% at 1, 3, and 5 years after the transplantation, respectively. The survival of black recipients was 4%, 11%, and 20% worse than that of white recipients at 1, 3, and 5 years, respectively (P < .002). When only pretransplantation variables were considered, black recipient race was the only variable that predicted graft loss in the multivariate analysis (relative risk [RR] = 1.6, P = .09). When posttransplantation and pretransplantation variables were used, cadaver donor (RR = 1.7), an episode of rejection (RR = 2.6), and the need for dialysis (RR = 2.7) were independent variables that predicted graft loss (P < .001). Black recipient race was a dependent variable. Four pretransplantation variables predicted the risk of dialysis: black race (RR = 3.6), male recipient (RR = 2.1), cadaveric donor (RR = 2.2), and a peak panel-reactive antibody level greater than 30% (RR = 2.8). Three pretransplantation variables predicted the risk of rejection: black race (RR = 1.7), male recipient (RR = 1.6), and a current panel-reactive antibody level greater than 30% (RR = 5.3). CONCLUSIONS: These data suggest that black recipient race is a dependent predictor of renal allograft survival when the posttransplantation events of rejection and dialysis are considered. Black recipients have more immunologic complications after renal transplantation that result in worse graft survival. These results confirm the importance of postallograft events as the major determinants of long-term graft survival and suggest that black recipients are receiving inadequate immunosuppression. These data support attempts to tailor immunosuppressive protocols to recipient pretransplantation risk profiles as a way to improve graft survival in the high-risk recipient.

Renal allograft rupture: a clinical review.

Rupture of a renal allograft (RAR) is an uncommon but serious complication of renal transplantation. A recent RAR prompted a review of our experience, with the purpose of (1) identifying conditions that may predispose this complication and (2) defining strategies for prevention. A 5-yr, consecutive living-related (LRD) and cadaver donor (CD) cohort of 331 patients was studied retrospectively. Twelve patients (3.6%) had RAR. Donor characteristics, procurement and preservation conditions, and recipient characteristics were major study categories. Data analysis was computer-based and included multivariate analysis. The nine White and two Black cadaver donors were "ideal", mean age 29 yr, with mean high creatinine (CR) of 1.3 and terminal CR of 1.1 mg/dl and mean terminal urine output of 423 ml/min. Nine of 11 CD had low-dose dopamine use (terminal, mean 8, range 5-13 micrograms/kg/min). Eleven of 11 donors had procurement en-bloc, 9 of which were multiple organ procurement. All had 4+/4+ flush and cold storage with UW solution. Mean cold ischemia time (CIT) was 22 h, 28 min (range 15 h, 16 min to 40 h). For patients with RAR mean age was 39 yr; there were 12 Black patients and 7 males, 5 females. HLA match was 1 antigen (AG) for 3, 2 AG for 8, and 4 AG for 1 (mean 1.9). Nine patients had delayed or declining renal function requiring dialysis. The panel reactive antibody was at peak, mean 47% (range 0-100%) and current, mean 18% (range 0-84%). Six of 12 had OKT3 therapy at time of RAR and six had biopsies. Day of RAR was mean 10, median 9 (range 4-21). Pain and drop in hematocrit were observed in most. There was one fatality (8%), and all kidneys were removed. All kidneys showed at least minimal rejection but six had severe acute tubular necrosis (ATN) with edema and minimal rejection. Statistically significant associations with RAR were older recipient age (p = 0.01), donor-recipient race mismatch (White donor to Black recipient) (p = 0.007), and dialysis requirement (p < 0.001). Other variables were not statistically correlated: gender, race, CIT, transplant number, LRD vs. CD, peak or current PRA, and total HLA and BDR mismatch. The data suggest that ATN and rejection act synergistically to cause RAR and that early delayed function requires intensive and perhaps novel immunosuppression, especially in Black recipients.

The quest for living-related kidney donors for children with end-stage renal disease.

In a pediatric renal transplant program that actively seeks living-related kidney donors, we achieved a living donor rate of 55% in 119 children. This approximates the national average but is less than an idealized goal. For black children, the living-donor transplant rate was 41%, a disconcertingly low rate. In an attempt to define factors that negatively affected living-related donor availability, we analyzed our evaluation process by distinct phases (interview, histocompatibility testing and medical evaluation). We classified our families on the basis of locale (urban, suburban and rural), family unit (two or less parents, adult sibs or other relatives presenting at interview) and economic status (designating only economic-disadvantaged and other). While histoincompatibility is predictably a negative factor, the negative impacts of medical illness in the donor pool, economic disadvantage and single parent family are striking and cumulative. Our data validate the relative success of an aggressive recruitment policy in a patient population that includes many economically disadvantaged families. For pediatric renal transplant programs with low living-related donor rates, our data should encourage review and possible modification of the donor recruitment process.

[Psoriasis and cancer]. / Psoriasis og cancer.

This study reports the cancer incidence among 6910 individuals in Denmark discharged from hospital over the period 1977-1987 with a diagnosis of psoriasis. Patients were identified in the National Hospital Discharge Register and information on cases of cancer was obtained through the files of the Danish Cancer Registry. A 2,5-fold increased risk was observed for nonmelanoma skin cancer in men and women, with no preponderance of any specific histologic subtype of cancer. The incidence of non-cutaneous cancers at all sites combined was significantly increased in the study group, owing mainly to excesses of lung cancer in men (relative risk (RR) = 1.4) and women (RR = 1.6), of cancer of the larynx and pharynx in men (RR = 2.8 and 3.9), and of colon and kidney cancer in women (RR = 1.6 and 2.3). The effect of cigarette smoking on the risk for non-cutaneous cancer could not be assessed in this study; however, antipsoriatic treatment such as ionizing radiation and oral arsenicals must be considered as a possible cause, particularly in relation to colon cancer which has been observed in excess in two other studies of psoriatic patients, but also in relation to kidney and lung cancer.

Malignant tumors in patients with psoriasis.

BACKGROUND: There is strong epidemiologic evidence that psoriasis treatments may cause nonmelanoma skin cancer and possibly other types of cancer. OBJECTIVE: This study from Denmark reports the cancer incidence in 6910 patients with psoriasis discharged from the hospital from 1977 through 1987. METHODS: Patients were identified in the National Hospital Discharge Register and information on cases of cancer was obtained through the files of the Danish Cancer Registry; observed figures were compared with those expected on the basis of cancer incidence rates for the national population. RESULTS: A 2.5-fold increased risk was observed for nonmelanoma skin cancer in men and women, with no preponderance of any specific histologic subtype of cancer. In addition, excesses were seen of lung cancer in men (relative risk [RR] = 1.4) and women (RR = 1.6), of cancer of the larynx and pharynx in men (RR = 2.8 and 3.9), and of colon and kidney cancer in women (RR = 1.6 and 2.3). CONCLUSION: The effect of cigarette smoking on the risk for noncutaneous cancer could not be assessed in this study; however, antipsoriatic treatment such as ionizing radiation and oral arsenicals must be considered as a possible cause of colon cancer, which has been observed in excess in two other studies of psoriatic patients.