Dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease (CD), which causes an itching and blistering rash, typically on the elbows, knees and buttocks. DH and CD share a similar genetic background, small bowel mucosal alterations, and an autoimmune response against tissue transglutaminase in the serum and small bowel. DH is typically diagnosed during adulthood, and it is slightly more common among males than females. The incidence of DH seems to be decreasing, in contrast to the detected four-fold increase in the incidence of CD. In addition to typical clinical picture, diagnosis of DH relies on the demonstration by direct immunofluorescence of pathognomonic granular IgA deposits in the papillary dermis. Circulating tissue transglutaminase antibodies support the diagnosis, but their absence does not exclude DH. Obtainment of small bowel mucosal biopsies is not necessary when DH is diagnosed, but if performed, the majority of patients are found to have villous atrophy, and even those with normal villous architecture evince CD-type inflammation. The treatment of choice in DH is a strict, life-long adherence to a gluten-free diet (GFD). In addition to alleviating the symptoms of DH and healing the small bowel mucosal damage, a GFD increases the quality of life for patients, and decreases the risk for lymphoma in DH. Further, the mortality rate of patients with DH treated with a GFD seems to be lower than that of the general population. However, as changing to a GFD has a rather slow effect on the DH rash, patients with severe skin symptoms should additionally be treated with dapsone medication. This review article is based on a presentation given at the British Society for Medical Dermatology blistering skin diseases meeting 2019.

Reduced mortality in dermatitis herpetiformis: a population-based study of 476 patients.

BACKGROUND: Dermatitis herpetiformis (DH) is an extra-intestinal manifestation of coeliac disease and most patients adhere to a life-long gluten free diet (GFD). Increased mortality rates have been reported in coeliac disease but knowledge in DH is scanty. OBJECTIVES: To survey the mortality rate and causes of death in a large cohort of patients with DH. MATERIAL AND METHODS: Patients with DH (n = 476 consecutive patients) diagnosed from 1970 onwards at the Tampere University Hospital were analysed for causes of death during 1971-2010. A questionnaire survey on key aspects of health behaviour was performed in patients with DH and comparisons were made with the Finnish population. RESULTS: The total number of deaths during 9079 person years followed up was 77 whereas 110 were expected. The standardized mortality rate (SMR) for all causes of death was significantly reduced, being 0·70 (95% CI 0·55-0·87), and similar in both sexes. The SMR was equal in the patients with DH with (0·73) and without (0·77) small bowel villous atrophy. The SMR was significantly reduced (0·38) for deaths due to cerebrovascular diseases. The SMR due to lymphoproliferative malignancies was significantly increased (6·86) in the first 5 years of follow-up but not thereafter. The questionnaire survey documented that 97·7% of the patients with DH adhered to a GFD. The patients reported significantly less hypercholesterolaemia and there were fewer current and past smokers compared with the age- and sex-matched control population. CONCLUSIONS: The present long-term follow-up study of DH documented significantly reduced all-cause and cerebrovascular disease mortality. Strict adherence to a GFD, less smoking and hypercholesterolaemia may play a role in the observed health benefit.

Prevalence and incidence of dermatitis herpetiformis: a 40-year prospective study from Finland.

BACKGROUND: Dermatitis herpetiformis (DH) is an external manifestation of coeliac disease presenting with blistering rash and pathognomonic cutaneous IgA deposits. Better knowledge of subclinical forms and serological testing has resulted in a sharp increase in the incidence and prevalence of coeliac disease. OBJECTIVES: To investigate the prevalence of DH and analyse whether the incidence of DH changed when the occurrence of coeliac disease increased. METHODS: All 477 patients with DH diagnosed from 1970 onwards at the Tampere University Hospital were analysed for prevalence in 2009. The incidence of DH was calculated in three 10-year periods from the year 1980. RESULTS: The prevalence of DH was 75·3 per 100,000 which is eight times lower than the prevalence of coeliac disease in our area. The annual incidence of DH in the whole period was 3·5 per 100,000, and in the three 10-year periods 5·2, 2·9 and 2·7 per 100,000, respectively. The decrease in incidence between the first and second 10-year period was significant (P<0·001). The male to female ratio of DH was 1·1:1. The mean age at diagnosis increased significantly during the study, in men from 35·3 to 51·1 years and in women from 36·3 to 45·8 years. CONCLUSIONS: The present study shows the highest prevalence of DH reported to date. Although the overall incidence of DH was also high, a significant decrease occurred in the 1990s, which is in contrast to the incidence of coeliac disease.

Diagnostic methods beyond conventional histology in coeliac disease diagnosis.

BACKGROUND: Coeliac disease diagnostic criteria currently require the detection of small bowel mucosal villous atrophy and crypt hyperplasia. AIMS: To compare conventional histological examination to the determination of small bowel mucosal intraepithelial lymphocytes (IELs) and to serum and intestinal coeliac autoantibodies in untreated coeliac disease with villous atrophy and in mild enteropathy coeliac disease. PATIENTS AND METHODS: Study comprised consecutive adult patients with coeliac disease suspicion; villous height-crypt depth ratio (Vh/CrD), the densities of CD3+, gammadelta+ and villous tip IELs and serum and intestinal transglutaminase 2 (TG2)-targeted autoantibodies were studied. Coeliac disease was diagnosed in 223 and excluded in 608 patients. Further, 66 patients were considered to suffer from mild enteropathy coeliac disease. Control group consisted of 138 patients. RESULTS: Vh/CrD determination detected 77% of untreated coeliac disease patients. Serum coeliac autoantibodies had 84% sensitivity for untreated coeliac disease with villous atrophy and 70% sensitivity for mild enteropathy coeliac disease; the specificity was 100%. Intestinal TG2-targeted autoantibodies had sensitivities of 100% and 93%, and 100% specificity, respectively. gammadelta+ and villous tip IELs proved more reliable than CD3+ IELs. CONCLUSIONS: Conventional histological examination as the golden standard in coeliac disease diagnosis is questionable. Serum and especially intestinal TG2-targeted autoantibodies seem promising in future coeliac disease diagnostics.

Male reproductive health after childhood cancer.

AIM: Twenty-five male patients were investigated to elucidate the correlation of semen parameters and other related parameters in the assessment of spermatogenesis after childhood cancer treatment. METHODS: Evaluation of given cancer treatment, anthropometric and testicular size measurements, semen analysis, and measurement of gonadotrophins, testosterone, sex hormone-binding globulin (SHBG), and inhibin B were performed according to a protocol. RESULTS: Median (range) sperm concentration (SC) was 35.5 (0-273)x10(6)/mL, and percentage of motile sperm 56 (0-86)%. Testicular size (r=0.73, p<0.001) and the level of inhibin B (r=0.66, p<0.001) correlated strongly to SC. SC correlated negatively to FSH (r=0.46, p=0.03). Only testicular size predicted SC significantly (p=0.03). Inhibin B showed highest area under ROC curve (0.83, 95%CI 0.67-0.99) in showing SC<20x10(6)/mL. Body mass index (BMI) did not correlate with SC, but negative correlation between BMI and SHBG was found (r=-0.41, p=0.04). CONCLUSION: Although semen analysis is a useful instrument for fertility assessment in men, it is often difficult to get these samples from childhood cancer survivors. Thus, indirect methods are needed in prediction of possible sperm count impairment in postpubertal adolescents after cancer treatment. When combined with the data on testicular size and follicle-stimulating hormone (FSH) level, inhibin B gives valuable addition to the estimations of spermatogenesis.

Scholastic achievements of children with brain tumors at the end of comprehensive education: a nationwide, register-based study.

BACKGROUND: Cancer treatment may affect school performance. Scholastic achievements after childhood brain tumors have not been previously reported on the level of actual grades. PATIENTS AND METHODS: Patients with brain tumor (n = 300) were identified from the Finnish Cancer Registry. Population controls (n = 1,473) were matched for age, gender, and place of living. Their ninth grade school reports were obtained from Statistics Finland. Age at diagnosis and cranial irradiation (CRT) were considered in analyses, and the level of parental education was taken into model as a covariate. RESULTS: Six percent of patients did not finish their comprehensive school at the usual age. Patients had lower overall averages than their controls (95% CI for the difference -0.30, -0.16). Girls differed from their controls independently of the age at diagnosis or CRT. Boys treated with CRT at school age, but not before school age, had poorer results than their controls (95% CI -0.65, -0.18). The grades of patients were significantly lower in each school subject, and differed most in foreign language. Young girls with CRT had greatest differences from their controls (95% CI -1.73, -0.86) in this subject. In mathematics, patients diagnosed before school age had greatest difference from their controls. In their mother tongue, patients differed less from their controls. CONCLUSIONS: Few patients with brain tumor missed the ninth grade certificate at the age of 16. Grades in foreign language (representing verbal performance) were most affected. However, the patients fared poorer than controls in each subject. The difference was most pronounced among girls. Girls were more sensitive to the adverse effects of irradiation.

Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease.

BACKGROUND: Reliable markers of early developing coeliac diseases are needed. Coeliac autoantibodies in the serum or Marsh I inflammation may be indicators of subsequent coeliac disease. AIM: To investigate whether determination of intestinal transglutaminase 2-targeted autoantibody deposits would detect early developing coeliac disease better than previous methods. METHODS: The study investigated patients previously excluded for coeliac disease: 25 had positive serum coeliac autoantibodies (endomysial), 25 antibody-negative had Marsh I, and 25 antibody-negative had Marsh 0 finding. Seven (median) years after baseline investigation, new coeliac cases were recorded, and small bowel biopsy was offered to the rest of the patients. Serum and intestinal coeliac autoantibodies and intraepithelial lymphocytes were assessed as indicators of developing coeliac disease. RESULTS: Seventeen patients had developed coeliac disease: 13 in the autoantibody-positive group, three in the Marsh I group and one in the Marsh 0 group. At baseline, intestinal coeliac autoantibody deposits had a sensitivity and specificity of 93% and 93% in detecting subsequent coeliac disease, CD3+ 59% and 57%, gammadelta+ 76% and 60%, and villous tip intraepithelial lymphocytes 88% and 71%, respectively. CONCLUSIONS: Endomysial antibodies with normal histology indicates early developing coeliac disease. Transglutaminase 2-targeted intestinal autoantibody deposits proved the best predictor of subsequent coeliac disease.

Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits.

BACKGROUND: Some patients with untreated coeliac disease are negative for serum endomysial autoantibodies (EmA) targeted against transglutaminase 2 (TG2). AIMS: To evaluate the clinical and histological features of EmA-negative coeliac disease, and to examine whether EmA-equivalent autoantibodies against TG2 can be seen in the small-bowel mucosa when absent in serum. PATIENTS: Serum EmA was studied in 177 biopsy-proved specimens from adult patients with coeliac disease. 20 patients with intestinal diseases served as non-coeliac controls; three had autoimmune enteropathy with villous atrophy. METHODS: Clinical manifestations, small-bowel mucosal morphology, intraepithelial inflammation and TG2-specific extracellular immunoglobulin A (IgA) deposits were investigated in both serum EmA-negative and EmA-positive patients. RESULTS: 22 patients with IgA-competent coeliac disease were negative for serum EmA. Three of these had small-bowel lymphoma. Patients with EmA-negative coeliac disease were older, had abdominal symptoms more often, and the density of gammadelta+ intraepithelial lymphocytes in their intestinal mucosa was lower than in EmA-positive patients; otherwise the histology was similar. All serum EmA-negative patients with coeliac disease, but none of the disease controls, had gluten-dependent mucosal IgA deposits alongside TG2 in the small-bowel mucosal specimens. In vivo deposited IgA was shown to be TG2-specific by its ability to bind recombinant TG2. CONCLUSIONS: Negative serum EmA might be associated with advanced coeliac disease. TG2-targeted autoantibodies were deposited in the small-bowel mucosa even when absent in serum. This finding can be used in the diagnosis of seronegative coeliac disease when the histology is equivocal. It may also be helpful in the differential diagnosis between autoimmune enteropathy and coeliac disease.

No GIST-type c-kit gain of function mutations in neuroblastic tumours.

AIMS: Neuroblastic tumours (NTs) have been shown to respond to imatinib treatment in vivo and in vitro, possibly via inactivating the c-kit receptor. The purpose of this study was to identify gastrointestinal stromal tumour (GIST)-type c-kit gene associated mutations in exons 9, 11, 13, and 17 in NTs to recognise a subset of tumours that would probably respond to imatinib treatment. METHODS: Expression of the c-kit protein was detected immunohistochemically in a total of 37 archival paraffin wax embedded NTs using polyclonal rabbit antihuman c-kit antibody. After immunohistochemistry, c-kit gene associated chromosomal mutations in all cases of NT were detected with denaturing high performance liquid chromatography (HPLC). RESULTS: Denaturing HLPC analysis did not reveal GIST-type mutations in four immunohistochemically detected c-kit positive or in 33 c-kit negative NTs. CONCLUSIONS: c-kit receptor expression and GIST-type c-kit gene mutations are rare events in NTs. Oncogenic activation of c-kit in NTs presumably differs from that of GISTs, which may influence their responsiveness to imatinib treatment. Whether c-kit has an essential role in the pathogenesis of NTs remains to be investigated.

The siblings of childhood cancer patients need early support: a follow up study over the first year.

BACKGROUND AND METHODS: In a 1 year follow up study, we assessed the life situation of 33 siblings of childhood cancer patients and 357 healthy controls. The hypothesis was that siblings have more behavioural and health related problems just after the cancer diagnosis. Validated assessment methods were used. RESULTS: Siblings below school age tended to have conduct problems, psychosomatic problems, and a mixed group of other behavioural problems, when assessed 3 months after the cancer diagnosis. These symptoms became less evident during follow up. Among the school aged siblings, however, conduct problems, learning problems, psychosomatic problems, impulsive-hyperactive symptoms, and other behavioural symptoms remained unchanged during follow up. In their self assessments, the school aged siblings showed both state and trait anxiety more often than controls at the first assessment, but later these symptoms settled to the same level as the controls. The overall Children's Depression Inventory (CDI) depression scores did not show differences between the study groups. CONCLUSIONS: The ratings of the parents were in keeping with the self assessment of the school aged siblings only in a few aspects; the emphasis of findings can be changed when proxies are used. The siblings have symptoms and adverse feelings which probably could be relieved by targeted, early information about the illness, and possibly by group discussions or activities, soon after the cancer diagnosis. In order to obtain necessary support for the siblings with educational problems, school personnel need to be informed about the sibling distress.

The life situation of parents over the first year after their child's cancer diagnosis.

AIM: To evaluate the impact of childhood cancer on the life of the parents. METHOD: A 1-y follow-up study, with two time points for questionnaires, was completed in 21 out of 26 eligible families, and there were 46 control families matched by mothers' educational status. RESULTS: Half of the mothers worked outside home during the first year of their child's illness. The perceived amount of lost family income was high during the first few months. The attitudes of the parents were fairly positive as their family life and spouse relations were concerned. Feelings of being under strain or stressed were, by the mothers, described as intolerable in the beginning. However, standardized anxiety assessment failed to show an increase in feelings of anxiety. Own health was rated significantly negative by cancer parents. CONCLUSIONS: Despite good family relationships, a need for supportive measures exists, especially during the first few months, and in-depth interviews by psychologists or special nurses might be a way of finding out possible anxiety. The perceived feelings of own health may also be an indicator of the level of distress. Parent support groups could also do more to offer opportunities of physical activities for the parents, not merely disease-related information and group discussions.

Induced leukemia and antineoplastic agent carmustine cause permanent changes in craniofacial growth of immature rats.

OBJECTIVES: The purpose of the present study was to investigate the possible effects of untreated terminal leukemia on craniofacial growth (Study I), and also the effects of the antineoplastic agent carmustine on craniofacial growth in both leukemic and healthy rats (Study II). MATERIAL: A total of 367 inbred Piebald variegated rats was used. METHOD: Transmission of leukemic cells was carried out intraperitoneally at 30 days of age, and without treatment (Study I), the rats reached the terminal phase within 17 +/- 1 days. Rats with induced leukemia was cured with 10 mg/kg carmustine (BCNU) given on days 6 and 13 following cell transmission (Study II), the rats remaining in remission until they were killed at 100 days of age. Final weight was recorded and 12 craniofacial dimensions and tibial length were measured with a digital sliding caliper. RESULTS: The results showed that the effect of untreated terminal rat leukemia (Study I) on craniofacial growth differed between the genders. Male rats showed clearly reduced dimensions of facial structures and also retarded general body growth, whereas females showed differences mainly in general body growth. The effect of cured leukemia (Study II) as such was minor, while BCNU had a strong and permanent reducing effect on both craniofacial and general body growth in both genders. CONCLUSION: We suggest that the results in Study I came both from a direct effect of leukemia and an indirect effect of untreated terminal leukemia through malnutrition. The alkylating agent BCNU seemed to be the main cause of permanent craniofacial and general growth retardation in Study II.

Childhood cancer patients at school.

The aim of this study was to assess the school-related problems of childhood cancer patients. A cross-sectional questionnaire study for school-aged children with extracranial malignancies, in the area of Turku University Hospital serving around 1000000 people. Siblings, healthy pupils and teachers were studied as controls. 43 patients responded. None of the patients or controls was placed in special educational programmes. However, 30.8% of the patients, 15.7% of the controls and 3.7% of the siblings had required extra tutoring. The patients' results differed statistically from both the siblings' (P=0.022) and the controls' (P=0.041) results. The school marks in mathematics (P=0.05) and in foreign languages (P=0.06) tended to be worse for the patients than for the healthy controls. Bullying was reported by 31.7% of the patients, 10.9% of controls (P=0.0012) and 8.3% of the siblings (P=0.056). The biggest problem faced by the cancer patients was bullying-the patients reported approximately 3 times as much bullying as the healthy children did. It seems that there are still several aspects which need to be reconsidered when these children return to school or start their school-life as survivors of childhood cancer. Some proposals are presented.

Disturbances in craniofacial morphology in children treated for solid tumors.

Because of increased survival rates in childhood cancer, special interest has been focused on the side-effects of the therapy and the quality of life in long-term survivors. Our aim was to investigate craniofacial growth in children who had received different kinds of antineoplastic therapies for solid tumors. A total of 40 children treated in the Turku University Central Hospital were examined and divided into three different groups. Group 1 comprised 18 children treated for intracranial tumors with cranial irradiation (CRI) and chemotherapy (CT) including alkylating agents. Seven children out of 18 in this group received growth hormone (GH) therapy. In Group 2, 11 children with extracranial solid tumors also received multiagent CT including alkylating agents, but no CRI. Group 3 consisted of 11 children treated for Wilm's tumor with CT, which did not include alkylating agents or CRI. A total of 19 linear and four angular variables from the lateral cephalograms of the subjects were measured. Most deviations in craniofacial structures were found in children treated with combined CRI and multiagent CT. All disturbances were seen in the vertical measurements which were reduced when compared to the matched controls. It seems reasonable to assume that impaired growth following combined radio- and chemotherapy, as well as GH treatment, particularly affects cartilage-mediated growth. However, the deviations seen in the present study were fairly minor and did not usually require clinical consideration.

Amifostine protects against early but not late toxic effects of doxorubicin in infant rats.

The improved prognosis and increased expected lifetime among long-term survivors of childhood malignancies have made these patients especially sensitiveto the late toxicity of cancer therapy and prone to secondary malignancies. Recently, new strategies aiming to protect against cancer treatment toxicity have been developed, including the drug amifostine (Ethyol), which is suggested to protect normal tissues from the toxic effects of radiation and cytotoxic agents. In the present study, the possible protective effect of amifostine against toxicity induced by a single injection of doxorubicin (3 mg/kg) in immature rats was evaluated. Specifically, we evaluated the protection against long-term toxicity and the effects of amifostine on growing immature tissues. Amifostine (50-200 mg/kg) given 15 min before doxorubicin had a significant protective effect against doxorubicin-induced early alopecia in young rats. Significant protection against cataract formation was obtained by the use of low-dose amifostine (50 mg/kg). However, amifostine did not protect young rats against the late toxic effect of doxoubicin on linear growth, body weight, plasma leptin levels, and heart or testicular tissue. Worrisome, and in contrast to earlier studies in adult rats, an increased doxorubicin toxicity actually was observed and mortality was increased when the higher doses of amifostine (100-200 mg/kg) were used. The present results suggest that more data from growing immature animal models are needed to analyze the safety of amifostine treatment and its mechanisms of action before wider clinical use of this drug in pediatric cancer patients is recommended.

Cognitive functions of adolescent childhood cancer survivors assessed by event-related potentials.

BACKGROUND: Neurophysiological methods were applied to examine subtle central nervous system (CNS) adverse effects for adolescent childhood cancer survivors. We analyzed auditory event-related potentials (ERPs)-P300 and MMN/P3a complex-to find out whether there was impaired attention orientation in asymptomatic cancer survivors, and whether these ERP methods could be used as more objective tools in detecting those survivors who might need academic testing. Previous clinical studies of P300 have focused on leukemia survivors. MMN for cancer survivors has not been reported. PROCEDURE: The subjects were survivors of childhood leukemia (n=11) and solid tumors (n=8), as well as healthy controls (n=10). The mean age was 15.5 years for survivors and 15.9 years for controls. Pure sine-wave tones (500 and 553 Hz, 100 ms) were used as stimuli in an oddball paradigm. The ERPs to frequency change were measured. MMN recordings were performed in a passive non-attended situation where the subject was watching a voiceless video cartoon. P300 was produced thereafter, but in an active attend situation, by the same auditory oddball paradigm as MMN. RESULTS: A significant difference was detected between the groups for the latency of P300 at electrodes Cz (P = 0.03) and C4 (P = 0.05). The cancer survivors had prolonged P300 latencies as an indication of prolonged short-term memory processing. The area and latency parameters of MMN did not differ significantly between the study groups, but in cancer survivors, the area and the mean amplitude of the subsequent P3a wave were diminished. The results indicate that the discrimination process was not as easy for the survivors as for the controls. However, it seems that in cancer survivors the basic mechanism starting attention shift to novel stimuli is not impaired. CONCLUSIONS: These results indicate that it is important to carefully evaluate the proper methods for the teaching of children who are survivors of malignancies. The auditory information may not always lead to the best possible learning results.

Initial P-glycoprotein expression in childhood acute lymphoblastic leukemia: no evidence of prognostic impact in follow-up.

Treatment results in childhood acute lymphoblastic leukemia (ALL) have improved remarkably during the past 20 years, but still 25% of children cannot be permanently cured. Drug resistance is a major cause of poor outcome. One of the most investigated resistance mechanisms is the P-glycoprotein (P-gp)-mediated multiple-drug resistance (MDR). The authors prospectively analyzed P-gp using flow cytometry with monoclonal antibody JSB1 in a population-based series of 103 children with ALL treated according to intensive Nordic ALL protocols. Increased P-gp expression was detected in 55 patients (53%). With a cutoff value of 1% P-gp-positive blasts in bone marrow, no difference was found in event-free survival (EFS) or overall survival between children with low vs. increased P-gp expression. The 4-year EFS in the whole series was 77%. Patients with T-ALL had higher P-gp levels than the others, 3.6% vs. 1.0% (p = .002). P-gp expression did not correlate with the white blood cell count, age, sex, or cytogenetics. The authors conclude that the level of P-gp expression cannot be used as a tool for treatment stratification in childhood ALL.