Åse Krogh Rasmussen

Long-Term Outcome and MGMT as a Predictive Marker in 24 Patients With Atypical Pituitary Adenomas and Pituitary Carcinomas Given Treatment With Temozolomide

CONTEXT/OBJECTIVE Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited. DESIGN AND SETTING We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas. MAIN OUTCOME Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry. RESULTS Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ. CONCLUSIONS This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.

Effects of human anti-IL-1α autoantibodies on receptor binding and biological activities of IL-1

Immunoglobulin G (IgG) antibodies to interleukin 1 alpha (IL-1 alpha) are frequently found in the sera of healthy human individuals. The effects of these autoantibodies on receptor binding and biological activities of human IL-1 were tested. Using the murine T-lymphocyte line NOB-1, human thyrocytes and human foreskin fibroblasts, the antibodies competitively inhibited the biological activity of human recombinant IL-1 alpha (rIL-1 alpha). The degree of inhibition correlated with 125I-rIL-1 alpha binding to IgG in different immunoglobulin preparations and in individual sera. These antibodies also neutralized the IL-1 activity of isolated membrane fragments and lysates of human blood monocytes activated by lipopolysaccharide. In contrast, the supernatant IL-1 activity was not affected. Stronger inhibition of biological activity and cell binding of 125I-rIL-1 alpha was obtained with NOB-1 cells than with human thyrocytes. The antibodies failed to interfere with the biological activity of rIL-1 beta. It is concluded that IgG autoantibodies of IL-1 alpha in the sera of healthy humans selectively inhibit the biological activity of the soluble and membrane-associated forms of IL-1 alpha in vitro, and that the degree of biological inhibition afforded by these antibodies depends upon the target cell.

Functional and structural nerve fiber findings in heterozygote patients with Fabry disease

ABSTRACT Fabry disease is an X‐linked inherited lysosomal disorder with dysfunction of the lysosomal enzyme &agr;‐galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system. Pain and somatosensory disturbances are prominent manifestations of this disease. Until recently disease manifestations in female carriers of Fabry disease have been questioned. To explore the frequency of symptoms and the functional and structural involvement of the nervous system in female patients we examined the presence of pain, manifestations of peripheral neuropathy and nerve density in skin biopsies in 19 female patients with Fabry disease and 19 sex‐ and age‐matched controls. Diaries, quantitative sensory testing, neurophysiologic tests and skin biopsies were performed. Daily pain was present in 63% of patients, with a median VAS score of 4.0. Tactile detection threshold and pressure pain threshold were lower and cold detection thresholds increased in patients. Sensory nerve action potential amplitude and maximal sensory conduction velocity were not different, whereas there was a highly significant reduction in intraepidermal nerve fiber density. We found no correlation between pain VAS score, quantitative sensory testing and intraepidermal nerve fiber density. Our study demonstrates that careful evaluation of symptoms in female Fabry patients is important as small fiber disease manifestations are present, which in some cases is only detected by skin biopsy.

Establishing construct validity for the thyroid-specific patient reported outcome measure (ThyPRO): an initial examination

ObjectiveTo establish a reliable and valid scale structure of a patient-reported outcome measuring thyroid-specific quality of life.MethodsThe 98-item ThyPRO questionnaire was administered to patients with benign thyroid diseases at two university hospitals. Multi-trait scaling was performed, evaluating lack of convergent validity (item-own scale polyserial correlation <0.40) or lack of discriminant validity (item-other scale correlation higher than item-own scale correlation) of the hypothesized scale structure. Analyses were repeated in clinical and sociodemographic subgroups and with Pearson correlations. Reliability was estimated by Cronbach’s α, both conventionally and with polychoric correlations.ResultsIn total, 904 patients (69%) responded. Initial multitrait scaling analysis identified 25 scaling errors. Twelve items were omitted from the scale structure, and a re-analysis showed complete convergent validity and only two instances of lack of discriminant validity. Pearson correlations yielded similar results. Across all subgroups, convergent validity was complete, and discriminant validity was found in 99.2% of tests. Lack of discriminant validity was mainly between physical symptoms and psychological and disease-impact scales. Cronbach’s α was acceptable (>0.70, >0.80 with polychoric correlations) for all 13 scales.ConclusionA reliable scale structure displaying complete convergent and almost complete discriminant validity was established in general analyses and in distinct clinical subgroups of patients with benign thyroid diseases.

Distribution of α-Galactosidase A in Normal Human Kidney and Renal Accumulation and Distribution of Recombinant α-Galactosidase A in Fabry Mice

Deficiency of lysosomal α-galactosidase A (α-Gal A) in Fabry disease results in cellular accumulation of globotriaosylceramide (Gl3), often leading to end-stage renal failure. Gl3 accumulates in endothelial, glomerular, and tubular cells. Replacement therapy with recombinant α-Gal A to some extent reduces cellular accumulation of Gl3 in the kidney. This study shows high lysosomal expression of α-Gal A in all tubular segments and interstitial cells of normal human kidney. However, glomeruli and endothelial cells did not express the enzyme to any significant extent. Recombinant enzyme was taken up by rat yolk sac cells in a receptor-associated protein–inhibitive manner, and surface plasmon resonance experiments revealed binding to megalin, indicating a possible mechanism for uptake of α-Gal A in the tubular cells. After infusion into experimental animals or patients, α-Gal A was recovered in the urine, indicating glomerular filtration. Recombinant α-Gal A was also found in kidneys of normal and α-Gal A knockout mice by Western blotting and localized to endosomes and lysosomes in proximal tubules, interstitial cells, and glomerular podocytes by immunocytochemistry and autoradiography but not in vascular endothelial cells. In conclusion, intravenously administered enzyme is taken up by interstitial cells, is to some extent filtered in glomeruli, and is taken up by podocytes and reabsorbed by receptor-mediated endocytosis in proximal tubule cells, directly indicating a potential beneficial effect of enzyme replacement therapy for these cells.

The chronic autoimmune thyroiditis quality of life selenium trial (CATALYST): study protocol for a randomized controlled trial

BackgroundPatients with chronic autoimmune thyroiditis have impaired health-related quality of life. The thyroid gland has a high selenium concentration, and specific selenoprotein enzyme families are crucial to immune function, and catalyze thyroid hormone metabolism and redox processes in thyroid cells. Previous randomized controlled trials have found that selenium supplementation decreases thyroid-disease-specific antibody levels. We hypothesize that selenium might be beneficial in the treatment of chronic autoimmune thyroiditis.Methods/DesignThe CATALYST trial is an investigator-initiated randomized, blinded, multicentre clinical trial of selenium supplementation versus placebo in patients with chronic autoimmune thyroiditis. Inclusion criteria: age ≥18 years; serum thyroid peroxidase antibody level ≥100 IU/ml within the previous 12 months; treatment with levothyroxine and written informed consent. Exclusion criteria: previous diagnosis of toxic nodular goitre, Graves’ hyperthyroidism, postpartum thyroiditis, Graves’ orbitopathy; previous antithyroid drug treatment, radioiodine therapy or thyroid surgery; immune-modulatory or other medication affecting thyroid function; pregnancy, planned pregnancy or breastfeeding; allergy towards any intervention or placebo component; intake of selenium supplementation >55 μg/day; inability to read or understand Danish or lack of informed consent. The trial will include 2 × 236 participants. The experimental intervention and control groups will receive 200 μg selenium-enriched yeast or matching placebo tablets daily for 12 months. The experimental supplement will be SelenoPrecise®. The primary outcome is thyroid-related quality of life assessed by the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire. Secondary outcomes include serum thyroid peroxidase antibody concentration; serum triiodothyronine/thyroxine ratio; levothyroxine dosage; adverse reactions and serious adverse reactions and events.DiscussionIn this pragmatic trial, participating patients follow their usual treatment at their usual hospitals. In order to collect high-quality data on the clinical course and quality of life, and to minimize missing data, an elaborate trial management system has been designed. 12 months intervention duration was selected in consideration of the primary outcome, thyroid-related quality of life.Trial registrationClinicalTrials.gov ID: NCT02013479.

Small-fibre neuropathy in female Fabry patients: reduced allodynia and skin blood flow after topical capsaicin.

Abstract  Fabry disease is a rare X‐linked lysosomal storage disorder. The mutations result in a deficiency of the lysosomal enzyme α‐galactosidase A causing accumulation of glycosphingolipids in the vascular endothelial cells and many other tissues. Given the X‐linked inheritance, male patients are severely affected. Recently, attention has been drawn to female patients whether they also show signs of nerve involvement. An early sign of the disease is painful small‐fibre neuropathy. The aim of this study was to evaluate a small‐fibre dysfunction in female Fabry patients by using capsaicin applied topically. The response to capsaicin was evaluated by laser Doppler imaging. We found that the female Fabry patients had a significantly smaller increase in blood flow (p = 0.0003) after capsaicin application. The area of static mechanical allodynia and dynamic mechanical hyperalgesia was also significantly smaller (p = 0.006) in female Fabry patients. This indicates that female Fabry patients have a significant loss of small‐fibre function and demonstrates that it is possible to evaluate this by a non‐invasive method.

Thyrotropin-Releasing Hormone Stimulation Test in Patients with Pituitary Pathology

Objectives: To evaluate the value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnostic work-up of the thyroid function in patients with pituitary pathology. Methods: To compare the thyrotropin (TSH) response and the absolute and fold changes after TRH administration in 35 patients with pituitary pathology and 26 normal subjects. Results: Nine of the patients and 2 of the normal subjects had a pathological response. No difference in the thyrotropic response to TRH was found either for the actual values, or for the absolute or fold changes of TSH between the groups. Conclusion: The role of the TRH test in the evaluation of thyroid function in patients with pituitary pathology is modest. The best variables for evaluation of the presence of central hypothyroidism are still a free thyroxine estimate combined with an inappropriately low TSH.

Thyroid function in survivors of childhood acute lymphoblastic leukaemia : the significance of prophylactic cranial irradiation

OBJECTIVE Focus on long‐term side‐effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic‐pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversal.

Hair removal in hirsute women with normal testosterone levels: a randomized controlled trial of long-pulsed diode laser vs. intense pulsed light

Background  Hirsutism is a common disorder in women of reproductive age, and androgen disturbances may aggravate the condition. Limited evidence exists regarding efficacy of hair removal in this specific population and no data are available for patients with verified normal testosterone levels.