| 1. |
- Maghnie, M., et al.
(författare)
-
Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort
- 2022
-
Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:12, s. 3287-3301
-
Tidskriftsartikel (refereegranskat)abstract
- Context The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. Objective This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Methods Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (>= 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. Results The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Conclusion Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.
|
|
| 2. |
- Donaldson, M., et al.
(författare)
-
Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy
- 2019
-
Ingår i: Hormone Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826. ; 91:3, s. 153-163
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Most girls with Turner syndrome (TS) require pubertal induction with estrogen, followed by long term replacement. However, no adequately powered prospective studies comparing transdermal with oral 17 beta-estradiol administration exist. This reflects the difficulty of securing funding to study a rare condition with relatively low morbidity/mortality when competing against conditions such as cancer and vascular disease. Protocol Consensus: The TS Working Group of the European Society for Paediatric Endocrinology (ESPE) has agreed to both a 3-year oral and a 3-year transdermal regimen for pubertal induction. Prerequisites include suitable 17 beta-estradiol tablets and matrix patches to allow the delivery of incremental doses based on body weight. Study Proposal: An international prospective cohort study with single centre analysis is proposed in which clinicians and families are invited to choose either of the agreed regimens, usually starting at 11 years. We hypothesise that pubertal induction with transdermal estradiol will result in better outcomes for some key parameters. The primary outcome measure chosen is height gain during the induction period. Analysis: Assessment of the demographics and drop-out rates of patients choosing either oral or transdermal preparations; and appropriate analysis of outcomes including pubertal height gain, final height, liver enzyme and lipid profile, adherence/acceptability, cardiovascular health, including systolic and diastolic blood pressure and aortic root diameter and bone health. Conclusion: The proposed model of prospective data collection according to internationally agreed protocols aims to break the current impasse in obtaining evidence-based management for TS and could be applied to other rare paediatric endocrine conditions. (C) 2019 S. Karger AG, Basel
|
|
| 3. |
- Nilsson, M. P., et al.
(författare)
-
Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer
- 2023
-
Ingår i: Acta Oncologica. - 0284-186X. ; 62:8, s. 897-906
-
Tidskriftsartikel (refereegranskat)abstract
- Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.
|
|
| 4. |
- Wit, J M., et al.
(författare)
-
Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models
- 2013
-
Ingår i: Hormone Research in Paediatrics. - : Karger. - 1663-2818 .- 1663-2826. ; 79:5, s. 257-270
-
Forskningsöversikt (refereegranskat)abstract
- The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.
|
|
| 5. |
|
|
| 6. |
- Hillman, M., et al.
(författare)
-
Skim milk powder with high content of Maillard reaction products affect weight gain, organ development and intestinal inflammation in early life in rats
- 2019
-
Ingår i: Food and Chemical Toxicology. - : Elsevier BV. - 0278-6915. ; 125, s. 78-84
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The intestinal tract is important for development of immune tolerance and disturbances are suggested to trigger autoimmune disorders. The aim of this study was to explore the effect of Maillard products in skim milk powder obtained after long storage, compared to fresh skim milk powder. Methods: Young rats were weaned onto a diet based on skim milk powder with high concentration of Maillard products (HM-SM, n = 18) or low (C-SM, n = 18) for one week or four weeks. Weekly body weight and feed consumption were noted. At the end, organ weights, intestinal histology, permeability and inflammatory cytokines were evaluated. Results: Rats fed with HM-SM had after one week, 15% less weight gain than controls, despite equal feed intake. After one week thymus and spleen were smaller, intestinal mucosa thickness was increased and acute inflammatory cytokines (IL-17, IL-1β, MCP-1) were elevated. After four weeks, cytokines associated with chronic intestinal inflammation (fractalkine, IP-10, leptin, LIX, MIP-2, RANTES and VEGF) were increased in rats fed with HM-SM compared to C-SM. Conclusion: High content of Maillard products in stored milk powder caused an intestinal inflammation. Whether this is relevant for tolerance development and future autoimmune diseases remains to be explored.
|
|
| 7. |
- Sjöblom, K, et al.
(författare)
-
Patient evaluation of a new injection pen for growth hormone treatment in children and adults.
- 1995
-
Ingår i: Acta paediatrica (Oslo, Norway : 1992). Supplement. - : Wiley. - 0803-5326 .- 0803-5253 .- 1651-2227. ; 411, s. 63-5
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate patients' perception and acceptance of a new multi-dose injection device (Genotropin Pen) for recombinant growth hormone (GH) supplied in a two-chamber cartridge. The pen is combined with a very thin needle (B-D Microfine + (29 G) and meets future demands when dosing of GH will be changed from International Units (IU) to milligrams (mg). A total of 39 children receiving GH treatment (East Hospital, Gothenburg and St Bartholomew's Hospital, London), aged between 7 and 17 years, and 39 GH-treated adults (Sahlgrenska Hospital, Gothenburg and Karolinska Hospital, Stockholm), aged between 20 and 68 years, participated in the study. The daily dose ranged from 0.3 mg to 2.6 mg. The injections were given subcutaneously, once daily, and most of the patients used the thigh as an injection site. After a trial period of 2 weeks, injection technique, pain, fear of injection and convenience of the Genotropin Pen were compared with the experience with the prestudy device (Genotropin KabiPen 16, 16(8) or 36) by questionnaire. A total of 95% of the patients preferred the Genotropin Pen to the prestudy device for the following reasons: a greater certainty of correct dosing with the digital display; the possibility of correcting the set dose; the lock function of the injection button when injection is complete; more comfortable to hold due to the design and the plastic material; and reduced pain when injecting due to the thinner needles. Four patients (5%) preferred the prestudy device KabiPen as they considered this to be 'good enough'. Thus, the Genotropin Pen is a convenient injection device and most patients prefer it to the KabiPen.
|
|
| 8. |
- Dekempeneer, Y., et al.
(författare)
-
Labeling of Anti-HER2 Nanobodies with Astatine-211: Optimization and the Effect of Different Coupling Reagents on Their in Vivo Behavior
- 2019
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 16:8, s. 3524-3533
-
Tidskriftsartikel (refereegranskat)abstract
- The use of nanobodies (Nbs) as vehicles in targeted alpha therapy (TAT) has gained great interest because of their excellent properties. They combine high in vivo affinity and specificity of binding with fast kinetics. This research investigates a novel targeted therapy that combines the alpha-particle emitter astatine-211 (At-211) and the anti-HER2 Nb 2Rs15d to selectively target HER2+ cancer cells. Two distinctive radiochemical methodologies are investigated using three different coupling reagents. The first method uses the coupling reagents, N-succinimidyl 4-(1,2-bis-tert-butoxycarbonyl)guanidinomethyl-3-(trimethylstannyl)benzo ate (Boc(2)-SGMTB) and N-succinimidyl-3-(trimethylstannyl)-benzoate (m-MeATE), which are both directed to amino groups on the Nb, resulting in random conjugation. The second method aims at obtaining a homogeneous tracer population, via a site-specific conjugation of the N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide (MSB) reagent onto the carboxyl-terminal cysteine of the Nb. The resulting radioconjugates are evaluated in vitro and in vivo. 2Rs15d is labeled with At-211 using Boc(2)-SGMTB, m-MeATE, and MSB. After astatination and purification, the binding specificity of the radioconjugates is validated on HER2+ cells, followed by an in vivo biodistribution assessment in SKOV-3 xenografted mice. alpha-camera imaging is performed to determine uptake and activity distribution in kidneys/tumors. 2Rs15d astatination resulted in a high radiochemical purity >95% for all radioconjugates. The biodistribution studies of all radioconjugates revealed comparable tumor uptake (higher than 8% ID/g at 1 h). [At-211]SAGMB-2Rs15d showed minor uptake in normal tissues. Only in the kidneys, a higher uptake was measured after 1 h, but decreased rapidly after 3 h. Astatinated Nbs consisting of m-MeATE or MSB reagents revealed elevated uptake in lungs and stomach, indicating the presence of released At-211. alpha-Camera imaging of tumors revealed a homogeneous activity distribution. The radioactivity in the kidneys was initially concentrated in the renal cortex, while after 3 h most radioactivity was measured in the medulla, confirming the fast washout into urine. Changing the reagents for Nb astatination resulted in different in vivo biodistribution profiles, while keeping the targeting moiety identical. Boc(2)-SGMTB is the preferred reagent for Nb astatination because of its high tumor uptake, its low background signals, and its fast renal excretion. We envision [At-211]SAGMB-2Rs15d to be a promising therapeutic agent for TAT and aim toward efficacy evaluation.
|
|
| 9. |
|
|
| 10. |
- Dauber, A., et al.
(författare)
-
A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness
- 2020
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:10
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. OBJECTIVE: To identify genetic variants associated with GH responsiveness. DESIGN: Genome-wide association study (GWAS). SETTING: Cohorts from multiple academic centers and a clinical trial. PATIENTS: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. INTERVENTION: Association of more than 2 million variants was tested. MAIN OUTCOME MEASURES: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. RESULTS: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. CONCLUSIONS: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height. © Endocrine Society 2020.
|
|
