Impaired Cognitive Functioning in Patients with Tyrosinemia Type I Receiving Nitisinone

ObjectiveTo examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet.Study designWe performed a cross-sectional study to establish cognitive functioning in children with tyrosinemia type I compared with their unaffected siblings. Intelligence was measured using age-appropriate Wechsler Scales. To assess cognitive development over time, we retrieved sequential IQ scores in a single-center subset of patients. We also evaluated whether plasma phenylalanine and tyrosine levels during treatment was correlated with cognitive development.ResultsAverage total IQ score in 10 patients with tyrosinemia type I receiving nitisinone was significantly lower compared with their unaffected siblings (71 ± 13 vs 91 ± 13; P = .008). Both verbal and performance IQ subscores differed (77 ± 14 vs 95 ± 11; P < .05 and 70 ± 11 vs 87 ± 15; P < .05, respectively). Repeated IQ measurements in a single-center subset of 5 patients revealed a decline in average IQ score over time, from 96 ± 15 to 69 ± 11 (P < .001). No significant association was found between IQ score and either plasma tyrosine or phenylalanine concentration.ConclusionPatients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet

Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging

PURPOSE: Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE). METHODS: Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic muPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo. RESULTS: (68)Ga-siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by muPET with both compounds and increased with severity of the infection, correlating with abnormal CT images. CONCLUSION: (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging

Motives for choosing growth-enhancing hormone treatment in adolescents with idiopathic short stature: a questionnaire and structured interview study

Background Growth-enhancing hormone treatment is considered a possible intervention in short but otherwise healthy adolescents. Although height gain is an obvious measure for evaluating hormone treatment, this may not be the ultimate goal for the person, but rather a means to reach other goals such as the amelioration of current height-related psychosocial problems or the enhancement of future prospects in life and society. The aim of our study was to clarify the motives of adolescents and their parents when choosing to participate in a growth-enhancing trial combining growth hormone and puberty-delaying hormone treatment. Methods Participants were early pubertal adolescents (25 girls, 13 boys) aged from 11 to 13 years (mean age 11.5 years) with a height standard deviation score (SDS) ranging from -1.03 to -3.43. All had been classified as idiopathic short stature or persistent short stature born small for the gestational age (intrauterine growth retardation) on the basis of a height SDS below -2, or had a height SDS between -1 and -2 and a predicted adult height SDS below -2. The adolescents and their parents completed questionnaires and a structured interview on the presence of height-related stressors, parental worries about their child's behavior and future prospects, problems in psychosocial functioning, and treatment expectations. Questionnaire scores were compared to norms of the general Dutch population. Results The adolescents reported normal psychosocial functioning and highly positive expectations of the treatment in terms of height gain, whereas the parents reported that their children encountered some behavioral problems (being anxious/depressed, and social and attention problems) and height-related stressors (being teased and juvenilized). About 40% of the parents were worried about their children's future prospects for finding a spouse or job. The motives of the adolescents and their parents exhibited rather different profiles. The most prevalent parental worries related to the current or future functioning of their children, while a few cases were characterized by no observed motives or by psychosocial problems only reported by the adolescents themselves. Conclusion The motives for participating in a growth-enhancing hormone trial are more obvious in the parents than in the adolescents themselves. Two out of three parents report worries about the future opportunities or observe modest current psychosocial problems in their children. The adolescents want to gain height, but the motivation underlying this remains unclear. Few of the adolescents experience psychosocial problems. Our analyses revealed differences among individuals in terms of motives, which implies that in an evaluation of hormone treatment, the importance of divergent outcome variables will also differ among individuals. Effectiveness evaluations of hormone treatment to increase height and the consequential fulfillment of other goals must be awaited

PET imaging of αvβ3 integrin expression in tumours with 68Ga-labelled mono-, di- and tetrameric RGD peptides

Contains fulltext : 97195.pdf (publisher's version ) (Closed access)PURPOSE: Due to the restricted expression of alpha(v)beta(3) in tumours, alpha(v)beta(3) is considered a suitable receptor for tumour targeting. In this study the alpha(v)beta(3)-binding characteristics of (68)Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their (111)In-labelled counterparts. METHODS: A monomeric (E-c(RGDfK)), a dimeric (E-[c(RGDfK)](2)) and a tetrameric (E{E[c(RGDfK)](2)}(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (68)Ga. In vitro alpha(v)beta(3)-binding characteristics were determined in a competitive binding assay. In vivo alpha(v)beta(3)-targeting characteristics of the compounds were assessed in mice with subcutaneously growing SK-RC-52 xenografts. In addition, microPET images were acquired using a microPET/CT scanner. RESULTS: The IC(50) values for the Ga(III)-labelled DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2) and DOTA-E{E[c(RGDfK)](2)}(2) were 23.9 +/- 1.22, 8.99 +/- 1.20 and 1.74 +/- 1.18 nM, respectively, and were similar to those of the In(III)-labelled mono-, di- and tetrameric RGD peptides (26.6 +/- 1.15, 3.34 +/- 1.16 and 1.80 +/- 1.37 nM, respectively). At 2 h post-injection, tumour uptake of the (68)Ga-labelled mono-, di- and tetrameric RGD peptides (3.30 +/- 0.30, 5.24 +/- 0.27 and 7.11 +/- 0.67%ID/g, respectively) was comparable to that of their (111)In-labelled counterparts (2.70 +/- 0.29, 5.61 +/- 0.85 and 7.32 +/- 2.45%ID/g, respectively). PET scans were in line with the biodistribution data. On all PET scans, the tumour could be clearly visualised. CONCLUSION: The integrin affinity and the tumour uptake followed the order of DOTA-tetramer > DOTA-dimer > DOTA-monomer. The (68)Ga-labelled tetrameric RGD peptide has excellent characteristics for imaging of alpha(v)beta(3) expression with PET

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19:an update from the Dutch Oncology COVID-19 Consortium

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic

Synthesis of [11C]methyl magnesium iodide and its application to the introduction of [11C]-N-tert-butyl groups and [11C]-sec-alcohols

The C-11 labelled Grignard reagent methyl magnesium iodide was synthesized carrier and non-carrier added from [C-11]methyl iodide and magnesium. This new C-11-synthon was applied in the synthesis of a [C-11]-N-tert-butyl group by reaction with 2,2,3,4-tetramethyl-5-phenyl-oxazolidine and in the synthesis of C-11-sec-alcohols by reaction with benzaldehyde and 3-phenylpropionaldehyde. The radiochemical yield was 18-29% (not corrected for decay) with a synthesis time of 18 min (from [C-11]CH3I). In the case of 2,2,3,4-tetramethyl-5-phenyl-oxazolidine an one-pot synthesis was developed according to the Barbier method

The views of young adults and their parents on hormone treatment for short stature in adolescence

Aim: To examine the view of young adults and their parents on growth hormone (GH) and gonadotropin-releasing hormone agonist (GnRHa) treatment in adolescence for idiopathic short stature (ISS) or short stature born small for gestational age (SGA). Methods: Thirty young adults with ISS or SGA (18 treated, 12 untreated; age 17-23 years; 5.5 years after treatment) completed questionnaires and they and their parents were interviewed. Results: Self-perceived current psychosocial functioning did not differ between the treated and untreated young adults, but several treated participants perceived psychosocial problems during adolescence. Most treated participants would have chosen again to receive hormone treatment, but they mentioned disadvantages of the treatment and were, as well as untreated participants, reticent upon recommending hormone treatment to others. Conclusion: GH/GnRHa treatment did not appear to have adverse long-term psychosocial consequences and the participants were glad to have taken the opportunity to receive hormone treatment. However, the treated group mentioned several disadvantages of the treatment and perceived some height-related psychosocial problems during adolescence. In considering hormone treatment, the positive as well as the negative aspects of the treatment as perceived by the participants are to be taken into consideration. Copyright (c) 2008 S. Karger AG, Basel

Metabolism of a [18F]fluorine labeled progestin (21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone) in humans:A clue for future investigations

Assessment of estrogen receptors and progesterone receptors (PR) with PET may allow the determination of the hormone responsiveness of tumors without the need for multiple biopsies, and the monitoring of the effect of hormonal therapy. In spite of the favourable characteristics of 21-[F-18]fluoro-16 alpha-ethyl-19-norprogesterone ([F-18]FENP) found in preclinical studies, the compound failed to reveal the presence of PR in breast carcinomas and meningiomas. In view of the clinical significance of the PR assay in human breast cancer, it is worthwhile to explore mechanisms that are potentially involved in the inadequacy of [F-18]FENP to image PR with PET. Our present study on the in vivo metabolism of[F-18]FENP in humans demonstrates a rapid clearance and biotransformation of the compound. Results of incubation experiments suggest that the metabolic conversion of [F-18]FENP is not restricted to the liver, but also occurs in blood cells (presumably the erythrocytes) and tumors (breast carcinomas and meningiomas). The predominant metabolite of [F-18]FENP in plasma during the rapid distribution phase and in tumors is identified as 20-dihydro-[F-18]FENP. The conversion of [F-18]FENP to its 20 alpha- or 20 beta-hydroxy metabolite has a deleterious effect on the binding affinity for PR. Our findings do not justify a conclusion as to the extent of in vivo extrahepatic biotransformation of [F-18]FENP, or its significance in the ineffectiveness of [F-18]FENP as an imaging agent for PR. On the other hand, the ability of breast carcinomas and meningiomas to metabolize [F-18]FENP avidly appears to preclude selective imaging of PR in these tumors during the time of a PET examination. It is imperative to evaluate the metabolic stability of a [F-18]fluorine labeled progestin in an early stage of future screening procedures