It is well known that thyroid dysfunction increases with age. This study is aimed to determine reference intervals, in males and females, suitable for thyroid disease exploration during adult life using routinely collected serum thyrotropin (TSH) data in a tertiary center from 2007 to 2018. Over 11 years, 295,775 TSH levels were measured in a single lab. Among the 156,025 TSH results available for analysis, 90,538 values were from female subjects, 82,019 were from patients aged >60 years and 26,825 were from patients aged >80 years. By using an indirect approach, we determined reference values of TSH adapted to age and sex, and we then evaluated the proportion of patients who would have been reclassified with these reference values. The median TSH ranged from 1.2-1.4 mUI/L during the study period. The upper limit of reference range of TSH increased with age; in females the median to 97.5th percentile values increased continuously from the age of 30 years to the oldest age group. Using new calculated reference values in patients with TSH above the conventional upper-limit reference value (4 mUI/L), the proportion of results reclassified as within the reference interval among patients aged >60 years ranged, according to age group, from 50.5% to 65.1% of females and from 33.0% to 37.7% of males. The use of TSH age-specific and sex-specific upper-limit reference values led to the reclassification of a great number of samples, notably among women. This suggests that age-specific TSH upper-limit reference intervals in daily practice should be used in order to avoid misclassification.

Purpose: Measurement of prolactin in clinical laboratories is an important part of the management of patients with pituitary adenoma. Prolactin is known to be sensitive to the high-dose hook effect, in the presence of extremely high concentrations. This interference is mentioned in most recent articles discussing prolactin assay and management of pituitary prolactin adenomas [1][2][3]. The objective of our study was to evaluate if the mention of the high dose hook effect is relevant in actual practice.Methods: A serum from a patient with giant macroprolactinoma was assayed by using all the different reagents available in France in 2020 on native serum and after dilution. Technical inserts from manufacturers were reviewed to study information of analytical principles, numbers of steps, and mention to high dose hook effect if necessary.Results: Fourteen reagents were studied; all were two-site immunometric assays, mostly in 1 step (11/14). One tested reagent was sensitive to high dose hook effect leading to falsely low prolactin concentration when measured on native serum. Conclusion:The high-dose hook effect still exists. The evolution of reagents may lead to new reagents sensitive to this effect in the future. We therefore advise that this hook effect be mentioned in the recommendations.

The recent meta-analysis by Pang et al 1 exploring the effect of L-thyroxine administration before breakfast versus at bedtime concludes that either approach results in similar outcomes. This conclusion stands in stark contrast to another excellent study done examining the timing issues of Prebreakfast vs. with breakfast or at Bedtime. 2 Bach-Huynh TG et al clearly demonstrate the superiority of prebreakfast LT4 ingestion when taken 60 minutes before the first meal of the day with significantly lower TSH values (mean 1.06 ± 1.23 mIU/L pre and 2.19 ± 2.66 at bedtime, P < .001). Additionally, they observe greater variability of TSH outcomes when the LT4 is taken at bedtime where 35% of TSH values were more than 1 mIU/L greater than the 60-minute fasting values and only 63% of TSH values were <1 mIU/L different. It seems that this excellent paper was not included in the meta-analysis. In fact, it seems that all of the prebreakfast studies included were timed to be 30 minutes of separation from food if this information was available. So it is misleading to assume that a 60-minute separation period is of no value. It may be that the 30-minute separation is equivalent to bedtime dosing and both are inferior to a 60-minute wait. As such, I believe that a fasting state of 60 minutes is the most reproducible and reliable approach to LT4 ingestion and council my patients in this manner for the best outcomes we can achieve.

No abstract

<b><i>Introduction:</i></b> Maternal TSH receptor antibodies (TRAbs) can cross the placenta and affect fetal and neonatal thyroid function. Maternal TSH receptor-blocking antibodies (TBAbs) are a rare cause of congenital hypothyroidism. <b><i>Case Report:</i></b> Following the discovery of a highly elevated TSH on her neonatal screening test, a 10-day-old girl with no familial history of thyroid disorder was referred to the pediatric endocrinology unit. Hypothyroidism was confirmed with a highly elevated TSH (817 mIU/L, reference range 0.4–3.1) and very low levels of FT4 (1.8 pmol/L, reference range 12–22). Anti-TPO antibodies were at 81 IU/mL (reference range &#x3c;34), TRAbs at 1.7 IU/L (reference range &#x3c;1.75), and thyroglobulin at 9.4 µg/L (reference range 3.5–77). The thyroid appeared normal on ultrasonography, and no radioiodine uptake was seen on the scintigraphy after the perchlorate discharge test. Concomitantly, a severe maternal hypothyroidism was discovered (TSH 224 mIU/L). The maternal ultrasound appeared normal, anti-TPO antibodies were moderately elevated, and TRAbs were at 3.2 IU/L. TBAbs activity was measured in the mother and her daughter, and a very high and similar blocking activity was observed in both patients (TBAbs 89%, reference range &#x3c;10%). L-thyroxine treatment was introduced in the newborn and was successfully discontinued at 6.5 months of age, as the TBAbs activity decreased. <b><i>Conclusion:</i></b> We report herein a case of transient congenital hypothyroidism with a normal neonatal TRAbs level. In case of maternal TBAbs, similar activity of maternal TBAbs must be expected in the neonate, independently of the neonatal level of TRAbs.

Introduction Il n’existe que peu de données concernant la présentation, l’incidence, la sévérité et l’évolution du COVID-19 chez les patients en hémodialyse chronique. Description Une étude observationelle prospective a été réalisée dans huit centres d’hémodialyse en Alsace, France, afin d’identifier les caractéristiques cliniques des patients en hémodialyse chronique atteints du COVID-19 et d’établir les déterminants associés au risque de décès. Méthodes Tous les patients en hémodialyse chronique testés positif pour le COVID-19 entre le 5 mars et le 28 avril 2020 ont été inclus. Les données collectées incluaient les caractéristiques du patients, la cliniques au diagnostic, les résultats biologiques, le traitement et l’évolution. Résultats Parmi les 1346 patients en hémodialyse, 123 ont été testés positif pour le COVID-19. Ils étaient âgés (77 [66-83] ans), avec un nombre important de comorbidités (3,2 ± 1,6 par patients). Les symptômes étaient jugés compatibles chez 63 % des patients. L’asthénie (77 %), la diarrhée (34 %) et l’anorexie (32 %) étaient fréquentes au diagnostic. Le délai moyen entre le début des symptômes et le diagnostic, la mort ou la guérison complète étaient respectivement de 2 [0-5], 7 [4-11] et 32 [26,5-35] jours. 23 % des patients ont bénéficié d’un traitement par lopinavir/ritonavir, hydroxychloroquine et/ou corticoïdes. La CRP et le compte des lymphocytes au diagnostic étaient respectivement de 55 (25-106) mg/L et 690 (450-960) Ly/μl. Le taux de létalité était de 24 % et les déterminants associés avec le risque de décès étaient la température corporelle (HR 1,96 ; 95 %CI 1,11-3,44 ; p = 0,02) et la CRP au diagnostic (HR 1,01 ; 95 %CI 1,005–1,017 ; p < 0,0001) ( Fig. 1 ). Conclusion Les patients en hémodialyse chronique s’avèrent être à haut risque de développer le COVID-19 avec un taux de mortalité élevé. La forme initiale de la maladie est le plus souvent sévère mais la présentation clinique est fréquemment atypique. Un taux de CRP élevé est hautement associé au risque de décès.

No abstract

Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal accumulation of malignant plasma cells in the bone marrow. CD38 is highly expressed on MM cells, and antibodies targeting CD38 (such as Isatuximab and Daratumumab) induce MM cell killing though several mechanisms, particularly by NK cell-mediated antibody dependent cellular cytotoxicity (ADCC). However, NK cells also express CD38 and treatment with anti-CD38 antibodies results in a rapid decrease of NK cells presumably due to fratricide, which may potentially limit NK cell mediated ADCC and reduce the efficacy of anti-CD38 antibody treatment. NK cells lacking CD38 in combination with Daratumumab have been shown to be resistant to NK cell fratricide and have improved ADCC. Here, we investigated the effect of knocking out CD38 in K-NK cells (CD38KO K-NK) in combination with Isatuximab. Peripheral blood NK cells were isolated from healthy donors and expanded using Kiadis PM21 particle technology (Oyer et al, Cytotherapy 2016) to produce highly activated K-NK cells. To produce CD38KO K-NK cells, CRISPR gene editing was applied during NK cell expansion by electroporating with Cas9/RNP complexes targeting CD38, and successful deletion of CD38 was confirmed by flow cytometry analysis. Analysis of key NK cell receptors by flow cytometry evidenced very similar receptor profiles between WT and CD38KO K-NK cells, suggesting that CD38 deletion does not affect the potent activation state of the K-NK cells. Importantly, CD38KO K-NK cells were found to be resistant to Isatuximab-induced fratricide. The cytotoxic activity of CD38KO K-NK cells in combination with Isatuximab against LP-1 and H929 MM cell lines was also measured. Calcein release assay and Incucyte based analysis revealed that cytotoxicity of CD38KO K-NK cells is enhanced in presence of Isatuximab, and that CD38KO K-NK cells are more cytotoxic than WT when combined with Isatuximab. Furthermore, the effect of Isatuximab/CD38KO K-NK cells combination also in association with SAR444245 (also termed THOR-707; Ptacin et al, Nat Commun 2021), an engineered non-α binding IL-2 that promotes NK cell activation and proliferation, was tested. Cytotoxicity of WT or CD38KO NK cells is enhanced in the presence of SAR444245. Indeed, addition of SAR444245 was found to further enhance the cytotoxic activity of CD38KO K-NK cells against LP-1 MM cells when combined with Isatuximab, resulting in an overall superior and sustained cytotoxicity. These data suggest that deletion of CD38 mitigates NK cell fratricide and improves Isatuximab-mediated ADCC against MM cells, and provide evidence for the therapeutic potential of the triple combination CD38KO NK cells, Isatuximab and SAR444245 in the setting of MM. Citation Format: Marco Meloni, Pauline Perrin, Erik Slinger, Chrissta Maracle, Alain Fournier, Nicole Acuff, Jill Mooney, Robert Y. Igarashi, Angela Virone-Oddos, Marielle Chiron. CD38KO K-NK cells prevent NK cell fratricide effect and improve isatuximab-mediated cytotoxicity against multiple myeloma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4209.