First Results from the Prospective German Registry for Childhood Glaucoma: Phenotype–Genotype Association

Childhood glaucoma is a heterogeneous disease and can be associated with various genetic alterations. The aim of this study was to report first results of the phenotype–genotype relationship in a German childhood glaucoma cohort. Forty-nine eyes of 29 children diagnosed with childhood glaucoma were prospectively included in the registry. Besides medical history, non-genetic risk factor anamnesis and examination results, genetic examination report was obtained (23 cases). DNA from peripheral blood or buccal swab was used for molecular genetic analysis using a specific glaucoma gene panel. Primary endpoint was the distribution of causative genetic mutations and associated disorders. Median age was 1.8 (IQR 0.6; 3.8) years, 64% participants were female. Secondary childhood glaucoma (55%) was more common than primary childhood glaucoma (41%). In 14%, parental consanguinity was indicated. A mutation was found in all these cases, which makes consanguinity an important risk factor for genetic causes in childhood glaucoma. CYP1B1 (30%) and TEK (10%) mutations were found in primary childhood glaucoma patients. In secondary childhood glaucoma cases, alterations in CYP1B1 (25%), SOX11 (13%), FOXC1 (13%), GJA8 (13%) and LTBP2 (13%) were detected. Congenital cataract was associated with variants in FYCO1 and CRYBB3 (25% each), and one case of primary megalocornea with a CHRDL1 aberration. Novel variants of causative genetic mutations were found. Distribution of childhood glaucoma types and causative genes was comparable to previous investigated cohorts. This is the first prospective study using standardized forms to determine phenotypes and non-genetic factors in childhood glaucoma with the aim to evaluate their association with genotypes in childhood glaucoma.

Adjusted Comparison of Outcomes between Patients from CARTITUDE-1 versus Multiple Myeloma Patients with Prior Exposure to PI, Imid and Anti-CD-38 from a German Registry

Ciltacabtagene autoleucel (cilta-cel) is a Chimeric antigen receptor T-cell therapy with the potential for long-term disease control in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM). As cilta-cel was assessed in the single-arm CARTITUDE-1 clinical trial, we used an external cohort of patients from the Therapie Monitor registry fulfilling the CARTITUDE-1 inclusion criteria to evaluate the effectiveness of cilta-cel for overall survival (OS) and time to next treatment (TTNT) vs. real-world clinical practice. Individual patient data allowed us to adjust the comparisons between both cohorts, using the inverse probability of treatment weighting (IPW; average treatment effect in the treated population (ATT) and overlap population (ATO) weights) and multivariable Cox proportional hazards regression. Outcomes were compared in intention-to-treat (HR, IPW-ATT: TTNT: 0.13 (95% CI: 0.07, 0.24); OS: 0.14 (95% CI: 0.07, 0.25); IPW-ATO: TTNT: 0.24 (95% CI: 0.12, 0.49); OS: 0.26 (95% CI: 0.13, 0.54)) and modified intention-to-treat (HR, IPW-ATT: TTNT: 0.24 (95% CI: 0.09, 0.67); OS: 0.26 (95% CI: 0.08, 0.84); IPW-ATO: TTNT: 0.26 (95% CI: 0.11, 0.59); OS: 0.31 (95% CI: 0.12, 0.79)) populations. All the comparisons were statistically significant in favor of cilta-cel. These results highlight cilta-cel’s potential as a novel, effective treatment to address unmet needs in patients with RRMM.

Multiple Tumorous Lesions of The Pituitary Gland

Multiple tumorous lesions with an adenoma make up 1.4 % (232 cases) in the large collection of the German Registry of Pituitary Tumors. 2.0% of all PitNETs are associated with a second lesion. Within the selected cases synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17,3%, PANCH cases for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2% and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years with a standard deviation of 18.5 years. 55.3% of the patients were female and 44.7% were male. From 1990 to 2018 there was a continuous increase in the number of multiple tumorous lesions.

Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”)

Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry “HypoDok” for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of l-thyroxine (l-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cutoffs predicting TCH by screening TSH concentrations and l-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cutoff screening TSH concentration was 73 mU/L. The cutoff daily l-T4 dosage at 1 year was 3.1 μg/kg (90% sensitivity, 63% specificity; 36 μg/day) and at 2 years of age 2.95 μg/kg (91% sensitivity, 59% specificity; 40 μg/day). At 2 years of age, specificity (71%) increased when both of these parameters were considered together.Conclusion: The decision to continue or cease l-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual l-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided; and affected families reassured. What is Known:• The course of congenital primary hypothyroidism may be transient, causing potential overtreatment.• The dose ofl-thyroxine at 1 or 2 years of age may predict a transient course of primary congenital hypothyroidism. What is New:• TSH screening concentration andl-thyroxine dosages at 1 and 2 years of age represent reliable predictors for transient congenital primary hypothyroidism with higher sensitivity and specificity when considered together in order to select eligible patients who qualify for treatment withdrawal.

German Registry for Cardiac Operations and Interventions in Patients with Congenital Heart Disease: Report 2020—Comprehensive Data from 6 Years of Experience

Background Based on a quality assurance initiative of the German Society for Thoracic and Cardiovascular Surgery (DGTHG) and the German Society for Pediatric Cardiology and Congenital Heart Defects (DGPK), a voluntary registry was founded for assessment of treatment and outcomes of patients with congenital heart disease in Germany. This evaluation by the German Registry for cardiac operations and interventions in patients with congenital heart disease reports the data and the outcome over a 6-year period in patients undergoing invasive treatment. Methods This real-world database collects clinical characteristics, in-hospital complications, and medium-term outcome of patients who underwent cardiac surgical and interventional procedures within the prospective, all-comers registry. Patients were followed-up for up to 90 days. Results In the period from 2013 to 2018, a total of 35,730 patients, 39,875 cases, respectively 46,700 procedures were included at up to 31 German institutions. The cases could be subcategorized according to the treatment intention into 21,027 (52.7%) isolated operations, 17,259 (43.3%) isolated interventions, and 1,589 (4.0%) with multiple procedures. Of these, 4,708 (11.8%) were performed in neonates, 10,047 (25.2%) in infants, 19,351 (48.5%) in children of 1 to 18 years, and 5,769 (14.5%) in adults. Also, 15,845 (33.9%) cases could be allocated to so-called index procedures which underwent a more detailed evaluation to enable meaningful comparability. The mean unadjusted in-hospital mortality of all cases in our registry ranged from 0.3% in patients with isolated interventions and 2.0% in patients with surgical procedures up to 9.1% in patients undergoing multiple procedures. Conclusion This annually updated registry of both scientific societies represents voluntary public reporting by accumulating actual information for surgical and interventional procedures in patients with congenital heart disease (CHD) in Germany. It describes advancements in cardiac medicine and is a basis for internal and external quality assurance for all participating institutions. In addition, the registry demonstrates that in Germany, both interventional and surgical procedures for treatment of CHD are offered with high medical quality.

Predictors of Transient Congenital Primary Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "HypoDok")

Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy we analysed the German registry "HypoDok" for infants with CH, which oversees 1,625 patients from 49 participating centres in Germany and Austria from 1997 until today. 357 Patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH n=24) or continuation (PCH n=333) of L-Thyroxine (L-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cut-offs predicting TCH by screening TSH concentrations and L-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cut-off screening TSH concentration was 73 mU/L. The cut-off daily L-T4 dosage at 1 year was 3.1 µg/kg (90% sensitivity, 63% specificity; 36 µg/d) and at 2 years of age 2.95 µg/kg (91% sensitivity, 59% specificity; 40 µg/d). At 2 years of age, specificity (71%) increased when these both parameters were considered together. Conclusion: The decision to continue or cease L-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual L-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided, and affected families reassured.

Standardisierte histomorphologische Aufarbeitung von Peritonealbiopsien im Rahmen des Deutschen Peritonealbiopsieregisters (GRIP, German Registry In PD)

Zusammenfassung Das Peritoneum stellt als seröse Haut, die mit ihrem viszeralen und parietalen Anteil den Bauchraum auskleidet, ein interessantes Organ dar, welches bei der sog. Peritoneal- oder Bauchfelldialyse (PD) klinische Beachtung findet. Bei diesem Nierenersatzverfahren wird die Semipermeabilität des Peritoneums genutzt, um mittels unterschiedlich osmolarer Dialyseflüssigkeiten die sog. harnpflichtigen Substanzen aus dem Körper zu eliminieren. Dies ist insbesondere bei jungen Patienten eine ideales Nierenersatzverfahren und funktioniert in der Regel zumindest einige Zeit sehr gut. Vorschäden des Peritoneums durch die Grunderkrankung der chronischen Niereninsuffizienz oder assoziierte Komorbiditäten sowie v. a. entzündliche Veränderungen während der PD führen zu einem morphologischen Umbau des Peritoneums mit der Konsequenz des Verlusts der Filtereigenschaften, sodass die PD beendet und auf ein anderes Nierenersatzverfahren gewechselt werden muss. Die Kenntnis des morphologischen Umbaus des Peritoneums sowie möglicher begünstigender Faktoren, zu denen es derzeit noch zu wenige Daten gibt, ist wichtig für die Therapie und Prognose der Patienten, die mit PD behandelt werden. Aus diesem Grund wurde vor einigen Jahren das Deutsche Peritonealbiopsieregister (GRIP, German Registry In PD) gegründet, das mittlerweile knapp 1700 Biopsate umfasst und an diesen standardisiert klinische und histomorphologische Parameter erhebt und dokumentiert.