Citations

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

538 Background: In biliary tract cancer (BTC), TP53 is the most commonly altered gene and may co-occur with KRAS alteration. The presence of a co-alterations in of TP53 and KRAS is associated with poor prognosis in many cancers. In patients (pts) with advanced BTC, the prognostic implications of such co-alterations have not been fully investigated. Methods: This is a pooled analysis of SCRUM-Japan GOZILA and MONSTAR-SCREEN-1 and -2 studies. Genomic profiling was conducted with Guardant360 for plasma in GOZILA, FoundationOne CDx for tissue and FoundationOne Liquid CDx for plasma in MONSTAR-SCREEN-1, and CARIS MI Profile for tissue in MONSTAR-SCREEN-2. Pts with advanced BTC receiving systemic therapy were included in this study. Results: Among 636 pts with advanced BTC, 85 had TP53/KRAS co-alteration, 293 had TP53, 44 had KRAS, and 214 had neither KRAS nor TP53 alteration (WT/WT). Tumors with TP53 alteration had significantly higher level of tumor mutation burden (TMB) compared to the other groups (3.8 mut/Mb for TP53/KRAS, 5.0 mut/Mb for TP53, 2.8 mut/Mb for KRAS, and 2.5 mut/Mb for WT/WT, respectively, P<0.001). In addition, the frequency of microsatellite instability-high (MSI-High) in the TP53/KRAS group (11.0%) was significantly higher compared to the TP53 group (3.1%, P<0.05), and the WT/WT group (0.6%, P<0.001), respectively. The objective response rate of first-line therapy in the TP53/KRAS group (8.2%) was significantly lower than in the other groups (20.8% for TP53, 23.3% for KRAS, and 19.7% for WT/WT groups, P=0.035). There was no pts treated with durvalumab plus gemcitabine and cisplatin. Two pts with TP53/KRAS alteration and MSI-High received pembrolizumab monotherapy, and partial response was achieved with a progression-free survival of 9.4 and 22.0 months. The median overall survival (OS) for pts treated with first-line therapy of the TP53/KRAS, KRAS, TP53, and WT/WT groups were 13.6 (95% confidence interval [CI], 11.5-15.5), 14.3 (95%CI, 9.7-25.9), 18.8 (95%CI, 16.9-20.6), and 22.7 months (95%CI, 20.4-25.9), respectively. Multivariate analysis identified TP53/KRAS alteration (hazard ratio [HR] 2.14, 95%CI 1.43-3.22, P<0.001), number of detected variants (≥2) (HR 1.50, 95%CI 1.04-2.16, P=0.029), locally advanced (HR 1.72, 95%CI 1.05-2.83, P=0.033), and metastatic status (HR 1.78, 95%CI 1.39-2.28, P<0.001) as independent prognostic factors for shorter OS. Conclusions: Patients with advanced BTC with co-occurring TP53/KRAS alterations have worse prognosis. Interestingly, the presence of these co-alterations was associated with a higher likelihood of MSI-High phenotype.

544 Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited treatment options. The prevalence of HER2 amplification in BTC has been reported to be 5-20%, and clinical trials suggested the clinical benefit of HER2-targeted treatment in this disease subpopulation. In a global collaboration, we investigated the comprehensive clinico-molecular characterization as well as the efficacy of anti-HER2 therapy in HER2-amplified BTC. Methods: Patients with advanced BTC who received systemic therapy were included from the GOZILA and MONSTAR studies in Japan and from the COLOMATE trial in the US. Genomic alterations were detected by tissue next-generation sequencing (NGS), including FoundationOne CDx and TempuslxT, and plasma circulating tumor DNA NGS including Guardant360 and FoundationOne Liquid CDx. The clinico-molecular characteristics were evaluated in an exploratory cohort comprised of patients from Japan, whereas the efficacy of anti-HER2 therapy was assessed in a biomarker selected cohort with patients from both Japan and the US. Results: Of 439 patients included in the exploratory cohort, 43 (10%) had HER2 amplification. BTC with primary tumor location in the gallbladder accounted for 58% of primary sites of patients with HER2 amplification. TP53 mutation (84% vs 61%, p=0.003) and BRAF amplification (9% vs 2%, p=0.030) were significantly more frequent in patients with HER2 amplification compared to those without, and no KRAS mutation co-occurred with HER2 amplification. There was no significant difference in overall survival (OS) between patients with and without HER2 amplification (17.7 months [M] vs 16.9 M, hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65-1.40, p=0.799). Of 58 patients with HER2-amplified BTC included in the biomarker selected cohort (43 Japan, 15 US), 27 (47%) received anti-HER2 therapy. The median OS of patients treated with anti-HER2 therapy was significantly longer than that of patients who did not receive anti-HER2 therapy (24.3 M vs. 12.1 M, HR 0.43, 95% CI 0.23-0.82, p=0.011). Multivariate analysis also identified anti-HER2 therapy as an independent prognostic factor for OS (HR 0.42, 95% CI 0.20-0.85, p=0.015). Conclusions: HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.

Evaluation of rapidly progressive dementia (RPD) is usually challenging. In most cases, patients progress to dementia in weeks to months, and the differential diagnosis is broad. In this case, a woman in her 60s presented with a 1-month history of episodic vertigo, cognitive decline, ataxia and myoclonus. Cerebrospinal fluid total tau was markedly elevated, which was helpful in establishing the diagnosis and discussing prognosis/end-of-life measures with the patient’s family. This case summarises a stepwise diagnostic approach for patients with RPD and highlights recent literature on biomarkers of Creutzfeldt-Jakob disease and autoimmune encephalitis.

Abstract Context Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. Objective (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. Methods (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. Results (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody–positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from –10.8% to –21.8% for TSH and –1.2% to –13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. Conclusion We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Background: Giant perivascular spaces (PVSs) are very rare condition in the brain and can be associated with neurological symptoms. It often enlarges and causes obstructive hydrocephalus which requires surgical intervention. However, the growth velocity has never been investigated. Case Description: Here, we report a woman in her early eighties with giant PVSs eventually followed up 17 years. She presented with dizziness and mild headache for a week and her neurological examination showed no abnormality. Her brain magnetic resonance imaging (MRI) showed a multiple cystic lesion, 28 mm in maximum diameter as a whole, in the left mesencephalothalamic region. There were no solid part, rim enhancement, or perilesional intensity change suggesting edema or gliosis. Smaller PVSs were also seen in bilateral-hippocampi, basal ganglia, white matter, and left frontal operculum. Retrospectively, five MRI studies over 17 years were analyzed using a 3-D volumetric software and found a very slow growth of the lesion, from 6.54 ml to 9.83 ml indicating gain of 0.1752 ml (2.68%) per year. Conclusion: This is the first report verifying a gradual enlargement of giant PVSs in a natural course. The prospective 3-D volumetric analysis on PVSs may elucidate the true nature of these lesions.