Aino Mutka

Objectives: To investigate the prognostic significance of aspartate aminotransferase to platelet ratio index (APRI) in relation to histopathological features across the clinical course of biliary atresia (BA). Methods: In this observational cohort study, we enrolled 135 BA patients with available APRI values at Kasai portoenterostomy (KPE, n = 116) or at post‐KPE follow‐up ( n = 70; serum samples, n = 139; liver biopsies, n = 139). APRI was matched to manual scorings of liver histology, ductular reaction (DR) analysed using neural network model and fibrosis quantified from Sirius Red‐stained sections. Results: APRI was elevated at both KPE and post‐KPE follow‐up (0.92 vs. 1.2, p = 0.5), and associated with biochemical markers of cholestasis, and decreased liver function. At KPE, APRI was higher in patients failing to resolve cholestasis postoperatively (0.80 vs. 0.96, p = 0.02) and both at KPE (0.77 vs. 0.94, p = 0.06) and post‐KPE (0.7 vs. 2.1, p < 0.001) in those with subsequent need for liver transplant (LT). Across the disease course, APRI moderately predicted LT need (at KPE, HR = 1.4, p = 0.01; post‐KPE, HR = 1.2, p < 0.001). APRI correlated with DR (at KPE, R = 0.37, p < 0.001; post‐KPE, R = 0.35, p < 0.001), composed of biliary epithelium ( R = 0.34, p < 0.001; R = 0.25, p < 0.01) and parenchymal intermediate hepatocytes ( R = 0.33, p < 0.001; R = 0.43, p < 0.001) during the entire clinical course. APRI showed no correlation with quantified liver fibrosis at KPE ( R = 0.16, p = 0.13), but correlated with quantified fibrosis ( R = 0.22, p = 0.02) and Metavir staging ( R = 0.46, p < 0.001) after KPE. No association was observed with portal inflammatory cell infiltration or histological cholestasis. Conclusions: APRI reflects biliary and portal injury rather than generalised liver fibrosis and associates with poor prognosis in BA.

While KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), KRAS-mutant tumors have long been considered difficult to treat and thus, an unmet need still remains. Partly due to the lack of targeted treatments, comprehensive real-world description of NSCLC patients with KRAS mutation is still largely missing in Finland. In this study, all adult patients diagnosed with locally advanced and unresectable or metastatic NSCLC from 1 January 2018 to 31 August 2020 at the Hospital District of Helsinki and Uusimaa were first identified in this retrospective registry-based real-world study. The final cohort included only patients tested with next generation sequencing (NGS) and was stratified by the KRAS mutation status. A total of 383 patients with locally advanced and unresectable or metastatic NSCLC and with NGS testing performed were identified. Patients with KRAS mutation (KRAS G12C n = 35, other KRAS n = 74) were younger than patients without KRAS mutations, were all previous or current smokers, and had more often metastatic disease at diagnosis. Also, these patients had poorer survival, with higher age, Charlson comorbidity index (CCI) being 5 or above, and KRAS G12C being the most significant risk factors associated with poorer survival. This suggests that the patients with KRAS mutation have a more aggressive disease and/or tumors with KRAS mutation are more difficult to treat, at least without effective targeted therapies.

Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1^R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1^R189W demonstrated longer thin filaments than GFP-TMOD1^wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1^R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant’s effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.

Background: We aimed to quantify ductular reaction (DR) in biliary atresia using a neural network in relation to underlying pathophysiology and prognosis. Methods: Image-processing neural network model was applied to 259 cytokeratin-7–stained native liver biopsies of patients with biliary atresia and 43 controls. The model quantified total proportional DR (DR%) composed of portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%). The results were related to clinical data, Sirius Red–quantified liver fibrosis, serum biomarkers, and bile acids. Results: In total, 2 biliary atresia biopsies were obtained preoperatively, 116 at Kasai portoenterostomy (KPE) and 141 during post-KPE follow-up. DR% (8.3% vs. 5.9%, p=0.045) and PIH% (1.3% vs. 0.6%, p=0.004) were increased at KPE in patients remaining cholestatic postoperatively. After KPE, patients with subsequent liver transplantation or death showed an increase in DR% (7.9%–9.9%, p = 0.04) and PIH% (1.6%–2.4%, p = 0.009), whereas patients with native liver survival (NLS) showed decreasing BE% (5.5%–3.0%, p = 0.03) and persistently low PIH% (0.9% vs. 1.3%, p = 0.11). In Cox regression, high DR predicted inferior NLS both at KPE [DR% (HR = 1.05, p = 0.01), BE% (HR = 1.05, p = 0.03), and PIH% (HR = 1.13, p = 0.005)] and during follow-up [DR% (HR = 1.08, pp = 0.001), and PIH% (HR = 1.04, p = 0.008)]. DR% correlated with Sirius red–quantified liver fibrosis at KPE (R = 0.47, pR = 0.27, p = 0.004). A close association between DR% and serum bile acids was observed at follow-up (R = 0.61, pp = 0.96) or follow-up (HR = 1.01, p = 0.29). Conclusions: DR predicted NLS in different disease stages before transplantation while associating with serum bile acids after KPE.