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Background The aim was to compare the prognostic accuracy of cross-sectional imaging of the 7th and 8th editions of the American Joint Committee on Cancer(AJCC) staging system for perihilar cholangiocarcinoma(PHC). Methods All patients with PHC between 2002 and 2014 were included. Imaging at the time of presentation was reassessed and clinical tumor–node–metastasis (cTNM) stage was determined according to the 7th and 8th editions of the AJCC staging system. Comparison of the prognostic accuracy was performed using the concordance index (c-index). Results A total of 248 PHC patients were included;45 patients(18.1%) underwent a curative-intent resection, whereas 203 patients(81.9%) did not because they were unfit for surgery or were diagnosed with locally advanced or metastatic disease during workup. Prognostic accuracy was comparable between the 7th and 8th editions (c-index 0.57 vs 0.58). For patients who underwent a curative-intent resection, the prognostic accuracy of the 8th edition (0.67) was higher than the 7th (0.65). For patients who did not undergo a curative-intent resection, the prognostic accuracy was poor in both the 7th as the 8th editions (0.54 vs 0.57). Conclusion The 7th and 8th editions of the AJCC staging system for PHC have comparable prognostic accuracy. Prognostic accuracy was particularly poor in unresectable patients.

Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr−/−.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy. Accurate non-invasive biomarkers to diagnose MASLD-related fibrosis are urgently needed. Here the authors show a disease mechanism-related blood-based biomarker panel consisting of three biomarkers which is able to accurately identify MASLD patients with mild or advanced hepatic fibrosis.

According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells. Upon inflammation and targeted gene mutation, some fully differentiated secretory and postmitotic intestinal epithelial lineages dedifferentiate to acquire stem-like features and promote tumor formation.

Background Formalin-fixed paraffin embedded (FFPE) tissues may provide an exciting resource to study microbial associations in human disease, but the use of these low biomass specimens remains challenging. We aimed to reduce unintentional bacterial interference in molecular analysis of FFPE tissues and investigated the feasibility of conducting quantitative polymerase chain reaction (qPCR) and 16S rRNA amplicon sequencing using 14 colorectal cancer, 14 normal adjacent and 13 healthy control tissues. Results Bacterial contaminants from the laboratory environment and the co-extraction of human DNA can affect bacterial analysis. The application of undiluted template improves bacterial DNA amplification, allowing the detection of specific bacterial markers ( Escherichia coli and Faecalibacterium prausnitzii ) by qPCR. Nested and non-nested PCR-based 16S rRNA amplicon sequencing approaches were employed, showing that bacterial communities of tissues and paired paraffin controls cluster separately at genus level on weighted Unifrac in both non-nested (R2 = 0.045; Pr(> F) = 0.053) and nested (R2 = 0.299; Pr(> F) = 0.001) PCR datasets. Nevertheless, considerable overlap of bacterial genera within tissues was seen with paraffin, DNA extraction negatives (non-nested PCR) or PCR negatives (nested PCR). Following mathematical decontamination, no differences in α- and β diversity were found between tumor, normal adjacent and control tissues. Conclusions Bacterial marker analysis by qPCR seems feasible using non-normalized template, but 16S rRNA amplicon sequencing remains challenging. Critical evaluation of laboratory procedures and incorporation of positive and negative controls for bacterial analysis of FFPE tissues are essential for quality control and to account for bacterial contaminants.

Objectives Hyper- or isointensity in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI has high specificity for focal nodular hyperplasia (FNH) but may be present in hepatocellular adenoma and carcinoma (HCA/HCC). This study aimed to identify imaging characteristics differentiating FNH and HCA/HCC. Materials and methods This multicenter retrospective cohort study included patients with pathology-proven FNH or HCA/HCC, hyper-/isointense in the HBP of gadoxetic acid-enhanced MRI between 2010 and 2020. Diagnostic performance of imaging characteristics for the differentiation between FNH and HCA/HCC were reported. Univariable analyses, multivariable logistic regression analyses, and classification and regression tree (CART) analyses were conducted. Sensitivity analyses evaluated imaging characteristics of B-catenin-activated HCA. Results In total, 124 patients (mean age 40 years, standard deviation 10 years, 108 female) with 128 hyper-/isointense lesions were included. Pathology diagnoses were FNH and HCA/HCC in 64 lesions (50%) and HCA/HCC in 64 lesions (50%). Imaging characteristics observed exclusively in HCA/HCC were raster and atoll fingerprint patterns in the HBP, sinusoidal dilatation on T2-w, hemosiderin, T1-w in-phase hyperintensity, venous washout, and nodule-in-nodule partification in the HBP and T2-w. Multivariable logistic regression and CART additionally found a T2-w scar indicating FNH, less than 50% fat, and a spherical contour indicating HCA/HCC. In our selected cohort, 14/48 (29%) of HCA were B-catenin activated, most (13/14) showed extensive hyper-/isointensity, and some had a T2-w scar (4/14, 29%). Conclusion If the aforementioned characteristics typical for HCA/HCC are encountered in lesions extensively hyper- to isointense, further investigation may be warranted to exclude B-catenin-activated HCA. Clinical relevance Hyper- or isointensity in the HBP of gadoxetic acid-enhanced MRI is specific for FNH, but HCA/HCC can also exhibit this feature. Therefore, we described imaging patterns to differentiate these entities. Key Points FNH and HCA/HCC have similar HBP intensities but have different malignant potentials . Six imaging patterns exclusive to HCA/HCC were identified in this lesion population . These features in liver lesions hyper- to isointense in the HBP warrant further evaluation .

Accurate needle placement in deep-seated liver tumours can be difficult. In this work, we disclose two new manually controlled steerable needles for 17G radio-frequency ablation probe placement. The needles contain stylets with embedded compliant joints for active tip articulations, and concentric tubes for (curved-path) guidance. Needle steering was evaluated sequentially by intended users and in intended-use tissue types. Six interventional radiologists evaluated the needle in repeated ultrasound-guided steering tasks in liver-mimicking phantoms. Targets were located at a 100 mm depth and 20 mm lateral offset from the initial insertion line. The resulting mean absolute tip placement error was 1.0 ± 1.0 mm. Subsequently, steering-induced tissue damage was evaluated in fresh cirrhotic human liver explants. The surface area of puncture holes was estimated in scanned histology slides, using a connected-components analysis. The mean surface area was 0.26 ± 0.16 mm 2 after steering with a median radius of curvature of 0.7 × 10 3  mm, versus 0.35 ± 0.15 mm 2 after straight-path insertions with the steerable needle and 0.15 ± 0.09 mm 2 after straight-path RFA probe insertions. The steering mechanisms proposed enable clinically relevant path corrections for 17G needles. Radiologists were quickly adept in curved-path RFA probe placement and the evaluation of histological tissue damage demonstrated a potentially safe use during liver interventions.

Mapping the brain’s fiber network is crucial for understanding its function and malfunction, but resolving nerve trajectories over large fields of view is challenging. Here, we show that computational scattered light imaging (ComSLI) can map fiber networks in histology independent of sample preparation, also in formalin-fixed paraffin-embedded (FFPE) tissues including whole human brain sections. We showcase this method in new and archived, animal and human brain sections, for different sample preparations (in paraffin, deparaffinized, various stains, unstained fresh-frozen). We convert microscopic orientations to microstructure-informed fiber orientation distributions (μFODs). Adapting tractography tools from diffusion magnetic resonance imaging (dMRI), we trace axonal trajectories revealing white and gray matter connectivity. These allow us to identify altered microstructure or deficient tracts in demyelinating or neurodegenerating pathology, and to show key advantages over dMRI, polarization microscopy, and structure tensor analysis. Finally, we map fibers in non-brain tissues, including muscle, bone, and blood vessels, unveiling the tissue’s function. Our cost-effective, versatile approach enables micron-resolution studies of intricate fiber networks across tissues, species, diseases, and sample preparations, offering new dimensions to neuroscientific and biomedical research. Georgiadis and colleagues conduct micron-resolution fibre mapping on multiple histological tissue sections. Their light-scattering technique works across different sample preparations and tissue types, including formalin-fixed paraffin-embedded brain sections.

Background The Surgery As Needed for Oesophageal cancer (SANO) trial compares active surveillance with standard oesophagectomy for patients with a clinically complete response (cCR) to neoadjuvant chemoradiotherapy. The last patient with a clinically complete response is expected to be included in May 2021. The purpose of this update is to present all amendments to the SANO trial protocol as approved by the Institutional Research Board (IRB) before accrual is completed. Design The SANO trial protocol has been published ( https://doi.org/10.1186/s12885-018-4034-1 ). In this ongoing, phase-III, non-inferiority, stepped-wedge, cluster randomised controlled trial, patients with cCR (i.e. after neoadjuvant chemoradiotherapy no evidence of residual disease in two consecutive clinical response evaluations [CREs]) undergo either active surveillance or standard oesophagectomy. In the active surveillance arm, CREs are repeated every 3 months in the first year, every 4 months in the second year, every 6 months in the third year, and yearly in the fourth and fifth year. In this arm, oesophagectomy is offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant metastases. The primary endpoint is overall survival. Update Amendments to the study design involve the first cluster in the stepped-wedge design being partially randomised as well and continued accrual of patients at baseline until the predetermined number of patients with cCR is reached. Eligibility criteria have been amended, stating that patients who underwent endoscopic treatment prior to neoadjuvant chemoradiotherapy cannot be included and that patients who have highly suspected residual tumour without histological proof can be included. Amendments to the study procedures include that patients proceed to the second CRE if at the first CRE the outcome of the pathological assessment is uncertain and that patients with a non-passable stenosis at endoscopy are not considered cCR. The sample size was recalculated following new insights on response rates (34% instead of 50%) and survival (expected 2-year overall survival of 75% calculated from the moment of reaching cCR instead of 3-year overall survival of 67% calculated from diagnosis). This reduced the number of required patients with cCR from 264 to 224, but increased the required inclusions from 480 to approximately 740 patients at baseline. Conclusion Substantial amendments were made prior to closure of enrolment of the SANO trial. These amendments do not affect the outcomes of the trial compared to the original protocol. The first results are expected late 2023. If active surveillance plus surgery as needed after neoadjuvant chemoradiotherapy for oesophageal cancer leads to non-inferior overall survival compared to standard oesophagectomy, active surveillance can be implemented as a standard of care.

Pancreatic ductal adenocarcinoma (PDAC) presents challenges in detecting somatic mutations due to its complex cellular composition. This study investigated the utility of patient-derived organoids (PDOs) to overcome these obstacles and enhance somatic mutation identification. Surgically resected PDAC tumors and their paired PDOs from 21 patients were examined. Whole-exome sequencing (WES) of tumor tissue, organoids, and peripheral blood mononuclear cells was performed to identify somatic mutations. Our findings demonstrate that PDOs retained about 80% of the somatic mutations from the original tumors, showing high concordance in mutation types. PDOs exhibited increased tumor purity and uncovered key driver mutations, aiding in identifying clinically relevant genomic alterations. Moreover, eight cycles of FOLFIRINOX treatment did not significantly alter the mutational landscape at the DNA level, indicating the stability of the mutational profile after therapeutic pressure in patients. In conclusion, PDOs are potentially important tools for exploring the somatic mutational landscape of PDAC. While they can reveal mutations that may be challenging to detect through traditional biopsy sequencing due to the inherently low tumor purity of PDAC, it is important to note that PDOs may not always fully recapitulate all mutations found in primary tumors. Despite this limitation, PDOs can still offer critical insights into the genomic complexities of PDAC, which is crucial for the development of personalized vaccines and therapies for this disease.

BackgroundBarrett’s esophagus (BE) is a known precursor lesion and the strongest risk factor for esophageal adenocarcinoma (EAC), a common and lethal type of cancer. Prediction of risk, the basis for efficient intervention, is commonly solely based on histologic examination. This approach is challenged by problems such as inter-observer variability in the face of the high heterogeneity of dysplastic tissue. Molecular markers might offer an additional way to understand the carcinogenesis and improve the diagnosis—and eventually treatment. In this study, we probed significant proteomic changes during dysplastic progression from BE into EAC.MethodsDuring endoscopic mucosa resection, epithelial and stromal tissue samples were collected by laser capture microdissection from 10 patients with normal BE and 13 patients with high-grade dysplastic/EAC. Samples were analyzed by mass spectrometry-based proteomic analysis. Expressed proteins were determined by label-free quantitation, and gene set enrichment was used to find differentially expressed pathways. The results were validated by immunohistochemistry for two selected key proteins (MSH6 and XPO5).ResultsComparing dysplastic/EAC to non-dysplastic BE, we found in equal volumes of epithelial tissue an overall up-regulation in terms of protein abundance and diversity, and determined a set of 226 differentially expressed proteins. Significantly higher expressions of MSH6 and XPO5 were validated orthogonally and confirmed by immunohistochemistry.ConclusionsOur results demonstrate that disease-related proteomic alterations can be determined by analyzing minute amounts of cell-type-specific collected tissue. Further analysis indicated that alterations of certain pathways associated with carcinogenesis, such as micro-RNA trafficking, DNA damage repair, and spliceosome activity, exist in dysplastic/EAC.