Clara Alfaro-Cervello

Background and Aims: Fecal immunochemical test‐based colorectal cancer screening is effective; however, colonoscopy demand exceeds endoscopy capacity. Delays in colonoscopy after a positive test reduce screening effectiveness. We developed and validated a decision‐tree model to stratify colorectal cancer risk among individuals with a positive test to prioritize colonoscopy for those at highest risk. Methods: Prospective study including participants with a positive fecal immunochemical test referred for colonoscopy within a Spanish regional population‐based screening program (2021–2024). Individuals were randomly assigned to derivation (65%) and validation (35%) cohorts using a stratified random split. Fecal hemoglobin concentration, clinical and laboratory data were collected to develop the decision‐tree model. The primary outcomes were colorectal cancer and advanced‐stage colorectal cancer. Results: A total of 1773 participants were included. Colorectal cancer was detected in 97 participants (5.5%), including 25 cases (1.5%) with advanced‐stage disease. The model stratified participants into low‐, intermediate‐, high‐, and very high‐risk groups. A progressive increase in the prevalence of colorectal cancer and advanced‐stage disease was observed across risk groups in both cohorts ( p < 0.001). The very high‐risk group (fecal hemoglobin > 100 μg/g and > 65 years) included 6.7% of participants, with colorectal cancer and advanced‐stage prevalence of 21.8% and 7.6%, respectively. Prioritizing colonoscopy for this group yielded a number needed to scope of 4.6 for colorectal cancer and 13.2 for advanced‐stage disease, both significantly lower than the current one‐size‐fits‐all strategy. Conclusions: A decision‐tree model was developed to stratify the risk of colorectal cancer and optimize endoscopic resources in screening programs.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumours and its incidence is increasing. Definitive diagnosis requires pathological confirmation. Cytology samples are obtained using endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA). The utility and storage conditions of residual liquid‐based cytology (LBC) for PDAC remain poorly defined. Methods: From 2020 to 2024, 268 patients were diagnosed with PDAC using EUS‐FNA and LBC. Cell blocks were prepared when possible, and residual LBC samples were stored. Results: Molecular studies were requested for 54 patients. Residual LBC was the only sample available in eight patients. Molecular analyses were requested at more than 2 months and up to 27 months after diagnosis in 31.7% of patients and performed on residual LBC or cell block based on availability and quality. Samples were not analysed in parallel. DNA concentration was higher in LBC than cell blocks, and MAPD (median absolute pairwise difference) was lower. LBC storage time did not affect NGS validity. Residual LBC provided an adequate proportion of valid studies in NGS DNA and MSI RT‐PCR, showing no difference to cell blocks. RNA provided fewer valid studies, with no differences between sample types. The most frequently detected mutations were KRAS (35/41) and TP53 (12/41). No fusions or MSI were detected. Conclusions: In a real clinical setting, we show that residual LBC samples from PDAC are valid for molecular analysis, preserving the quality of nucleic acids. Residual LBC may be the only available sample and should be preserved to ensure patient access to targeted therapies.

Background and Aims: Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up. Methods: A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk. Results: A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04–1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07–1.85)] and used other drugs (OR=2.65 [95% CI: 1.74–4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25–7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86–14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67–6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025). Conclusions: The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality.

For steatosis and iron quantification, automated whole-liver MRI segmentation measurements correlated with histologic data in chronic liver disease and showed similar diagnostic accuracy to manual ... Background Standardized manual region of interest (ROI) sampling strategies for hepatic MRI steatosis and iron quantification are time consuming, with variable results. Purpose To evaluate the perf...

Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-score: proportionate area of staining intensities clusters) measurements were independently performed. Our data show that I-scores and C-scores increase with inflammation grades (p < 0.001). High correlation was seen for CH (ρ = 0.85–0.88), but only moderate for NAFLD (ρ = 0.5–0.53). I-score (p = 0.008) and C-score (p = 0.002) were higher for CH than NAFLD. Our MATLAB algorithm performed better than QuPath software for the diagnosis of low-moderate inflammation (p < 0.05). C-score AUC for classifying NASH was 0.75 (95%CI, 0.65–0.84) and for moderate/severe CH was 0.99 (95%CI, 0.97–1.00). Digital pathology measurements increased with fibrosis stages (p < 0.001). In conclusion, quantitative and morphometric metrics of inflammatory burden obtained by digital pathology correlate well with pathologists’ scores, showing a higher accuracy for the evaluation of CH than NAFLD.

The term “cutaneous lymphadenoma” was coined in this journal for an unusual lymphoepithelial cutaneous adnexal neoplasm, possibly with immature pilosebaceous differentiation. Some authors further proposed that cutaneous lymphadenoma was an adamantinoid trichoblastoma. However, although a hair follicle differentiation is widely accepted, the fact that this is a lymphoepithelial tumor is not appropriately explained by the trichoblastoma hypothesis. Our goal was to further clarify the phenotypic and genotypic features of cutaneous lymphadenoma in a series of 11 cases. Histologically, a lobular architecture surrounded by a dense fibrous stroma was present in all cases. The lobules were composed of epithelial cells admixtured with small lymphocytes and isolated or clustered large Reed-Sternberg–like (RS-L) cells. The epithelial cells were diffusely positive for the hair follicle stem cell markers CK15, PHLDA1, and for androgen receptor. No immunostaining for markers of sebaceous differentiation was found. Intraepithelial lymphocytes were predominantly CD3⁺, CD4⁺, FoxP3⁺ T cells. RS-L cells showed both strong Jagged-1 and Notch1 cytoplasmic immunostaining. Androgen-regulated NKX3.1 nuclear immunostaining was present in a subset of large intralobular cells in all cases. Double immunostaining showed coexpression of NKX3.1 and CD30 in a subset of RS-L cells. No immunostaining for lymphocytic or epithelial markers was present in RS-L cells. EGFR, PIK3CA, and FGFR3 somatic mutations were found by next-generation sequencing in 56% of the cases. We consider that cutaneous lymphadenoma is a distinct benign lymphoepithelial tumor with androgen receptor and hair follicle bulge stem cell marker expression, RS-L cell-derived Notch1 ligand, and common EGFR gene mutations.

Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas’s poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.

Summary: Background: Histological evaluation of metabolic‐associated fatty liver disease (MAFLD) biopsies is subjective, descriptive and with interobserver variability.Aims: To examine the relationship between different histological features (fibrosis, steatosis, inflammation and iron) measured with automated whole‐slide quantitative digital pathology and corresponding semiquantitative scoring systems, and the distribution of digital pathology measurements across Fatty Liver Inhibition of Progression (FLIP) algorithm and Steatosis, Activity and Fibrosis (SAF) scoring systemMethods: We prospectively included 136 consecutive patients who underwent liver biopsy for MAFLD at three Spanish centres (January 2017‐January 2020). Biopsies were scored by two blinded pathologists according to the Non‐alcoholic Steatohepatitis (NASH) Clinical Research Network system for fibrosis staging, the FLIP/SAF classification for steatosis and inflammation grading and Deugnier score for iron grading. Proportionate areas of collagen, fat, inflammatory cells and iron deposits were measured with computer‐assisted digital image analysis. A test‐retest experiment was performed for precision repeatability evaluation.Results: Digital pathology showed strong correlation with fibrosis (r = 0.79; P < 0.001), steatosis (r = 0.85; P < 0.001) and iron (r = 0.70; P < 0.001). Performance was lower when assessing the degree of inflammation (r = 0.35; P < 0.001). NASH cases had a higher proportion of collagen and fat compared to non‐NASH cases (P < 0.005), whereas inflammation and iron quantification did not show significant differences between categories. Repeatability evaluation showed that all the coefficients of variation were ≤1.1% and all intraclass correlation coefficient values were ≥0.99, except those of collagen.Conclusion: Digital pathology allows an automated, precise, objective and quantitative assessment of MAFLD histological features. Digital analysis measurements show good concordance with pathologists´ scores.