Neoadjuvant therapy (NAT) is increasingly used to treat patients with initially unresectable intrahepatic cholangiocarcinoma (iCCA). A histopathologic grading system for residual tumors that can predict patient survival is lacking in the literature. This retrospective study enrolled 151 iCCA patients who received NAT. The percentage of residual viable tumor (%RVT) extent was calculated by RVT surface area/total tumor bed area ×100 and scored in 5% increments. Kaplan-Meier and Cox regression analyses were used to investigate its correlations with recurrence-free survival (RFS) and overall survival (OS). Tumor regression grading by the College of American Pathologists (CAP) and MD Anderson (MDA) methodologies were also validated. A 10% RVT-based tumor regression score (TRS) showed a significant correlation with both OS and RFS. TRS and major pathologic response (mPR) were therefore defined as follows: TRS 1/mPR, tumor with 0 to 10% RVT; TRS 2, more than 10% RVT. Patients graded as TRS 1/mPR had superior OS (P=0.006) and RFS (P<0.001) compared with those with TRS 2 in univariate analysis. In a multivariate analysis including ypTNM stages, lymphovascular invasion, and perineural invasion, TRS 1/mPR was also found to be an independent prognostic factor for both OS (hazard ratio [HR]: 0.226; 95% CI: 0.053-0.966, P=0.045) and RFS (HR: 0.474; 95% CI: 0.231-0.974, P=0.042). As for the CAP and MDA grading methodologies, they were found to correlate with RFS (CAP: P=0.002; MDA: P=0.001), but not with OS (CAP: P=0.181; MDA: P=0.09). Our study revealed that a TRS of ≤10% RVT significantly correlates with longer OS and RFS and can be suggested as an mPR in iCCA. This indicator is easily applicable, prognostically relevant, and could be further validated in future prospective clinical trials.

Tumor budding (TB) has been associated with poor survival in a variety of cancers including intrahepatic cholangiocarcinoma (iCCA). As tumor histomorphological features are significantly altered after neoadjuvant therapy (NAT), our study aims to assess the prognostic significance of TB in iCCA patients before and after NAT, by the modified International Tumor Budding Consensus Conference (ITBCC) criteria. 147 NAT-treated iCCA cases were included in this study. In biopsy specimens obtained before NAT, the TB-positive subgroup had lower overall survival (OS) in univariate analysis (P = 0.010). In resection specimens obtained after NAT, the TB-positive subgroup had reduced OS (P = 0.002) and recurrence-free survival (RFS) (P = 0.013) in univariate analysis. In multivariate analysis including TNM stage, lymphovascular invasion and perineural invasion, TB-positive in post-NAT resection was also found as an independent prognostic factor for both OS and RFS (OS, HR, 3.005; 95% CI, 1.333–6.775, P = 0.008; RFS, HR, 1.748; 95% CI, 1.085–2.816, P = 0.022). In conclusion, assessing the presence of TB by modified ITBCC criteria provides robust prognostic information in the NAT setting of iCCA patients and can be considered to be included in routine pathological reporting.

Introduction: The tumor microenvironment (TME) plays a critical role in determining the clinical outcomes in patients with intrahepatic cholangiocarcinoma (iCCA). This study investigates the prognostic significance of CD8+ T cells and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs) and their relationship to histopathological features. Methods: Immunofluorescence analysis was conducted on a cohort of 34 resected iCCA cases to assess CD8+ T cell and Treg densities. Statistical correlations with survival and immune and histopathological features were examined. Validation was performed on an independent cohort of 95 iCCA pre-neoadjuvant therapy (NAT) biopsy specimens to assess the prognostic power of the immune and histopathological features to survival and NAT response. Results: In the cohort of resected iCCA cases, immunofluorescence revealed that increased CD8+ T-cell infiltration is associated with improved survival (p = 0.018), underscoring their role in anti-tumor immunity. Conversely, higher density of Tregs is linked to poorer survival (p = 0.038), suggesting its tumor-promoting, immunosuppressive effects. Intriguingly, CD8+ T cells and Tregs are associated with distinct histopathological features, with CD8+ T cells correlating with dense tumor-infiltrating lymphocytes (TILs, Pearson’s R = 0.498; p = 0.004) and Tregs being more prevalent in regions of tumor budding (TB, Pearson’s R = 0.382; p = 0.029). These observations were validated in an independent pre-NAT cohort (n = 95), whereby higher TIL density, particularly increased CD8+ T cells and reduced Treg, and lower TB predict favorable response to NAT, as shown by improved overall and disease-free survival. Conclusion: These findings provide critical insights for stratifying patients and highlight the potential for optimizing immune-targeted therapies in patients with iCCA.

Widespread adoption of mpMRI has led to a decrease in the number of patients requiring prostate biopsies. ⁶⁸Ga-PSMA-11 PET/CT has demonstrated added benefits in identifying csPCa. Integrating the use of these imaging techniques may hold promise for predicting the presence of csPCa without invasive biopsy. A retrospective analysis of 42 consecutive patients who underwent mpMRI, ⁶⁸Ga-PSMA-11 PET/CT, prostatic biopsy, and radical prostatectomy (RP) was carried out. A lesion-based model (n = 122) using prostatectomy histopathology as reference standard was used to analyze the accuracy of ⁶⁸Ga-PSMA-11 PET/CT, mpMRI alone, and both in combination to identify ISUP-grade group ≥ 2 lesions. ⁶⁸Ga-PSMA-11 PET/CT demonstrated greater specificity and positive predictive value (PPV), with values of 73.3% (vs. 40.0%) and 90.1% (vs. 82.2%), while the mpMRI Prostate Imaging Reporting and Data System (PI-RADS) 4–5 had better sensitivity and negative predictive value (NPV): 90.2% (vs. 78.5%) and 57.1% (vs. 52.4%), respectively. When used in combination, the sensitivity, specificity, PPV, and NPV were 74.2%, 83.3%, 93.2%, and 51.0%, respectively. Subgroup analysis of PI-RADS 3, 4, and 5 lesions was carried out. For PI-RADS 3 lesions, ⁶⁸Ga-PSMA-11 PET/CT demonstrated a NPV of 77.8%. For PI-RADS 4–5 lesions, ⁶⁸Ga-PSMA-11 PET/CT achieved PPV values of 82.1% and 100%, respectively, with an NPV of 100% in PI-RADS 5 lesions. A combination of ⁶⁸Ga-PSMA-11 PET/CT and mpMRI improved the radiological diagnosis of csPCa. This suggests that avoidance of prostate biopsy prior to RP may represent a valid option in a selected subgroup of high-risk patients with a high suspicion of csPCa on mpMRI and ⁶⁸Ga-PSMA-11 PET/CT.