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Simple Summary The investigation of predictive and prognostic markers is pivotal in patients affected by hepatocellular carcinoma treated with immune-checkpoint-inhibitors. Inflammation has a central role in hepatocellular carcinoma development and progression; however, its role in influencing outcomes in the context of immunotherapy has not been fully elucidated yet. In the following study, we investigated the prognostic role of bloods derived inflammatory markers and we found that they predict survival and response of patients treated with immunotherapy for advanced hepatocellular carcinoma. Abstract Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs.

Simple Summary Patients receiving chemotherapy for liver metastases from colorectal cancer may develop liver injuries that impair hepatic function and postoperative outcome. The non-invasive diagnosis of these damages is still an unmet need. Recently, advanced imaging analysis techniques, including the so-called “radiomics”, achieved adequate prediction of pathology data. The present study demonstrated that radiomic analysis of liver parenchyma in combination with clinical and laboratory data improves non-invasive diagnosis of chemotherapy-related liver injuries. Abstract Non-invasive diagnosis of chemotherapy-associated liver injuries (CALI) is still an unmet need. The present study aims to elucidate the contribution of radiomics to the diagnosis of sinusoidal dilatation (SinDil), nodular regenerative hyperplasia (NRH), and non-alcoholic steatohepatitis (NASH). Patients undergoing hepatectomy for colorectal metastases after chemotherapy (January 2018-February 2020) were retrospectively analyzed. Radiomic features were extracted from a standardized volume of non-tumoral liver parenchyma outlined in the portal phase of preoperative post-chemotherapy computed tomography. Seventy-eight patients were analyzed: 25 had grade 2–3 SinDil, 27 NRH, and 14 NASH. Three radiomic fingerprints independently predicted SinDil: GLRLM_f3 (OR = 12.25), NGLDM_f1 (OR = 7.77), and GLZLM_f2 (OR = 0.53). Combining clinical, laboratory, and radiomic data, the predictive model had accuracy = 82%, sensitivity = 64%, and specificity = 91% (AUC = 0.87 vs. AUC = 0.77 of the model without radiomics). Three radiomic parameters predicted NRH: conventional_HUQ2 (OR = 0.76), GLZLM_f2 (OR = 0.05), and GLZLM_f3 (OR = 7.97). The combined clinical/laboratory/radiomic model had accuracy = 85%, sensitivity = 81%, and specificity = 86% (AUC = 0.91 vs. AUC = 0.85 without radiomics). NASH was predicted by conventional_HUQ2 (OR = 0.79) with accuracy = 91%, sensitivity = 86%, and specificity = 92% (AUC = 0.93 vs. AUC = 0.83 without radiomics). In the validation set, accuracy was 72%, 71%, and 91% for SinDil, NRH, and NASH. Radiomic analysis of liver parenchyma may provide a signature that, in combination with clinical and laboratory data, improves the diagnosis of CALI.

Background: Systemic therapy is the standard treatment for patients with hepatic and extrahepatic colorectal metastases. It is assumed to have the same effectiveness on all disease foci, independent of the involved organ. The present study aims to compare the response rates of hepatic and extrahepatic metastases to systemic therapy. Methods: All consecutive patients undergoing simultaneous resection of hepatic and extrahepatic metastases from colorectal cancer after oxaliplatin- and/or irinotecan-based preoperative chemotherapy were analyzed. All specimens were reviewed. Pathological response to chemotherapy was classified according to tumor regression grade (TRG). Results: We analyzed 45 patients undergoing resection of 134 hepatic and 72 extrahepatic metastases. Lung and lymph node metastases had lower response rates to chemotherapy than liver metastases (TRG 4&ndash, 5 95% and 100% vs. 67%, p = 0.008, and p = 0.006). Peritoneal metastases had a higher pathological response rate than liver metastases (TRG 1&ndash, 3 66% vs. 33%, p &lt, 0.001) and non-hepatic non-peritoneal metastases (3%, p &lt, 0.001). Metastases site was an independent predictor of pathological response to systemic therapy. Conclusions: Response to chemotherapy of distant metastases from colorectal cancer varies in different organs. Systemic treatment is highly effective for peritoneal metastases, more so than liver metastases, while it has a very poor impact on lung and lymph node metastases.

Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression), and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included—20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4–2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively, p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.