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Background: Transarterial chemoembolisation (TACE) and radioembolisation (TARE) can lead to the deterioration of liver function, especially in cases of a high tumour burden, potentially lessening the benefits of subsequent systemic treatments. We aimed to verify whether a high number of previous transarterial treatments modified the outcomes of patients who received sorafenib as a frontline systemic treatment. Methods: A retrospective analysis of a large multicenter dataset containing prospectively collected data of sorafenib-treated patients was conducted. Results: Data from 696 patients were analysed, with 139 patients having received >two transarterial procedures before starting sorafenib. A propensity score matched 139 identified pairs of patients. Having received >two locoregional treatments was independently associated with a shorter survival (hazard ratio 1.325, 95% confidence interval 1.018–1.725, p = 0.039). This pattern was confirmed amongst responders to sorafenib, but not in progressors. A trend toward a higher rate of the permanent discontinuation of sorafenib due to liver failure (18.7 vs. 10.8%, p = 0.089) and a lower rate of eligibility for second-line treatments (24.5 vs. 17.3%, p = 0.184) was observed in patients who had received >two transarterial procedures. Conclusions: Repeated endovascular treatments negatively impacted the survival of HCC patients, especially sorafenib-responders. An early switch to systemic therapies should be considered in cases that are unlikely to respond. [ABSTRACT FROM AUTHOR]

Background: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients' prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. Methods: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. Results: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). Conclusions: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems. [ABSTRACT FROM AUTHOR]

Background: The TOPAZ‐1 phase III trial reported a survival benefit with the anti‐programmed death cell ligand 1 (anti‐PD‐L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real‐world setting. Methods: The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression‐free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. Results: From February 2022 to November 2022, 145 patients were enrolled. After a median follow‐up of 8.5 months (95% CI: 7.9–13.6), the median PFS was 8.9 months (95% CI: 7.4–11.7). Median OS was 12.9 months (95% CI: 10.9–12.9). The investigator‐assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3–4 AEs occurred in 51 patients (35.2%). The rate of immune‐mediated AEs (imAEs) was 22.7%. Grades 3–4 imAEs occurred in 2.1% of the patients. In univariate analysis, non‐viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. Conclusion: The results reported in this first real‐world analysis mostly confirmed the results achieved in the TOPAZ‐1 trial in terms of PFS, ORR and safety. [ABSTRACT FROM AUTHOR]

Simple Summary: Several retrospective studies tried to assess the prognostic role of different sites of metastases in patients with advanced HCC, but results are often contradictory. These studies also presented results based on population samples with several confounding factors. Although the therapeutic scenario is moving towards immunotherapy, a better knowledge of a different metastatic site response rate to sorafenib is needed, also considering the potential future advent of combination therapies with immune checkpoint and tyrosine-kinase inhibitors. We tried to perform a large-scale multicentric study by enrolling metastatic HCC patients treated with sorafenib as front-line therapy. A low rate of concomitant locoregional treatments during sorafenib in our population study allowed us to focus on the actual response of different sites of metastases to systemic treatment with sorafenib, showing that lymph nodes and lung metastases have worse prognosis. Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is now the standard front-line therapy for patients with advanced hepatocellular carcinoma. However, there remains a substantial proportion of patient who do not respond to this treatment, and few predictive and prognostic biomarkers exist that can identify patients most likely to benefit from immunotherapy. Inflammation plays a role in driving tumor formation and progression. The aim of our study was to evaluate the prognostic utility of two blood-based markers of inflammation, which have the advantage of being easily accessible and inexpensive, and we found that one may predict survival outcomes in patients with hepatocellular carcinoma treated with our current standard of care immunotherapy regimen. Systemic inflammation is a key risk factor for hepatocellular carcinoma (HCC) progression and poor outcomes. Inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) may have prognostic value in HCC treated with standard of care atezolizumab plus bevacizumab (Atezo-Bev). We conducted a multicenter, international retrospective cohort study of patients with unresectable HCC treated with Atezo-Bev to assess the association of NLR and PLR with overall survival (OS), progression-free survival (PFS), and objective response rates. Patients with NLR ≥ 5 had a significantly shorter OS (9.38 vs. 16.79 months, p < 0.001) and PFS (4.90 vs. 7.58 months, p = 0.03) compared to patients with NLR < 5. NLR ≥ 5 was an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22–3.56, p = 0.007) but not PFS. PLR ≥ 300 was also significantly associated with decreased OS (9.38 vs. 15.72 months, p = 0.007) and PFS (3.45 vs. 7.11 months, p = 0.04) compared to PLR < 300, but it was not an independent prognosticator of OS or PFS. NLR and PLR were not associated with objective response or disease control rates. NLR ≥ 5 independently prognosticated worse survival outcomes and is worthy of further study and validation. [ABSTRACT FROM AUTHOR]

Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8–5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT. [ABSTRACT FROM AUTHOR]

Simple Summary: A multispecialty discussion may represent a benefit for cancer patients in receiving the most updated pathway of cure. The aim of this study was to describe the activity of our multidisciplinary team (MDT) meeting on patients with colorectal liver metastases (CRLMs). Information about 847 consecutive CRLMs patients over an 11-year period was retrospectively collected. Their characteristics were analyzed, and the populations were compared based on received treatment. There is still debate over how reviewing oncological histories and addressing appropriate therapies in multidisciplinary team (MDT) discussions may affect patients' overall survival (OS). The aim of this study was to describe MDT outcomes for a single cancer center's patients affected by colorectal liver metastases (CRLMs). From 2010 to 2020, a total of 847 patients with CRLMs were discussed at our weekly MDT meeting. Patients' characteristics and MDT decisions were analyzed in two groups: patients receiving systemic therapy (ST) versus patients receiving locoregional treatment (LRT). Propensity-score matching (PSM) was run to reduce the risk of selection bias. The median time from MDT indication to treatment was 27 (IQR 13–51) days. The median OS was 30 (95%CI = 27–34) months. After PSM, OS for patients undergoing LRT was 51 (95%CI = 36–64) months compared with 15 (95%CI = 13–20) months for ST patients (p < 0.0001). In this large retrospective study, the MDT discussions were useful in providing the patients with all available locoregional options. [ABSTRACT FROM AUTHOR]

Introduction: The treatment of unresectable hepatocellular carcinoma (HCC) has radically changed after the approval of the combination of atezolizumab plus bevacizumab as first-line treatment. A strong preclinical rationale exists to support the combination of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody (mAb), and atezolizumab, an anti-programmed death ligand 1 mAb. The efficacy of the combination was first assessed in the phase Ib GO30140 study, and the combination was then proven superior to the prior standard of care, sorafenib, in the phase III IMbrave150 trial. Areas covered: This article focuses on the mechanism of action of atezolizumab and bevacizumab, their synergistic action, and the two clinical trials leading to approval. We also collected the body of post-hoc analyses and meta-analyses to help guide the decision-making process in terms of patient selection and subsequent treatments. Expert opinion: Atezolizumab plus bevacizumab are the current standard of care for first-line treatment of unresectable or metastatic HCC and treatment-naïve patient should be treated with the combination, unless contraindications to the drugs. Since all the available agents for further lines of treatment have been approved for sorafenib-pretreated patients, prospective trials, post-hoc analyses, and real-world data assessing valid treatment sequencing are strongly needed. [ABSTRACT FROM AUTHOR]

Introduction: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials. [ABSTRACT FROM AUTHOR]

The incidence rate of hepatocellular carcinoma is growing and age at diagnosis is increasing; however, despite the unprecedented wealth of therapeutic options for advanced HCC, its optimal management in some categories, such as older adults, is yet to be defined. Even though age is not an exclusion criterion per se, most of the landmark trials enrolled a limited number of senior patients, raising some concerns on the potential benefit of active treatments in this group. The identification of more vulnerable patients remains a crucial issue in clinical practice. In fact, the suitability assessment for systemic therapy through performance status metrics might underestimate or conversely overestimate the fitness of older patients, failing to detect other relevant impairments. Thus, the assessment of frailty through geriatric screening scales is largely necessary. In addition, most of the available data relate to the use of sorafenib, while very little is known about the most recent therapeutic agents. Age subgroup analyses provided by many of the pivotal trials did not find significant efficacy or safety differences across ages; however, the most widely used cut-off age of 65 years may not be very informative for the current older population. Regarding immunotherapy, the clinical benefit reported with immune checkpoint inhibitors reassures their safe use in senior patients and supports further investigations to assess their efficacy in this population. [ABSTRACT FROM AUTHOR]

Background: Antibiotic exposure has been associated with worse outcomes with immune checkpoint inhibitors (ICIs) in cancer patients, likely due to disruption of the gut microbiome. Other commonly prescribed medications, such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs), are also known to disrupt the microbiome, but data on their association with ICI outcomes are conflicting. Methods: We conducted a retrospective, multicenter, international cohort study including 314 hepatocellular carcinoma (HCC) patients treated with ICIs from 2017 to 2019 to assess the association between PPI or H2RA exposure (up to 30 days before ICI) and overall survival. Secondary outcomes included overall response rate (ORR) and development of any treatment-related adverse events (AEs). Results: Baseline PPI/H2RA exposure was not associated with overall survival in univariable (HR 1.01, 95% CI 0.75–1.35) or multivariable analysis (HR 0.98, 95% CI 0.71–1.36). Baseline PPI/H2RA exposure was not associated with either ORR (OR 1.32, 95% CI 0.66–2.65) or AEs (OR 1.07, 95% CI 0.54–2.12) in multivariable analysis. Conclusions: Our results suggest that exposure to PPI/H2RA prior to ICIs does not adversely affect outcomes in HCC patients. [ABSTRACT FROM AUTHOR]

COVID-19 and liver cancer clinical trials: Not everything is lost Keywords: BTC; clinical trials; COVID-19; HCC; liver cancer; SARS-CoV-2 EN BTC clinical trials COVID-19 HCC liver cancer SARS-CoV-2 1541 1544 4 06/25/20 20200701 NES 200701 Since the first cases in Wuhan, China, during the month of December 2019, coronavirus disease (COVID-19) evolved into a worldwide emergency, becoming one of the deadliest pandemics of modern history. Furthermore, these patients do not always have a valid therapeutic standard-of-care alternative, so for us it was of utmost importance to ensure the continuum of care for these patients even during the pandemic. Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper. [Extracted from the article]

Aim: Regorafenib may be active in different cancer types. This Phase II trial included patients with various refractory cancer types treated with regorafenib. Here, we report the results of the pancreatic adenocarcinoma cohort. Methods: The primary end point was progression-free survival (PFS) rate at 8 weeks; further investigation of regorafenib would be warranted with a PFS rate ≥50%. Results: A total of 20 patients were enrolled. The best response was stable disease in four patients (20%). The 8-week PFS rate was 25% with a median PFS of 1.7 months (95% CI: 1.5-2.0). A total of 13 patients (65%) experienced grade 3-4 treatment-related adverse events. Conclusion: The study did not meet its primary end point. Further investigation of regorafenib monotherapy in this setting is not recommended. Clinical Trial Registration: NCT02307500. [ABSTRACT FROM AUTHOR]

Introduction: The randomized, placebo-controlled, phase III CELESTIAL trial demonstrated statistically and clinically significant improvement in overall survival with cabozantinib in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. Most frequently reported adverse events included palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea. Areas covered: In this review we analyze and discuss preclinical and clinical data of cabozantinib. We summarize efficacy and safety results of phase II and III trials of cabozantinib in the treatment of patients with advanced HCC and we present ongoing trials of cabozantinib in combination with checkpoint inhibitors. Expert opinion: Cabozantinib is a new second-line and the only third-line treatment for patients with advanced HCC, nevertheless some data are still missing to better inform clinical decisions on how to treat specific patient populations. Next trials designs will have to incorporate heavy efforts in terms of translational research to maximize the benefits of such treatments. [ABSTRACT FROM AUTHOR]

Over the past 10 years, sorafenib has been the only systemic agent approved for the treatment of patients with unresectable hepatocellular carcinoma. Recently, lenvatinib was demonstrated noninferior to sorafenib, and regorafenib and ramucirumab were demonstrated superior to placebo in patients progressing on sorafenib and in patients with elevated α-fetoprotein-failing sorafenib, respectively. Phase I-II trials of immune checkpoint inhibitors reported promising efficacy signals. Recently, the randomized, placebo-controlled, Phase III CELESTIAL trial demonstrated statistically and clinically significant increase in overall survival from 8 months with placebo to 10.2 months with cabozantinib in patients failing sorafenib. Furthermore, the study showed a significant improvement in all the efficacy end points. Main adverse events were palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue and diarrhea. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients' health-related quality of life. Fatigue, diarrhoea, hand-foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI-drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs. [ABSTRACT FROM AUTHOR]

Introduction: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC) and well preserved liver function. However, until recent approval of regorafenib by the Food and Drug Administration (FDA), no effective therapeutic options were available for patients resistant to sorafenib. Areas covered: The present article reviews the preclinical and clinical data of regorafenib, putting them into the context of current and future landscape of treatment options for patients with HCC. Recently, the randomized, placebo-controlled, Phase III RESORCE trial, demonstrated a statistically and clinically significant increase in overall survival from 7.8 months with placebo to 10.6 months with regorafenib in patients progressing on sorafenib. Furthermore, the study showed a significant improvement in all the other efficacy endpoints. Main adverse events were hypertension, hand-foot skin reaction, fatigue and diarrhea, with no negative impact on quality of life. Expert commentary: Regorafenib is a recently approved treatment option for HCC patients who have been previously treated with sorafenib. The RESORCE trial demonstrates the beneficial effect of a sequential approach involving two multikinase inhibitors, namely sorafenib and regorafenib, whose antitumor activity extends beyond their antiangiogenic functions. [ABSTRACT FROM AUTHOR]

KRAS mutant colorectal cancer ( CRC) patients develop lung and brain metastases more frequently than KRAS wild-type ( WT) counterpart. We retrospectively investigated the prognostic role of KRAS, BRAF, and PIK3 CA (exon 20) mutations and loss of phosphatase and tensin homolog ( PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC ( mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty-four percent of patients had KRAS WT lung metastases. PTEN loss-of-function was found in 75%. BRAF and PIK3 CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival ( OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression-free survival ( PFS) and lung disease-free survival ( LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status ( OS Hazard ratio ( HR) 2.17, 95% IC 1.19-3.96, P = 0.012) and lack of adjuvant chemotherapy ( OS HR 0.10, 95% IC 0.01-0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy ( LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Current guidelines recommend pre-therapeutic UGT1A1 genotyping to guide irinotecan dosing, but the usefulness of this approach remains to be clarified. In 247 patients with advanced gastrointestinal cancers undergoing irinotecan-based chemotherapy, we prospectively performed UGT1A1*28 genotyping and we analyzed the incidence of severe neutropenia according to genotype-guided dose reductions. Overall, 28 (11.3%) and 92 (37.2%) patients were homozygous or heterozygous UGT1A1*28 carriers, respectively. Grade ≥ 3 neutropenia was reported in 39% of homozygous patients receiving an upfront dose reduction of irinotecan (median 40%, range 22–58%), in 20% of heterozygous or wild-type patients receiving full dose (ORvs*28/*28 genotype = 0.38; 95% CI: 0.14–1.03; p = 0.058), and in 15.3% of those receiving a reduced dose for clinical reasons (OR vs*28/*28 genotype = 0.28, 95% IC: 0.12–0.67; p = 0.004). Occurrence of severe neutropenia was inversely associated with dose reduction in UGT1A1*28 homozygous carriers (ORx10 unit = 0.62, 95% CI: 0.27–1.40, p = 0.249) and UGT1A1 heterozygous or wild-type patients (ORx10 unit = 0.87, 95% CI: 0.59–1.28, p = 0.478). Incidence of severe neutropenia was related to irinotecan doses and UGT1A1 polymorphisms. Upfront irinotecan dose reductions do not reduce the burden of grade ≥ 3 neutropenia in UGT1A1*28 homozygous carriers. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-dose aspirin has a preventive effect against multiple malignancies, including hepatocellular carcinoma. Whether aspirin could also ameliorate the prognosis of patients who already developed advanced cancer remains an elusive question. In the case of hepatocellular carcinoma, randomized clinical trials are difficult to design and observational studies suffer from multiple biases. We tried to address these problems performing a large-scale observational study, which allowed multiple corrections to reduce the main known biases. We found that among patients who received sorafenib as an antineoplastic treatment, patients who concurrently received aspirin had better outcomes than non-aspirin users. Once the confounders were properly addressed, this advantage was confirmed, albeit at the cost an increased rate of minor bleeding events. Even if we are aware that confirmatory randomized clinical trials are difficult to organize, our results warrant further investigation, as aspirin might be a low-cost, effective and safe additional treatment for selected patients with advanced hepatocellular carcinoma. Case–control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders and safety concerns are to be considered. In our retrospective analyses of a prospective dataset (n = 699), after assessing the factors associated with aspirin prescription, we applied an inverse probability treatment weight analysis to address the prescription bias. Analyses of post-sorafenib survival were also performed to reduce the influence of subsequent medications. Among the study population, 133 (19%) patients were receiving aspirin at the time of sorafenib prescription. Aspirin users had a higher platelet count and a lower prevalence of esophageal varices, macrovascular invasion, and Child–Pugh B status. The benefit of aspirin was confirmed in terms of overall survival (HR 0.702, 95% CI 0.543–0.908), progression-free survival, disease control rate (58.6 vs. 49.5%, p < 0.001), and post-sorafenib survival even after weighting. Minor bleeding events were more frequent in the aspirin group. Aspirin use was associated with better outcomes, even after the correction for confounders. While safety concerns arguably remain a problem, prospective trials for patients at low risk of bleeding are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatitis is a relatively frequent immune-related adverse event in patients with hepatocellular carcinoma receiving immunotherapy, but risk factors and clinical course are unclear. Herein, we show that the development of high-grade hepatitis is associated with increased baseline ALT levels and infectious etiology of hepatocellular carcinoma (related to prior hepatitis B or C virus exposure). In addition, when resolved, high-grade hepatitis does not preclude treatment resumption and does not affect subsequent time to treatment failure. Analysis of baseline tumor specimens, at a preliminary level, suggests that biological features reminiscent of the hepatocellular carcinoma "immune class" could protect against high-grade hepatitis development, thereby warranting further investigation. 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. [ABSTRACT FROM AUTHOR]