SEOM-GEMCAD-TTD clinical guidelines for the management of hepatocarcinoma patients (2023).

Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child-Pugh class A.

Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma.

The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-ß) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-ß-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-ß. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells. Results have indicated that NOX4 is required for an efficient SMAD2/3 phosphorylation in response to TGF-ß, whereas non-canonical signals, such as the phosphorylation of the Epidermal Growth Receptor or AKT, are higher in NOX4 silenced cells. TGF-ß-mediated inhibition of cell proliferation and viability is attenuated in NOX4 silenced cells, correlating with decreased response in terms of apoptosis, and maintenance of high expression of MYC and CYCLIN D1. These results would indicate that NOX4 is required for all the tumor suppressor actions of TGF-ß in HCC. However, analysis in human HCC tumors has revealed a worse prognosis for patients showing high expression of TGF-ß1-related genes concomitant with high expression of NOX4. Deepening into other tumorigenic actions of TGF-ß that may contribute to tumor progression, we found that NOX4 is also required for TGF-ß-induced migratory effects. The Epithelial-Mesenchymal transition (EMT) program does not appear to be affected by attenuation of NOX4 levels. However, TGF-ß-mediated regulation of cytoskeleton dynamics and focal adhesions require NOX4, which is necessary for TGF-ß-induced increase in the chaperone Hsp27 and correct subcellular localization of Hic-5 within focal adhesions, as well for upregulation of the metalloprotease MMP9. All these results together point to NOX4 as a key element in the whole TGF-ß signaling in HCC cells, revealing an unknown role for NOX4 as tumor promoter in HCC patients presenting activation of the TGF-ß pathway.

Efficacy and safety of maintenance therapy with pamiparib versus placebo for advanced gastric cancer responding to first-line platinum-based chemotherapy: Phase 2 study results.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB-290) is a small molecule inhibitor of PARP1 and PARP2. METHODS: The PARALLEL-303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line chemotherapy. The primary endpoint of this double-blind, randomized, global phase 2 study was progression-free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. RESULTS: In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. CONCLUSIONS: Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified.

Survival and adverse events of elderly patients treated with sorafenib for hepatocellular carcinoma.

Introduction: The first-line treatment for advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab, but its availability is not universal and elderly patients are underrepresented in clinical trials. There is little evidence of efficacy and tolerability in elderly patients under systemic treatment. The aims of this study were to characterize the profile of elderly patients treated with sorafenib, assess their survival and safety profile in order to extrapolate their eligibility for systemic treatment. Methods: Retrospective multicentre study of HCC patients aged ≥75 years old treated with sorafenib from January 2008 to December 2019. Demographic data, baseline characteristics, and variables related to HCC and sorafenib were recorded. Overall survival (OS) and safety were analyzed. Results: The study included 206 patients from 11 hospitals, median age 77.9 years; 71.4% men and 62.6% stage Barcelona Clinic Liver Cancer- C (BCLC-C). The main causes of cirrhosis were hepatitis C (60.7%) and alcohol (14.7%). Most patients (84.5%) started with sorafenib 800mg and 15.5% at lower dosage. Arterial hypertension (AHT) (74.2 vs 62.2%; standardized mean differences (STD): 26) and baseline ECOG-PS>0 (45.3 vs 34.7%; STD: 38.2) differed significantly between patients receiving low and full doses. Median OS was 15.4 months (18.2 in BCLC-B vs 13.6 in BCLC-C). OS was not modified by comorbidities, age or period with more expertise. Conclusions: Sorafenib appears to be safe in elderly patients with HCC. This is the first study to characterize the profile of elderly patients to be considered for systemic treatment. These findings could be used as the reference profile for elderly candidates for atezolizumab-bevacizumab.

Myasthenia Gravis Induced by Immune Checkpoint Inhibitors: An Emerging Neurotoxicity in Neuro-Oncology Practice: Case Series.

Immunotherapy with immune checkpoint inhibitors (ICIs) have been reported to induce de novo or exacerbate pre-existing Myasthenia Gravis (MG). We present a single center case series of patients who developed an immune-related myasthenia gravis (irMG) related with ICIs. We performed a retrospective chart review of the electronic medical records between 1 September 2017 and 2022. We report the clinical features, presentation forms, diagnostic workflows, general management and outcomes of six patients who received ICIs for different solid organ malignancies and developed an irMG frequently overlapping with immune-related myocarditis and/or myositis. The aim of the article is to describe the clinical features, treatment and outcomes of this challenging and potentially life-threating syndrome, comparing our data with those described in the literature. Differences between irMG and classic MG are highlighted.

The TGF-ß Pathway: A Pharmacological Target in Hepatocellular Carcinoma?

Transforming Growth Factor-beta (TGF-ß) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-ß signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-ß plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-ß can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-ß pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-ß inhibitory therapies. Here we review the functions of TGF-ß on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-ß signaling for cancer therapy. We also summarize the clinical impact of TGF-ß inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.

Duloxetine against symptomatic chemotherapy-induced peripheral neurotoxicity in cancer survivors: a real world, open-label experience.

The objective of this observational study was to evaluate the efficacy and safety of duloxetine in a cohort of 100 cancer survivors with chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN was graded employing the TNSc and the NCI-CTCv4. The Patient Global Impression of Change (PGIC) scale measured the efficacy of duloxetine (1: no benefit; to 7: excellent response). A clinically meaningful response was considered a PGIC > 4. Median age was 62 (29-81) years and 42% were male. CIPN was graded as grades 1, 2 and 3 in 20, 66, and 14% of patients, respectively. Median time to duloxetine initiation was 6 (1-63) months after chemotherapy. Fifty-seven patients early dropped out from duloxetine, due to lack of efficacy (20%) or side effects (37%). Male patients more frequently discontinued duloxetine due to lack of efficacy (35.7 vs. 8.6% P = 0.001). PGIC scores were higher in female patients (4 vs. 1, P = 0.001), taxane-treated patients (4 vs. 1, P = 0.042) and with short-lasting (<6 months) CIPN (4 vs. 1, P = 0.008). Patients with long-lasting CIPN had a higher rate of adverse events (47 vs. 27%, P = 0.038) and discontinuation (54.8 vs. 45.1%, P = 0.023). In the multivariate analysis, female gender and short-lasting CIPN were independently associated with a favorable response to duloxetine. Low tolerability, male gender, and long-lasting CIPN significantly limited duloxetine use in daily practice setting. A minority of cancer survivors with CIPN treated with duloxetine had a meaningful CIPN improvement, and tolerability was overall low. Female gender and short-term CIPN were independently associated with a favorable response to duloxetine.

External validity of docetaxel triplet trials in advanced gastric cancer: are there patients who still benefit?

BACKGROUND: The purpose of our study was to develop an online calculator to estimate the effect of docetaxel triplets (DPF) in first line of advanced gastric cancer (AGC), and to assess the external validity of docetaxel trials in individual patients. METHODS: The study includes patients with HER2(-) AGC treated with platin and fluoropyrimidine (PF) or with DPF in first line. Treatment effect and interactions were assessed using Bayesian accelerated failure time models. RESULT: The series comprises 1376 patients; 238 treated with DPF and 1138 with PF between 2008 and 2019. DPF was associated with increased progression-free survival (PFS) and overall survival (OS) with time ratio (TR) 1.27 (95% credible interval [CrI], 1.15-1.40), and TR 1.19 (95% CrI, 1.09-1.27), respectively. Serious adverse events were more common with DPF, particularly hematological effects (32% vs 22%). Younger participants received greater DPF dose density without achieving greater disease control, while severe toxicity was likewise higher. DPF yielded superior OS in Lauren intestinal (TR 1.27, 95% CrI, 1.08-1.11) vs diffuse subtype (TR 1.17, 95% CrI, 1.09-1.24) and the probability of increasing OS > 15% was 90% vs 67% in each subtype, respectively. The effect dwindles over time, which can be attributed to pathological changes and clinical practice changes. CONCLUSION: Our study confirms the effect of DPF is highly dependent on several clinical-pathological variables, with discreet and gradually declining benefit over platinum doublets in later years, at the expense of increased toxicity. These results may help to underpin the idea that external validity of AGC trials should be revised regularly.

Endoscopic biliary drainage in unresectable biliary obstruction: the role of endoscopic ultrasound-guidance in a cohort study.

BACKGROUND AND STUDY AIMS: the use of endoscopic ultrasound-guided biliary drainage (EUS-BD) has increased in cases of failed endoscopic retrograde cholangiopancreatography (ERCP) and there are some concerns. The main aim of the study was to determine the role of EUS-BD in a palliative case cohort. The secondary aim was to compare the efficacy, safety and survival of EUS-BD and ERCP procedures. PATIENTS AND METHODS: this was an observational study at a single tertiary institution, with a consecutive inclusion from January 2015 to December 2016. The inclusion criteria were unresectable tumors of the biliopancreatic region with an indication of BD. Statistical comparison analysis was performed between the ERCP and EUS-BD groups. The incidence between groups was compared using the Chi-square and Fisher exact tests. The log rank test was used to compare the risk of death. RESULTS: fifty-two cases with an indication of palliative BD were included in the study. Transpapillary drainage via ERCP was possible in 44 procedures and EUS-BD was required in eight cases; 15.4% of the cohort and seven using lumen apposing metal stent (LAMS). The technical and clinical success of global endoscopic BD was 100% and 88.5% (ERCP: 84.6% and 78.9%; EUS-BD: 100% and 62.5%, respectively). Pancreatitis was the most frequent adverse event (AE) in the ERCP group (9.62%) and bleeding in the EUS-BD (25%). There were fatal AEs in ERCP (1.9%) and EUS-BD (25%) cases. Patient survival was higher with ERCP transpapillary stents compared to EUS-guided stents, which was statistically significant (p = 0.007). CONCLUSIONS: the requirement of EUS-BD in palliative biliopancreatic pathology is not marginal. EUS-BD is associated with a lower survival rate and a higher rate of fatal AE, which argues against its use as a first choice procedure.

A fresh look at polymicrobial bloodstream infection in cancer patients.

OBJECTIVES: To assess the current incidence, clinical features, risk factors, aetiology, antimicrobial resistance and outcomes of polymicrobial bloodstream infection (PBSI) in patients with cancer. METHODS: All prospectively collected episodes of PBSI in hospitalised patients were compared with episodes of monomicrobial bloodstream infection (MBSI) between 2006 and 2015. RESULTS: We identified 194 (10.2%) episodes of PBSI and 1702 MBSI (89.8%). The presence of cholangitis, biliary stenting, neutropenia, corticosteroids, neutropenic enterocolitis and other abdominal infections were identified as risk factors for PBSI. Overall, Gram-negative organisms were the most frequent aetiology, but Enterococcus spp. were especially frequent causes of Gram-positive PBSI (30.8%). Multidrug-resistant (MDR) organisms were more commonly found in PBSI than in MBSI (20.6% vs 12.9%; p = 0.003). Compared to patients with MBSI, those with PBSI presented with higher early (15% vs 1.4%; p = 0.04) and overall (32% vs 20.9%; p<0.001) case-fatality rates. Risk factors for overall case-fatality were a high-risk MASCC (Multinational Association of Supportive Care in Cancer) index score, corticosteroid use, persistent bacteraemia and septic shock. CONCLUSIONS: PBSI is a frequent complication in patients with cancer and is responsible for high mortality rates. Physicians should identify patients at risk for PBSI and provide empiric antibiotic therapy that covers the most frequent pathogens involved in these infections, including MDR strains.

Clinical relevance of histologic subtypes in locally advanced esophageal carcinoma treated with pre-operative chemoradiotherapy: Experience of a monographic oncologic centre.

BACKGROUND: Locally advanced esophageal carcinoma (LAEC) represents less than 30% of all diagnosed esophageal carcinoma worldwide. The standard of care for resectable tumours consists of preoperative chemoradiotherapy (CRT) followed by surgery. Despite the curative intent, the prognosis is still poor mainly due to relapse. A multidisciplinary approach is required in order to optimize the therapeutic strategy and follow-up. Differences in outcomes between the two main histological subtypes, adenocarcinoma (ADC) and squamous cell carcinoma (SCC), have been reported. Nevertheless, the heterogeneity in trials design and data available have hampered the achievement of clear conclusions. The purpose of this study is to report the outcomes from a cohort of patients with LAEC treated with a multidisciplinary approach and to remark the differences observed between the two main histologic subtypes and their clinical implications. METHODS: We retrospectively reviewed 100 patients diagnosed with LAEC that were treated with preoperative CRT at our institution and integrated centres. Histopathological characteristics and toxicities during treatment were recorded. Patterns of recurrence at the first relapse were analysed. Survival curves were plotted using the Kaplan Meier method and multivariate Cox proportional hazards models were used. RESULTS: Among the patients who received preoperative CRT, 83% underwent surgery. The median overall survival (mOS) was 31.7 months, 26.9 months for ADC and 45.5 for SCC (p-value = 0.33). In the multivariate Cox regression analysis, ypN+ was the only factor that negatively influenced in OS (OR = 4.1, p-value = 0.022). Patterns of recurrence differed according to histologic subtype. Distant relapse was more frequent in ADC (62%), whereas locoregional relapse was higher in SCC (50%) (p-value = 0.027). Second line therapeutic strategies could be offered to 50% of those patients who relapsed. CONCLUSIONS: Differences in outcomes and recurrence pattern could be observed between the two main histologic subtypes of LAEC. A better molecular characterization, adapted therapeutic regimens and follow up strategies should be adopted in order to improve survival of these patients.

Bloodstream infections in neutropenic patients with cancer: differences between patients with haematological malignancies and solid tumours.

OBJECTIVES: We sought to identify the characteristics, aetiology, antibiotic resistance and outcomes of bloodstream infection (BSI) in neutropenic patients with haematological malignancies (HM) and in those with solid tumours (ST) and assess their impact on empirical therapy and outcomes. METHODS: All episodes of BSI in neutropenic patients with HM and ST were prospectively recorded and compared. RESULTS: Of 579 episodes of BSI, 493 occurred in patients with HM and 86 in patients with ST. An endogenous source and catheter-related infection were more frequent in patients with HM, whereas pneumonia and urinary tract were more common in the ST group. BSI was mainly due to Gram-negative bacilli. Coagulase-negative staphylococci were more frequent in patients with HM, while Pseudomonas aeruginosa was more common in patients with ST and was the leading cause of pneumonia. Multidrug-resistant Gram-negative bacilli (MDRGNB) were more frequently isolated in haematological patients who more often received inadequate empirical therapy than those with ST. Case-fatality rates were higher in patients with ST. CONCLUSIONS: We identified significant differences in BSI in neutropenic patients with HM and ST. MDRGNB were more often isolated in patients with HM. Pneumonia due to P. aeruginosa was particularly frequent among patients with ST. Case-fatality rates were higher in patients with ST.

Epidemiology, antibiotic therapy and outcomes of bacteremia caused by drug-resistant ESKAPE pathogens in cancer patients.

PURPOSE: Infection due to the six ESKAPE pathogens has recently been identified as a serious emerging problem. However, there is still a lack of information on bacteremia caused by these organisms in cancer patients. We aimed to assess the epidemiology, antibiotic therapy and outcomes of bacteremia due to drug-resistant ESKAPE pathogens (rESKAPE) in patients with cancer. METHODS: All episodes of bacteremia prospectively documented in hospitalized adults with cancer from 2006 to 2011 were analyzed. RESULTS: Of 1,148 episodes of bacteremia, 392 (34 %) were caused by ESKAPE pathogens. Fifty-four episodes (4.7 %) were due to rESKAPE strains (vancomycin-resistant Enterococcus faecium 0, methicillin-resistant Staphylococcus aureus (MRSA) 13, extended-spectrum beta-lactamase (ESLB)-producing Klebsiella pneumoniae 7, carbapenem-resistant Acinetobacter baumannii 4, carbapenem- and quinolone-resistant Pseudomonas aeruginosa 18 and derepression chromosomic ß-lactam and ESBL-producing Enterobacter species 12. Risk factors independently associated with rESKAPE bacteremia were comorbidities, prior antibiotic therapy, urinary catheter and urinary tract source. Inappropriate empirical antibiotic therapy was more frequent in patients with rESKAPE bacteremia than in the other cases (55.6 % vs. 21.5 %, p < 0.001). Persistence of bacteremia (25 % vs. 9.7 %), septic metastasis (8 % vs. 4 %) and early case-fatality rate (23 % vs. 11 %) were more frequent in patients with rESKAPE bacteremia than in patients with other etiologies (p < 0.05). CONCLUSIONS: Bacteremia due to rESKAPE pathogens in cancer patients occurs mainly among those with comorbidities who have received prior antibiotic therapy and have a urinary tract source. These patients often receive inappropriate empirical antibiotic therapy and have a poor outcome.