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Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine-arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte-specific SRSF3 knockout mice (SKO mice) also overexpress insulin-like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3-dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.

UnlabelledAlterations in RNA splicing are associated with cancer, but it is not clear whether they result from malignant transformation or have a causative role. We show here that hepatocyte-specific deletion of serine/arginine-rich splicing factor 3 (SRSF3) impairs hepatocyte maturation and metabolism in early adult life, and mice develop spontaneous hepatocellular carcinoma (HCC) with aging. Tumor development is preceded by chronic liver disease with progressive steatosis and fibrosis. SRSF3 protects mice against CCl4 -induced fibrosis and carcinogenesis and suppresses inclusion of the profibrogenic EDA exon in fibronectin 1. Loss of SRSF3 increases expression of insulin-like growth factor 2 and the A-isoform of the insulin receptor, allowing aberrant activation of mitogenic signaling, promotes aberrant splicing and expression of epithelial to mesenchymal transition (EMT) genes, and activates Wnt/β-catenin signaling leading to c-Myc induction. Finally, SRSF3 expression is either decreased or the protein mislocalized in human HCC.ConclusionOur data suggest a potential role for SRSF3 in preventing hepatic carcinogenesis by regulating splicing to suppress fibrosis, mitogenic splicing, and EMT. Thus, these mice may provide an attractive model to discover the pathogenic mechanisms linking aberrant pre-messenger RNA splicing with liver damage, fibrosis, and HCC.

Objective: To investigate whether exercise improves outcomes of surgery on fatty liver, and whether pharmacological approaches can substitute exercising programs. Summary of Background Data: Steatosis is the hepatic manifestation of the metabolic syndrome, and decreases the liver's ability to handle inflammatory stress or to regenerate after tissue loss. Exercise activates adenosine monophosphate-activated kinase (AMPK) and mitigates steatosis; however, its impact on ischemia-reperfusion injury and regeneration is unknown. Methods: We used a mouse model of simple, diet-induced steatosis and assessed the impact of exercise on metabolic parameters, ischemia-reperfusion injury and regeneration after hepatectomy. The same parameters were evaluated after treatment of mice with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Mice on a control diet served as age-matched controls. Results: A 4-week-exercising program reversed steatosis, lowered insulin levels, and improved glucose tolerance. Exercise markedly enhanced the ischemic tolerance and the regenerative capacity of fatty liver. Replacing exercise with AICAR was sufficient to replicate the above benefits. Both exercise and AICAR improved survival after extended hepatectomy in mice challenged with a Western diet, indicating protection from resection-induced liver failure. Conclusions: Exercise efficiently counteracts the metabolic, ischemic, and regenerative deficits of fatty liver. AICAR acts as an exercise mimetic in settings of fatty liver disease, an important finding given the compliance issues associated with exercise. Exercising, or its substitution through AICAR, may provide a feasible strategy to negate the hepatic consequences of energy-rich diet, and has the potential to extend the application of liver surgery if confirmed in humans. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed., Objective: To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib., Design, Setting, and Participants: Patients enrolled in KEYNOTE-426 were included in this study., Outcome Measurements and Statistical Analysis: Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s)., Results and Limitations: The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to <3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT <3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred., Conclusions: A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment., Patient Summary: Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management., (Copyright © 2021. Published by Elsevier B.V.)

Background/aims: This retrospective analysis compared progression-free survival (PFS) in 111 patients who developed or had preexisting hypertension with those who did not during treatment with second-line sunitinib. Secondary objectives included overall survival (OS) and safety., Methods: Patients with metastatic renal cell carcinoma (mRCC) received sunitinib 50 mg orally once daily in 6-week cycles according to a 4-week on/2-week off treatment schedule. Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. Resting blood pressure (BP) was monitored by clinic and home measurements. Hypertension was defined as systolic BP ≥140 and/or diastolic BP ≥90 mm Hg. Subsequent antihypertensive treatment was empirical, depending on the patient., Results: Fifty-four (48.6%) patients experienced elevated BP related to sunitinib. Of these, 10 had preexisting hypertension. Patients who developed hypertension related to sunitinib treatment experienced significantly longer PFS and OS compared to those who did not (p < 0.00001). Patients who required at least 3 antihypertensive drugs had the longest PFS (p = 0.00002) and OS (p = 0.00001)., Conclusions: The development of hypertension during sunitinib treatment was a positive predictive factor associated with a significantly longer PFS and OS in patients with mRCC., (Copyright © 2011 S. Karger AG, Basel.)

Purpose: When a patient with germ cell tumor (GCT) fails to be cured with high dose chemotherapy (HDC) and autologous haematopoietic stem cell transplantation (auto- BMT) the overall prognosis is very poor and any further treatment has only palliative character. A question requiring answer is how intense should this kind of treatment be, and what can be expected from it., Patients and Methods: Of 44 patients with GCT who were transplanted after HDC in our centre between 1999- 2005, 17 experienced treatment failure. Amongst them 14 had marker-positive relapse or confirmed germ cell histology. Another 3 had second primary neoplasms. Of the 17 patients 14 received further treatment that consisted of surgery alone in 2, chemotherapy in 2, radiotherapy in 1, combined surgery + chemotherapy in 5, chemotherapy +surgery + radiotherapy in 3 and chemotherapy + radiotherapy in 1 patient., Results: The median survival from the time of relapse was 3 months in all patients, and 6 months in the 14 patients who received further treatment. In 6 patients with relapse confined to a single site the median survival was 11 months. Three patients in this group are alive with overall survival (OS) of 37.4+, 24.3+ and 6.2+ months (all had multimodal treatment: chemotherapy + surgery or radiotherapy, and all achieved durable complete response/CR)., Conclusion: Our results suggest that GCT patients who have relapsed/ progressed after HDC may benefit from further treatment. Best chances for long term survival have those who experience relapse confined to one metastatic site and receive combined treatment (surgery or radiotherapy plus systemic therapy).

We evaluated the efficacy of allogeneic non-myeloablative stem cell transplantation (NST) in patients with metastatic renal cell carcinoma (RCC). A total of 5 patients received blood stem cells from HLA identical siblings. Conditioning consisted of: cyclophosphamide 60 mg/kg/d, days -7 to -6 and fludarabine 25 mg/m2/d for consecutive days [days -5, -4, -3, -2, -1]. The median CD34+ cell dose was 3.34 million/kg. Immunosuppression consisted of cyclosporine A and methotrexate. Among all, four patients achieved full donor chimerism with a median of 89 days. One patient rejected the graft and received the second transplantation. Grade II-III acute GVHD occured in 3 patients. None of patients achieved complete or partial response and there were only two mixed responses. All patients died due to cancer progression. There were no transplant-related deaths. Summarising, NST regimen allows allogeneic engraftment with low treatment related mortality in this high-risk population of patients. Acute and chronic GVHD are the major morbidities. Progression is common after NST in unselected patients with advanced RCC. However, regression of some metastases suggests that the graft versus tumor effect may occur after this type of treatment. At present such a procedure should be considered as an experimental approach.