The global burden of hepatocellular carcinoma (HCC) is increasing and might soon surpass an annual incidence of 1 million cases Genomic studies have established the landscape of molecular alterations in HCC; however, the most common mutations are not actionable, and only ~25% of tumours harbour potentially targetable drivers Despite the fact that surveillance programmes lead to early diagnosis in 40–50% of patients, at a point when potentially curative treatments are applicable, almost half of all patients with HCC ultimately receive systemic therapies Sorafenib was the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months New drugs — lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line — have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year; thus, therapeutic breakthroughs are still needed Immune-checkpoint inhibitors are now being incorporated into the HCC treatment armamentarium and combinations of molecularly targeted therapies with immunotherapies are emerging as tools to boost the immune response Research on biomarkers of a response or primary resistance to immunotherapies is also advancing Herein, we summarize the molecular targets and therapies for the management of HCC and discuss the advancements expected in the near future, including biomarker-driven treatments and immunotherapies

/pdf/molecular-therapies-and-precision-medicine-for-2x6pqv3elt.pdf

Molecular therapies and precision medicine for hepatocellular carcinoma

The targeting of vascular endothelial growth factor A (VEGFA), a crucial regulator of both normal and pathological angiogenesis, has revealed innovative therapeutic approaches in oncology and ophthalmology. The first VEGFA inhibitor, bevacizumab, was approved by the US Food and Drug Administration in 2004 for the first-line treatment of metastatic colorectal cancer, and the first VEGFA inhibitors in ophthalmology, pegaptanib and ranibizumab, were approved in 2004 and 2006, respectively. To mark this tenth anniversary of anti-VEGFA therapy, we discuss the discovery of VEGFA, the successes and challenges in the development of VEGFA inhibitors and the impact of these agents on the treatment of cancers and ophthalmic diseases.

/pdf/ten-years-of-anti-vascular-endothelial-growth-factor-therapy-1grc0lcuq6.pdf

Ten years of anti-vascular endothelial growth factor therapy

https://www.auajournals.org/doi/pdf/10.1097/JU.0000000000000309

Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline Amendment

Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline

Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.

Advances in targeted therapies for hepatocellular carcinoma in the genomic era

Results of a randomized phase III trial of mirabegron in patients with overactive bladder.

1958 THE SELECTIVE β3-ADRENORECEPTOR AGONIST MIRABEGRON IS EFFECTIVE AND WELL TOLERATED IN PATIENTS WITH OVERACTIVE BLADDER SYNDROME

Hypothesis / aims of study Oral anti-muscarinic agents are currently the mainstay of the therapeutic armamentarium for the treatment of overactive bladder (OAB), However, some patients have a suboptimal response to anti-muscarinic agents or find that anti-muscarinic therapy is limited by associated adverse events (AEs; e.g. dry mouth) [1]. In the absence of another class of therapeutic agent for the treatment of OAB symptoms, these patients either persist with an unsatisfactory treatment or simply discontinue pharmacotherapy. Mirabegron, a potent and selective β3-adrenoceptor agonist, is currently in development for the treatment of OAB and may provide an alternative therapeutic option to anti-muscarinics in such patients. β3-adrenoceptor agonist-elicited relaxation of the detrusor is only manifested during the storage phase of the micturition cycle, improving the storage capacity of the bladder without impeding bladder contraction during voiding. The aim of this phase 3 study was to assess the efficacy and tolerability of once-daily mirabegron in North American patients with OAB.

Efficacy and tolerability of once-daily mirabegron, a potent and selective ß3-adrenoceptor agonist, in patients with overactive bladder – results from a North American Phase III trial

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Results of a randomized phase III trial of mirabegron in patients with overactive bladder.

1958 THE SELECTIVE β3-ADRENORECEPTOR AGONIST MIRABEGRON IS EFFECTIVE AND WELL TOLERATED IN PATIENTS WITH OVERACTIVE BLADDER SYNDROME

Efficacy and tolerability of once-daily mirabegron, a potent and selective ß3-adrenoceptor agonist, in patients with overactive bladder – results from a North American Phase III trial