Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer

Antiangiogenic therapy with vascular endothelial growth factor (VEGF) inhibitors is the current first-line treatment in metastatic renal cell carcinoma (mRCC). Immunotherapy with checkpoint inhibitor has been recently added to the armamentarium of mRCC treatment. These therapies are based on treatment with antibodies that block programmed cell death-1 (PD-1), programmed cell death ligand 1 (PD-L1) pathways, demonstrating impressive response rates and improved survival in several tumour types. So far, nivolumab is the only approved anti-PD-1 monoclonal antibody after VEGF therapy in mRCC. According to preclinical and clinical studies, combination therapies with VEGF- and checkpoint inhibitors have synergistic effect achieving improved response rates. However, toxicity in some combinations is high. In this article, we present a review of the ongoing trials with these drug combinations for RCC.     

Small molecule and novel treatments for chronic hepatitis C virus infection

The development of molecular-based therapies for the treatment of chronic hepatitis C virus (HCV) infection is an area of intense clinical research, driven by the inability of the current standard of care, combination therapy with pegylated interferon alfa (PEG-IFNalpha) and ribavirin (RBV), to achieve a sustained virologic response (SVR) in a large proportion of patients and by the lack of approved alternative therapies for PEG-IFNalpha/RBV nonresponders and relapsers. Agents being developed against specific HCV viral proteins have recently been termed Specifically Targeted Antiviral Therapy for HCV (STAT-C). Preliminary data for several agents show they have high antiviral activity, especially when used in combination with PEG-IFNalpha, and are tolerable, but resistance mutations have been identified. Further study is needed to clarify the safety, tolerability, and efficacy of these compounds. Once established, the potential for shorter treatment strategies could then be evaluated. Other novel therapies in development that may improve both outcomes and tolerability include a prodrug of RBV and an albumin-modified IFNalpha. In conclusion, small molecule and novel therapies for HCV infection are showing promise in clinical trials, and research to develop new agents and optimize treatment regimens is ongoing.     

Recent treatment advances in Hodgkin lymphoma: a concise review

The majority of patients with Hodgkin lymphoma enjoy durable remissions following front‐line treatment. This typically involves combination chemotherapy with or without radiotherapy. A significant minority of patients experience relapsed/refractory disease, of whom only approximately half can be ‘salvaged’ with conventional second‐line treatments. Until recently, for those patients either failing or who are not fit for salvage, there have been few curative alternatives. Furthermore, there is a significant risk of delayed treatment complications to conventional therapies, including secondary malignancies and cardiac disease. However, novel targeted therapies are producing excellent results in clinical trials. They provide additional treatment options for those with relapsing/refractory disease; they may have potential in front‐line therapy. The anti‐CD30 antibody brentuximab vedotin (BV) has been tested as monotherapy and in combination in a variety of clinical settings, including in relapsed/refractory patients and as consolidative therapy following standard second‐line therapy. Nivolumab and pembrolizumab, currently used in other malignancies that are known to utilise the programmed death pathway for survival, have shown outstanding results when used as single agents in heavily pre‐treated (including BV refractory) patients. Individualising and adapting a patient's treatment course, whether augmenting or rationalising therapy, based on an interim positron emission tomography/computed tomography response is an important strategy currently under exploration to minimise toxicity while maximising response. Further work is needed to explore clinical and biological factors associated with improved outcomes. Knowledge of these factors combined with the movement of novel therapies into the front‐line setting will enable individualised therapy to enhance clinical responses and minimise toxicities.     

Endoscopic therapy for gastroesophageal reflux disease

Endoscopic therapies aimed to reduce gastroesophageal reflux have gained an enormous enthusiasm during the last 5 years when several of them were approved by the regulatory agencies and released on the market. These novel therapies comprise 3 types of techniques: injection/bulking, plicating/suturing and radiofrequency thermal injury. Open-labelled trials performed on proton pump inhibitors-responding patients with typical gastroesophageal reflux disease (GERD) symptoms have shown an improvement in reflux symptoms during short term follow-up. Longer-term data are now available and show disappointing results with partial-thickness plications of the cardia. Randomized sham-controlled trials, which are essential to proof the efficacy of GERD endotherapy because of a known high placebo effect in the management of GERD patients, have been conducted, one with radiofrequency and one with polymer injection, and have confirmed the clinical efficacy of both techniques, although the clinical benefit was less impressive than suggested in open-labelled trials. While mechanistic studies have suggested that the compliance of the gastroesophageal junction might be altered by GERD endotherapy, objective assessment of acid reflux with ambulatory pH-metry has shown, however, minimal or no modification by the treatment. Concerns about the safety of these new techniques have raised when complications were reported as the number of treated cases increased. Currently, no definite indication is established for each technique, but numerous potential indications exist and should be addressed in the setting of carefully designed clinical trials. Physicians should be patient and wait for proof of efficacy and safety of these techniques before using them in their clinical practice. Specific and extensive warning should be obtained before starting clinical application. The present review aims to provide a comprehensive and critical view of endoscopic therapy in GERD management.     

Current concepts in the antithrombotic management of non-ST-elevation acute coronary syndromes

The recognition that thrombosis is fundamental to acute coronary syndromes (ACS) has inspired the development of novel therapies to inhibit platelet aggregation and thrombus formation. Several recent advances have been made in the management of patients with non-ST-segment elevation ACS (NSTE ACS) to improve early and late clinical outcomes. The research efforts leading to these improvements in care have focused on antiplatelet and anticoagulant therapies coupled with early invasive treatment options. In particular, ongoing clinical trials seek to refine treatment strategies for patients relative to individual risk presentation, the availability of facilities for invasive procedures, and the timing of revascularization. However, even despite the proven efficacy of currently available therapies to reduce the occurrence of death and/or myocardial infarction, still many eligible patients with high-risk NSTE ACS do not receive such treatments. This review provides a pathophysiologic rationale for antithrombotic therapies in ACS, examines the results of recent trials, and presents future directions for clinical investigation.     

Liraglutide in oral antidiabetic drug combination therapy

The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide is indicated as an add-on to oral antidiabetic drug regimens in subjects with type 2 diabetes. Herein, the results of clinical trials assessing the efficacy, safety and tolerability of liraglutide when used in combination with either one or two oral antidiabetic therapies are summarised, then contrasted with the effects of exenatide and dipeptidyl peptidase (DPP-4) inhibitors. GLP-1 receptor agonists lead to effective glycaemic control when used as combination therapy with either one or two oral antidiabetic agents, and may confer overall benefits in weight loss and blood pressure in some subjects. These agents are well tolerated; the most commonly reported adverse effect is mild-to-moderate gastrointestinal symptoms, which are usually transient. Rates of hypoglycaemia in these trials were low, although higher rates were noted when combined with a sulphonylurea. While further study will be required, GLP-1 receptor agonists may offer important advantages over other diabetic therapies, including DPP-4 inhibitors.     

Randomized trials with checkpoint inhibitors in acute myeloid leukaemia and myelodysplastic syndromes: What have we learned so far and where are we heading?

The treatment of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) has seen dramatic advances with the approval of multiple novel agents in recent years. However, unlike solid malignancies, immune checkpoint inhibitors have yet to garner regulatory approval in AML and MDS with recent randomized clinical trials yielding only underwhelming results. Novel targets have been explored in early phase clinical trials with impressive results leading to ongoing subsequent controlled trials. However, major challenges in the field remain such as the validation of predictive genetic, molecular, and immunophenotypic biomarkers, optimization of clinical trial design, and the identification of novel synergistic combination therapies. Herein, we review recent clinical trial data focusing on randomized clinical trials and highlight limitations of the currently available evidence in an effort to suggest options for advancing the field.     

Fixed combination therapies in COPD �C effect on quality of life

Chronic obstructive pulmonary disease (COPD) represents a major global cause of disability and death. COPD is currently the fourth most common global cause of death and also exerts an enormous toll on patients quality of life. The present database analysis aimed to identify clinical trials using fixed combination therapies that have assessed the impact on the patients quality of life. Within the different studies, questionnaires including the George’s Respiratory Questionnaire (SGRQ) the Chronic Respiratory Disease Questionnaire (CRDQ) and the Clinical COPD Questionnaire (CCQ) were used and differing results in quality of life were obtained when combination therapies such as fluticasone/salmeterol or fluticasone/salmeterol were compared with monotherapies. While there were some differences in favor of combination therapies reported when the combination therapy was compared to inhaled steroid monotherapy there were no consistent differences when combination therapies were compared to bronchodilator monotherapies. Future trials will lead to a proof-of-principle stage concerning the use of combination therapies.     

CAR T and CAR NK cells in multiple myeloma: Expanding the targets

Multiple myeloma (MM) is a haematologic malignancy with significant improvements in the overall survival over the last decade. However, patients still relapse and die due to a lack of treatment options. Ultimately, novel therapies with the potential for long term remissions are needed for patients with advanced MM. Research efforts for such immune therapies were not successful until recently when the first immunotherapies for MM were approved in 2015 and many more are under development. In this review, we focus on adoptive cell therapies including CAR T-cell and CAR NK-cell therapies for patients with MM. We will provide an update on clinical and translational advances with a focus on results from ongoing clinical trials with BCMA targeted cellular therapies and the development of other novel targets, changes in the manufacturing process, trials focusing on earlier lines of therapy and combinations with other therapies as well as off the shelf products.     

New therapeutic approaches to hepatitis C virus

Year 201X will see a huge battle against hepatitis C virus (HCV) infection. HCV, a leading cause of end stage diseases and hepatocellular malignancies, is a negative legacy of the past in many regions worldwide, and has long been refractory to conventional treatments. The most effective peginterferons and ribavirin-based antiviral therapies can eliminate the virus in only half of patients treated, and the treatments are often poorly tolerated. Recently, the development of an HCV cell culture system has become a turning point of basic research. At present, novel therapeutic agents with different mechanisms of action are under development or on clinical trials. Some of these drugs have been proven to be effective when used with the conventional treatments, and may constitute antiviral therapies without being used in combination with interferons. This article reviews the current status of preclinical drug development, ongoing clinical trials, and near future perspectives in the field of HCV therapeutics.     

In vitro preclinical models for a rational design of chemotherapy combinations in human tumors

Today, drug combinations are frequently used in the treatment of cancer to increase therapeutic efficacy. Currently used clinical protocols for cancer combination therapies are mainly obtained empirically or on the basis of results from previous clinical trials. Information obtained from clinical protocols is invaluable, but it is time-consuming, expensive and does not provide data on the biochemical and molecular mechanisms of interaction of the drugs used in combination treatments at cellular level. Therefore, in vitro drug combination studies on established cell lines or primary cell cultures play an important role in designing and optimising combination protocols. A variety of in vitro assays and different mathematics models have been developed to investigate cytotoxic effects and to analyse the type of drug interactions. Increased knowledge of the cellular targets of traditional and new drugs and the development of new technologies have resulted in a new role for the in vitro tests which are no longer used only to evaluate the cytotoxic effects of drugs, but also to investigate the interference on cell cycle, induction of apoptosis and molecular or biochemical interactions. A review on in vitro preclinical tests used to evaluate the effects of drug combinations and to design the rationale of combined chemotherapy protocols is presented.     

Combining drug and immune therapy: a potential solution to drug resistance and challenges of HIV vaccines?

According to the World Health Organization's 2007 estimates, close to 33 million people worldwide are living with HIV/AIDS. Over the past two decades, significant progress has been made in understanding HIV pathogenesis and disease progression, which has allowed the identification of a multitude of drug and vaccine targets. Although currently available drug therapies have greatly increased the time from HIV infection to development of AIDS, drug resistance is an inevitable consequence that limits the duration of successful treatment. Consequently, a preventative vaccine remains the top priority; however, no vaccine trial performed to date has shown efficacy in human trials. Therefore, we must use all of our current resources in new creative therapies and strive to develop new methods to reduce persistent viral levels until an effective preventative vaccine is developed. One possible strategy is to use therapeutic vaccination or immune modulators to augment the immune response while antiretroviral chemotherapy limits viral replication. This combination approach is being utilized with success in the treatment of Hepatitis B infections and several trials have been completed and others are ongoing to determine the potential of combination immunological and chemical therapies for HIV infection. We will review the progress to date of anti-HIV drugs, preventative vaccines, and therapeutic vaccines and discuss the future strategies of combination drug and vaccine therapeutic strategies in the fight against HIV.     

Bleeding profiles of anticoagulants, including the novel oral direct thrombin inhibitor ximelagatran: definitions, incidence and management

Ximelagatran is a novel oral direct thrombin inhibitor (oral DTI) that is currently in advanced clinical development for the prevention and treatment of thromboembolic events in a wide range of patient populations and indications. The clinical development of novel anticoagulant therapies requires that treatments be assessed according to both their clinical benefit (reduction of risk of thromboembolic events) and safety profile (primarily bleeding). Definition and assessment of bleeding severity is thus an important factor in clinical trial design. Lack of consistency in bleeding definitions used in different clinical trial programmes makes comparison of bleeding event data difficult. Standard bleeding definitions would be required to make fair comparisons between clinical trials possible. The definitions of bleeding events used in clinical trials of ximelagatran are broadly consistent with those used in many other major trials. Results of phase II and III trials comparing ximelagatran with currently available anticoagulant therapies demonstrate that ximelagatran can be used with fixed dosing with no coagulation monitoring, dose titration, or dose adjustment, without compromising efficacy or safety. The incidences of major bleeding events in clinical trials of ximelagatran have been low and similar to those with other anticoagulant drugs. Adequate treatment in case of emergency situations such as serious bleeding should include cessation of treatment and maintenance of adequate diuresis.     

Comparison of efficacy and safety of complementary and alternative therapies for scapulohumeral periarthritis: A protocol for Bayesian network meta-analysis

Background:Scapulohumeral periarthritis is a disease with high incidence and great pain. The current western treatments with many side effects, poor efficacy cannot fundamentally solve the problem. Complementary and alternative therapies have played an excellent role in the treatment of scapulohumeral periarthritis. However, it is not clear which complementary and alternative therapy is more effective. Therefore, we propose a protocol to compare the efficacy and safety of various complementary and alternative therapies through network meta-analysis (NMA) to provide choice guidance for the therapy.Methods:A comprehensive search will be conducted for randomized controlled trials of complementary and alternative therapy for scapulohumeral periarthritis as well as ongoing trials. The time limit is from the establishment of the database until January 2021. Literature and data extraction were completed independently by two researchers. Through pairwise comparison and meta-analysis of Bayesian NMA, all the evidences are evaluated comprehensively. STATA16.0 and WinBUGS1.4.3 software will be used for data processing and analysis, and recommendation evaluation will be used to develop and assess grades to classify the quality of NMA evidence.Results:Through the analysis, we will obtain the ranking of the efficacy and safety of different complementary and alternative therapies in the treatment of scapulohumeral periarthritis, in order to provide reference for clinical selection of treatment methods.Conclusion:Complementary and alternative therapies of scapulohumeral periarthritis plays a positive role in improving the symptoms of scapulohumeral periarthritis. This study can provide evidence support for clinicians and patients.International Platform of Registered Systematic Review and Meta-Analysis Protocols registration number: INPLASY202140044.     

Antiviral therapy for patients with chronic hepatitis C

Several large, randomized, controlled treatment trials in persons with hepatitis C and ongoing hepatitis have been reported recently. These have shown that, in patients without other comorbid conditions, treatment for from 6 to 12 months with a combination of interferon-alpha 2b, 3 MU three times a week (ttw), plus ribavirin, 1,000-1,200 mg daily, results in a higher incidence of sustained virologic response than does treatment with interferon-alpha 2b monotherapy, 3 MU ttw, given for similar durations. Patients who have relapsed after interferon monotherapy may achieve a sustained virologic response when retreated with interferon plus ribavirin for 6 months or when given a higher dose of interferon for a longer duration than the initial treatment. By contrast, patients who had no virologic response to prior interferon monotherapy have only a small chance of achieving a sustained response when similarly retreated. Although the efficacy of treatment for hepatitis C has improved steadily over the last decade, current interferon-based therapies still achieve a sustained virologic response in fewer than half of patients who initiate therapy, are associated with appreciable side effects, and are expensive. Furthermore, the natural history of chronic hepatitis C suggests that even in the absence of therapy, most patients with chronic hepatitis C infection may experience little morbidity or mortality for decades. Finally, published therapeutic trials stem largely from tertiary referral centers, where an especially high level of commitment is expected from both the patients and the team in charge of therapy. Typically, such trials have also excluded patients with comorbid diseases, thus reducing their "generalizability." This review focuses on two fundamental questions about the currently available treatments for this disease: Who should be treated with them? And when should they be treated? Critical analysis suggests that the answers to these questions are not as clear as they may superficially appear.     

Interferon and nucleoside analog combination therapy for hepatitis B

Interferon therapy has several advantages over nucleoside or nucleotide analog therapy: finite duration, durable treatment response, and no viral resistance. However, it is only effective in about 30% of patients. To improve its efficacy, the combination of interferon and nucleoside/nucleotide analogs may facilitate additive or synergistic effects. This is because interferon and nucleoside/nucleotide analogs have different mechanisms of action. Recent studies demonstrate that concomitant use of lamivudine and peginterferon does not improve biochemical and virological responses compared with peginterferon monotherapy. By contrast, sequential or staggered administration of lamivudine and interferon appears to have some benefits over monotherapies. There is a paucity of data on interferon combined with drugs other than lamivudine, such as adefovir and entecavir. Although combination therapies have the potential to improve efficacy against hepatitis-B virus, it is unclear how interferon should be combined with other drugs or which patients should be treated with combination therapies.     

An Update on the Clinical Development of Proprotein Convertase Subtilisin Kexin 9 Inhibitors,Novel Therapeutic Agents for Lowering Low‐Density Lipoprotein Cholesterol

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an essential role in the degradation of low‐density lipoprotein C (LDL‐C) receptors, and PCSK9 inhibitors have recently emerged as a potential treatment option to reduce LDL‐C. Our paper reviewed the current available Phase II clinical trials of PCSK9 inhibitors for the treatment of dyslipidemia. A second objective of this review was to evaluate the potential clinical role of PCSK9 inhibitors in the management of dyslipidemia. Studies evaluating the efficacy and safety of any PCSK9 inhibitors in patients with dyslipidemia were included. The monoclonal antibodies REGN727/SAR236553 and AMG145 have the most published clinical data. Seven phase II trials were retrieved that evaluated the efficacy and safety of REGN727/SAR236553 or AMG145 in patients with either hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). These two agents significantly decreased LDL‐C levels either as monotherapy or in combination with other lipid‐lowering agents. REGN727/SAR236553 and AMG145 have been well tolerated. The ongoing phase III trials of these two agents are summarized. REGN727/SAR236553 and AMG145 have demonstrated the potential to further decrease LDL‐C levels when added to conventional lipid‐lowering therapy. Morbidity and mortality data are required to define their roles in clinical practice.     

Recapitulation of the round-table discussion--assessing the role of anti-tumour necrosis factor therapy in the treatment of rheumatoid arthritis

Clinical trials specifically targeting and neutralizing the cytokine, tumour necrosis factor (TNF), have recently provided evidence of efficacy and a promise of a novel approach for the treatment and management of rheumatoid arthritis (RA). With the evolving emergence of anti-TNF therapeutics, several unresolved issues have come to light, including the assessment of safety and efficacy of current therapies, study design for new agents and cost-benefit issues. During an international meeting of leading rheumatologists and specialists, the majority opinion regarding the use of anti-TNF therapy was that these agents are most appropriate in patients with active disease who have insufficient response to methotrexate, which is presently considered the standard for RA treatment. Anti-TNF therapy was also recommended in patients with active disease unable to tolerate methotrexate therapy, or who have not responded to at least two other disease-modifying anti-rheumatic drugs (DMARDs). In patients with RA who have serious infection or malignancy, the use of anti-TNF therapies was not advised. Time, experience and clinical data from recently completed and currently ongoing studies of infliximab and etanercept, which will be available in the future, will help determine the ultimate role of such targeted therapeutics. Additional data on anti-TNF therapeutics as monotherapy or in various combinations are still needed to achieve maximum disease control safely with currently available DMARDs.     

Reporting of hypoglycaemia in clinical trials of basal insulins: A need for consensus

Hypoglycaemia is a common side-effect of diabetes therapies, particularly insulin, and imposes a substantial burden on individuals and healthcare systems. Consequently, regulatory approval of newer basal insulin (BI) therapies has relied on demonstration of a balance between achievement of good glycaemic control and less hypoglycaemia. Randomized controlled trials (RCTs) are the gold standard for assessing efficacy and safety, including hypoglycaemia risk, of BIs and are invaluable for obtaining regulatory approval. However, their highly selected patient populations and their conditions lead to results that may not be representative of real-life situations. Real-world evidence (RWE) studies are more representative of clinical practice, but they also have limitations. As such, data both from RCTs and RWE studies provide a fuller picture of the hypoglycaemia risk with BI therapies. However, substantial differences exist in the way hypoglycaemia is reported across these studies, which confounds comparisons of hypoglycaemia frequency among different BIs. This problem is ongoing and persists in recent trials of second-generation BI analogues. Although they provide a lower risk of hypoglycaemia when compared with earlier BIs, they do not eliminate it. This review describes differences in the way hypoglycaemia is reported across RCTs and RWE studies of second-generation BI analogues and examines potential reasons for these differences. For studies of BIs, there is a need to standardize aspects of design, analysis and methods of reporting to better enable interpretation of the efficacy and safety of such insulins among studies; such aspects include length of follow-up, glycaemic targets, hypoglycaemia definitions and time intervals for determining nocturnal events.     

Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues

In recent years, several authors have argued that placebo-controlled trials are invariably unethical when known effective therapy is available for the condition being studied, regardless of the condition or the consequences of deferring treatment. Some have also disputed the value of placebo-controlled trials in such a setting, asserting that the comparison of new treatment with old treatment is sufficient to establish efficacy and is all that should be of interest. This article considers the ethical concerns about use of placebo controls and describes the limited ability of active-control equivalence (also known as noninferiority) trials to establish efficacy of new therapies in many medical contexts. The authors conclude that placebo-controlled trials are not uniformly unethical when known effective therapies are available; rather, their acceptability is determined by whether the patient will be harmed by deferral of therapy. If patients are not harmed, such trials can ethically be carried out. Furthermore, active-control trials, although valuable, informative, and appropriate in many circumstances, often cannot provide reliable evidence of the effectiveness of a new therapy.