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Haematologica Sep 2023The last decade has seen steadfast progress in drug development in acute myeloid leukemia (AML) which has moved progressively towards genomic-based therapy. With these... (Review)
Review
The last decade has seen steadfast progress in drug development in acute myeloid leukemia (AML) which has moved progressively towards genomic-based therapy. With these advances, outcomes in AML have improved but remains far from satisfactory. One approach towards preventing relapse in AML is to use maintenance therapy in patients, after attaining remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective post-remission therapy that has been proven to reduce the risk of relapse. However, in patients who are ineligible for HSCT or have a high risk of relapse, other effective measures to prevent relapse are needed. There is also a need for post-HSCT maintenance to reduce relapse in high-risk subsets. Over the last 3 decades maintenance therapy in AML has evolved from the use of chemotherapeutic agents to more targeted therapies and better modulation of the immune system. Unfortunately, improvements in survival outcomes as a result of using these agents have not been consistently demonstrated in clinical trials. To derive the optimum benefit from maintenance therapy the time points of therapy initiation need to be defined and therapy must be selected precisely with respect to the AML genetics and risk stratification, prior treatment exposure, transplant eligibility, expected toxicity and the patient's clinical profile and desires. The far-reaching goal is to facilitate patients with AML in remission to achieve a normal quality of life while improving remission duration and overall survival. The QUAZAR trial was a welcome step towards a safe maintenance drug that is easy to administer and showed survival benefit but leaves many open issues for discussion. In this review we will discuss these issues, highlighting the development of AML maintenance therapies over the last 3 decades.
Topics: Humans; Quality of Life; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Recurrence
PubMed: 37139599
DOI: 10.3324/haematol.2022.281810 -
Nature Feb 2024Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress,... (Review)
Review
Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress, particularly tumour cells and cells infected with viruses. They combine both direct effector functions against their cellular targets and participate in the generation, shaping and maintenance of a multicellular immune response. As our understanding has deepened, several therapeutic strategies focused on NK cells have been conceived and are currently in various stages of development, from preclinical investigations to clinical trials. Here we explore in detail the complexity of NK cell biology in humans and highlight the role of these cells in cancer immunity. We also analyse the harnessing of NK cell immunity through immune checkpoint inhibitors, NK cell engagers, and infusions of preactivated or genetically modified, autologous or allogeneic NK cell products.
Topics: Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Immunity, Innate
PubMed: 38383621
DOI: 10.1038/s41586-023-06945-1 -
Targeted Oncology Jul 2023Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive... (Review)
Review
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive overview of data for the PARPis olaparib, niraparib, and rucaparib in patients with OC and discusses their role in disease management, with a focus on the use of PARPis as maintenance therapy in the United States (US). Olaparib was the first PARPi to be approved as first-line maintenance monotherapy in the US, with maintenance niraparib subsequently approved in the first-line setting. Data also support the efficacy of rucaparib as first-line maintenance monotherapy. PARPi maintenance combination therapy (olaparib plus bevacizumab) also provides benefit in patients with newly diagnosed advanced OC whose tumors tested positive for homologous recombination deficiency (HRD). Biomarker testing is critical in the newly diagnosed setting to identify patients most likely to benefit from PARPi maintenance therapy and guide treatment decisions. Clinical trial data support the use of PARPis (olaparib, niraparib, rucaparib) as second-line or later maintenance therapy in patients with platinum-sensitive relapsed OC. Although distinct differences in tolerability profile were observed between PARPis, they were generally well tolerated, with the majority of adverse events managed by dose modification. PARPis had no detrimental effect on patients' health-related quality of life. Real-world data support the use of PARPis in OC, although some differences between PARPis are apparent. Data from trials investigating novel combination strategies, such as PARPis plus immune checkpoint inhibitors, are awaited with interest; the optimal sequencing of novel therapies in OC remains to be established.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Bevacizumab
PubMed: 37268756
DOI: 10.1007/s11523-023-00970-w -
Pharmacological Reviews Jul 2023Personalized medicine tailors therapies, disease prevention, and health maintenance to the individual, with pharmacogenomics serving as a key tool to improve outcomes... (Review)
Review
Personalized medicine tailors therapies, disease prevention, and health maintenance to the individual, with pharmacogenomics serving as a key tool to improve outcomes and prevent adverse effects. Advances in genomics have transformed pharmacogenetics, traditionally focused on single gene-drug pairs, into pharmacogenomics, encompassing all "-omics" fields (e.g., proteomics, transcriptomics, metabolomics, and metagenomics). This review summarizes basic genomics principles relevant to translation into therapies, assessing pharmacogenomics' central role in converging diverse elements of personalized medicine. We discuss genetic variations in pharmacogenes (drug-metabolizing enzymes, drug transporters, and receptors), their clinical relevance as biomarkers, and the legacy of decades of research in pharmacogenetics. All types of therapies, including proteins, nucleic acids, viruses, cells, genes, and irradiation, can benefit from genomics, expanding the role of pharmacogenomics across medicine. Food and Drug Administration approvals of personalized therapeutics involving biomarkers increase rapidly, demonstrating the growing impact of pharmacogenomics. A beacon for all therapeutic approaches, molecularly targeted cancer therapies highlight trends in drug discovery and clinical applications. To account for human complexity, multicomponent biomarker panels encompassing genetic, personal, and environmental factors can guide diagnosis and therapies, increasingly involving artificial intelligence to cope with extreme data complexities. However, clinical application encounters substantial hurdles, such as unknown validity across ethnic groups, underlying bias in health care, and real-world validation. This review address the underlying science and technologies germane to pharmacogenomics and personalized medicine, integrated with economic, ethical, and regulatory issues, providing insights into the current status and future direction of health care. SIGNIFICANCE STATEMENT: Personalized medicine aims to optimize health care for the individual patients with use of predictive biomarkers to improve outcomes and prevent adverse effects. Pharmacogenomics drives biomarker discovery and guides the development of targeted therapeutics. This review addresses basic principles and current trends in pharmacogenomics, with large-scale data repositories accelerating medical advances. The impact of pharmacogenomics is discussed, along with hurdles impeding broad clinical implementation, in the context of clinical care, ethics, economics, and regulatory affairs.
Topics: Humans; Pharmacogenetics; Precision Medicine; Artificial Intelligence; Neoplasms; Proteomics; Pharmaceutical Preparations
PubMed: 36927888
DOI: 10.1124/pharmrev.122.000810 -
Journal of Sleep Research Dec 2023In the management of insomnia, physicians and patients are seeking alternative therapeutics to sleeping pills, in addition to sleep hygiene and cognitive behavioural... (Meta-Analysis)
Meta-Analysis Review
In the management of insomnia, physicians and patients are seeking alternative therapeutics to sleeping pills, in addition to sleep hygiene and cognitive behavioural therapy. Bright light therapy (LT) has proven its efficacy in circadian and mood disorders. We conducted a systematic literature review and meta-analysis according to Cochrane and PRISMA guidelines and using the databases Medline, Cochrane, and Web of Science, with a special focus on light therapy and insomnia. Twenty-two studies with a total of 685 participants were included, five of which with a high level of proof. Meta-analysis was performed with 13 of them: light therapy for insomnia compared with control conditions significantly improved wake after sleep onset (WASO: SMD = -0.61 [-1.11, -0.11]; p = 0.017; weighted difference of 11.2 min ±11.5 based on actigraphy, and SMD = -1.09 [-1.43, -0.74] (p < 0.001) weighted difference of -36.4 min ±15.05) based on sleep diary, but no other sleep measures such as sleep latency, total sleep time (TST), or sleep efficiency. Qualitative analysis of the review showed some improvement mainly in subjective measures. Morning light exposure advanced sleep-wake rhythms and evening exposure led to a delay. No worsening was observed in objective nor subjective measures, except for TST in one study with evening exposure. A light dose-response may exist but the studies' heterogeneity and publication bias limit the interpretation. To conclude, light therapy shows some effectiveness for sleep maintenance in insomnia disorders, but further research is needed to refine the light parameters to be chosen according to the type of insomnia, in the hope of developing personalised therapeutics.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Sleep; Phototherapy; Cognitive Behavioral Therapy; Polysomnography; Treatment Outcome
PubMed: 37002704
DOI: 10.1111/jsr.13895 -
JAMA Apr 2024Hemodialysis requires reliable vascular access to the patient's blood circulation, such as an arteriovenous access in the form of an autogenous arteriovenous fistula or... (Review)
Review
IMPORTANCE
Hemodialysis requires reliable vascular access to the patient's blood circulation, such as an arteriovenous access in the form of an autogenous arteriovenous fistula or nonautogenous arteriovenous graft. This Review addresses key issues associated with the construction and maintenance of hemodialysis arteriovenous access.
OBSERVATIONS
All patients with kidney failure should have an individualized strategy (known as Patient Life-Plan, Access Needs, or PLAN) for kidney replacement therapy and dialysis access, including contingency plans for access failure. Patients should be referred for hemodialysis access when their estimated glomerular filtration rate progressively decreases to 15 to 20 mL/min, or when their peritoneal dialysis, kidney transplant, or current vascular access is failing. Patients with chronic kidney disease should limit or avoid vascular procedures that may complicate future arteriovenous access, such as antecubital venipuncture or peripheral insertion of central catheters. Autogenous arteriovenous fistulas require 3 to 6 months to mature, whereas standard arteriovenous grafts can be used 2 to 4 weeks after being established, and "early-cannulation" grafts can be used within 24 to 72 hours of creation. The prime pathologic lesion of flow-related complications of arteriovenous access is intimal hyperplasia within the arteriovenous access that can lead to stenosis, maturation failure (33%-62% at 6 months), or poor patency (60%-63% at 2 years) and suboptimal dialysis. Nonflow complications such as access-related hand ischemia ("steal syndrome"; 1%-8% of patients) and arteriovenous access infection require timely identification and treatment. An arteriovenous access at high risk of hemorrhaging is a surgical emergency.
CONCLUSIONS AND RELEVANCE
The selection, creation, and maintenance of arteriovenous access for hemodialysis vascular access is critical for patients with kidney failure. Generalist clinicians play an important role in protecting current and future arteriovenous access; identifying arteriovenous access complications such as infection, steal syndrome, and high-output cardiac failure; and making timely referrals to facilitate arteriovenous access creation and treatment of arteriovenous access complications.
Topics: Humans; Arteriovenous Shunt, Surgical; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Renal Insufficiency; Renal Replacement Therapy; Retrospective Studies; Treatment Outcome; Referral and Consultation; Clinical Protocols
PubMed: 38497953
DOI: 10.1001/jama.2024.0535 -
The British Journal of Dermatology Oct 2023Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40-OX40 ligand (OX40L) costimulation pathway by targeting OX40L on... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial.
BACKGROUND
Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40-OX40 ligand (OX40L) costimulation pathway by targeting OX40L on antigen-presenting cells (APCs) with a fully human noncytotoxic, nondepleting anti-OX40L monoclonal antibody (amlitelimab; SAR445229; KY1005) is a novel way to modulate persistent inflammation.
OBJECTIVES
To assess the safety and efficacy of amlitelimab over 16 weeks in adults with AD in a phase IIa double-blind placebo-controlled study.
METHODS
The study was conducted at 19 hospitals in Germany, Poland, Spain and the UK. Eligible patients with moderate-to-severe AD were randomized (1 : 1 : 1) to low-dose intravenous (IV) amlitelimab (200 mg), high-dose IV amlitelimab (500 mg) or placebo, followed by three maintenance doses (50% of loading dose) at 4, 8 and 12 weeks, with safety follow-up to week 36. The co-primary endpoints were the incidence of treatment-emergent adverse events (all patients who received ≥ 1 dose of the study drug) and mean percentage change in Eczema Area and Severity Index (EASI) to week 16 (full analysis set).
RESULTS
Between 13 December 2018 and 12 May 2020, 89 patients were randomly assigned to low- (n = 29) or high-dose amlitelimab (n = 30) or placebo (n = 29), of whom 88 proceeded to treatment [37 women (42%), 51 (58%) men; mean (SD) age 33.6 (11.9) years]. Amlitelimab was generally well tolerated with an unremarkable safety profile; no hypersensitivity events were reported. For the primary endpoint, the least square mean percentage change in EASI from baseline to week 16 was -80.12% [95% confidence interval (CI) -95.55 to -64.68; P = 0.009 vs. placebo] and -69.97% (95% CI -85.04 to -54.60; P = 0.07 vs. placebo) for the low- (n = 27) and high-dose (n = 27) amlitelimab groups, respectively, vs. -49.37% (95% CI -66.02 to -32.72) for placebo (n = 24). Numerically greater reductions in EASI were observed for amlitelimab vs. placebo from weeks 2 to 16.
CONCLUSIONS
Novel targeting of OX40L-expressing APCs with amlitelimab was well tolerated and resulted in clinically meaningful improvements in AD.
Topics: Adult; Male; Humans; Female; Dermatitis, Atopic; Treatment Outcome; Antibodies, Monoclonal; Injections, Subcutaneous; Germany; Antineoplastic Agents; Double-Blind Method; Severity of Illness Index
PubMed: 37463508
DOI: 10.1093/bjd/ljad240 -
Journal of Sleep Research Dec 2023Despite the success of cognitive behavioural therapy for insomnia and recent advances in pharmacotherapy, many patients with insomnia do not sufficiently respond to... (Review)
Review
Despite the success of cognitive behavioural therapy for insomnia and recent advances in pharmacotherapy, many patients with insomnia do not sufficiently respond to available treatments. This systematic review aims to present the state of science regarding the use of brain stimulation approaches in treating insomnia. To this end, we searched MEDLINE, Embase and PsycINFO from inception to 24 March 2023. We evaluated studies that compared conditions of active stimulation with a control condition or group. Outcome measures included standardized insomnia questionnaires and/or polysomnography in adults with a clinical diagnosis of insomnia. Our search identified 17 controlled trials that met inclusion criteria, and assessed a total of 967 participants using repetitive transcranial magnetic stimulation, transcranial electric stimulation, transcutaneous auricular vagus nerve stimulation or forehead cooling. No trials using other techniques such as deep brain stimulation, vestibular stimulation or auditory stimulation met the inclusion criteria. While several studies report improvements of subjective and objective sleep parameters for different repetitive transcranial magnetic stimulation and transcranial electric stimulation protocols, important methodological limitations and risk of bias limit their interpretability. A forehead cooling study found no significant group differences in the primary endpoints, but better sleep initiation in the active condition. Two transcutaneous auricular vagus nerve stimulation trials found no superiority of active stimulation for most outcome measures. Although modulating sleep through brain stimulation appears feasible, gaps in the prevailing models of sleep physiology and insomnia pathophysiology remain to be filled. Optimized stimulation protocols and proof of superiority over reliable sham conditions are indispensable before brain stimulation becomes a viable treatment option for insomnia.
Topics: Adult; Humans; Sleep Initiation and Maintenance Disorders; Transcranial Magnetic Stimulation; Sleep; Polysomnography; Brain; Treatment Outcome
PubMed: 37202368
DOI: 10.1111/jsr.13927 -
Expert Review of Neurotherapeutics 2023Essential Tremor (ET) is one of the most common tremor syndromes typically presented as action tremor, affecting mainly the upper limbs. In at least 30-50% of patients,... (Review)
Review
INTRODUCTION
Essential Tremor (ET) is one of the most common tremor syndromes typically presented as action tremor, affecting mainly the upper limbs. In at least 30-50% of patients, tremor interferes with quality of life, does not respond to first-line therapies and/or intolerable adverse effects may occur. Therefore, surgery may be considered.
AREAS COVERED
In this review, the authors discuss and compare unilateral ventral intermedius nucleus deep brain stimulation (VIM DBS) and bilateral DBS with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy, which comprises focused acoustic energy generating ablation under real-time MRI guidance. Discussion includes their impact on tremor reduction and their potential complications. Finally, the authors provide their expert opinion.
EXPERT OPINION
DBS is adjustable, potentially reversible and allows bilateral treatments; however, it is invasive requires hardware implantation, and has higher surgical risks. Instead, MRgFUS is less invasive, less expensive, and requires no hardware maintenance. Beyond these technical differences, the decision should also involve the patient, family, and caregivers.
Topics: Humans; Essential Tremor; Tremor; Treatment Outcome; Quality of Life; Deep Brain Stimulation
PubMed: 37288812
DOI: 10.1080/14737175.2023.2221789 -
Clinical Gastroenterology and... Sep 2023This study aimed (1) to systematically review controlled trials of solid food diets for the treatment of inflammatory bowel disease (IBD); and (2) to grade the overall... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
This study aimed (1) to systematically review controlled trials of solid food diets for the treatment of inflammatory bowel disease (IBD); and (2) to grade the overall quality of evidence.
METHODS
Systematic review of prospective controlled trials of solid food diets for the induction or maintenance of remission in IBD. Two authors independently performed study selection, data extraction, and assessment of certainty of evidence. Meta-analyses were performed on studies with quantitative data on response, remission, and relapse.
RESULTS
There were 27 studies for meta-analysis. For induction of remission in Crohn's disease (CD), low refined carbohydrate diet and symptoms-guided diet outperformed controls, but studies had serious imprecision and very low certainty of evidence. The Mediterranean diet was similar to the Specific Carbohydrate Diet (low certainty of evidence), and partial enteral nutrition (PEN) was similar to exclusive enteral nutrition (very low certainty of evidence). PEN reduced risk of relapse (very low certainty of evidence), whereas reduction of red meat or refined carbohydrates did not (low certainty of evidence). For ulcerative colitis, diets were similar to controls (very low and low certainty of evidence).
CONCLUSIONS
Among the most robust dietary trials in IBD currently available, certainty of evidence remains very low or low. Nonetheless, emerging data suggest potential benefit with PEN for induction and maintenance of remission in CD. Reduction of red meat and refined carbohydrates might not reduce risk of CD relapse. As more dietary studies become available, the certainty of evidence could improve, thus allowing for more meaningful recommendations for patients.
Topics: Humans; Prospective Studies; Inflammatory Bowel Diseases; Crohn Disease; Remission Induction; Carbohydrates; Recurrence
PubMed: 36470529
DOI: 10.1016/j.cgh.2022.11.026