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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 Hematology & Oncology Mar 2023Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold... (Review)
Review
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.
Topics: Adult; Humans; Aged; Leukemia, Myeloid, Acute; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36966300
DOI: 10.1186/s13045-023-01424-6 -
Nutrition in Clinical Practice :... Apr 2021Individuals with chronic kidney disease (CKD), particularly those undergoing maintenance dialysis, are prone to protein-energy wasting (PEW), the latter of which can be... (Review)
Review
Individuals with chronic kidney disease (CKD), particularly those undergoing maintenance dialysis, are prone to protein-energy wasting (PEW), the latter of which can be ameliorated with different methods of nutrition support. Dietary counseling guided by dietitians is the key for preventing and managing PEW in CKD. If dietary counseling per se fails to meet the recommended energy and protein requirements, the addition of oral nutrition supplements (ONSs) would be necessary. When these initial measures cannot attain the recommended energy and protein requirements, nutrition support, including enteral tube feeding or parenteral nutrition (PN), should be considered as a viable option to improve nutrition status. Partial PN, comprising intraperitoneal PN (IPPN) and intradialytic PN (IDPN) therapies, may be attempted as supplemental nutrition support in patients with PEW requiring peritoneal dialysis and hemodialysis, respectively. Despite the debatable effectiveness of IPPN for patients undergoing peritoneal dialysis, it remains a feasible means in these patients. The indications for IPPN in patients undergoing peritoneal dialysis include inadequate dietary intake of energy and protein, and barriers of oral intake and other forms of enteral supplementation such as issues with suitability, tolerance, and compliance. Nonetheless, in the case of spontaneous dietary consumption of energy and protein meeting the difference between the IDPN provision and the nutrition targets, the use of IDPN is rational. In patients with PEW and malfunctioning gastrointestinal tract, as well as those whose enteral intake (with or without partial PN) is below the recommended nutrient requirements, total PN becomes a relevant nutrition intervention.
Topics: Humans; Kidney Failure, Chronic; Nutritional Support; Protein-Energy Malnutrition; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 33734473
DOI: 10.1002/ncp.10658 -
American Journal of Hematology Nov 2019Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post-remission therapy to... (Review)
Review
Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post-remission therapy to prevent relapse. High relapse rates after consolidation therapy and after allogeneic stem cell transplant contribute to suboptimal outcomes in AML patients, and continue to represent a difficult challenge. Effective maintenance therapy could play an important role in prolonging the remission interval in the post-consolidation setting, especially in high risk AML patients. Maintenance treatment approaches based on conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have been explored in this setting, but no data so far have been convincing enough to establish this approach as the standard of care. However, ongoing and future studies including novel targeted therapies may demonstrate promising efficacy that could facilitate incorporation of maintenance therapy into clinical practice. In this review we summarize previous and ongoing approaches of maintenance therapy in AML and discuss the most promising strategies.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; DNA Methylation; Disease-Free Survival; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Interferons; Interleukin-2; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasm, Residual; Recurrence; Remission Induction
PubMed: 31429099
DOI: 10.1002/ajh.25620 -
Critical Care Nursing Clinics of North... Mar 2020Acute stroke care is completed, and it is time for discharge. Depending on patient needs, they may continue care with outpatient therapies, home health, long-term acute... (Review)
Review
Acute stroke care is completed, and it is time for discharge. Depending on patient needs, they may continue care with outpatient therapies, home health, long-term acute care, or an acute inpatient rehabilitation facility. This is an overview of the rehabilitation process, nursing care, an interdisciplinary team approach, and psychosocial aspects of acute inpatient rehabilitation. Rehabilitation nursing focuses on goals, outcomes, the attainment or maintenance of functional capacity, understanding long-range patient needs, and wellness. From the moment care delivery is initiated we should all be a part of the rehabilitation process, a link in the chain toward improved quality of life.
Topics: Humans; Patient Care Team; Patient Discharge; Quality of Life; Recovery of Function; Rehabilitation Nursing; Stroke Rehabilitation
PubMed: 32014164
DOI: 10.1016/j.cnc.2019.11.004 -
Continuum (Minneapolis, Minn.) Oct 2020This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US... (Review)
Review
PURPOSE OF REVIEW
This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US Food and Drug Administration (FDA)-approved gene-targeted therapies and mainstays of supportive SMA care.
RECENT FINDINGS
Over the past decades, an understanding of the role of SMN protein in the development and maintenance of the motor unit and the intricate genetics underlying SMA has led to striking developments in therapeutics with three FDA-approved treatments for SMA, one targeting SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others enhancing SMN protein production from the SMN2 gene (nusinersen and risdiplam). These therapies are most effective in infants treated at younger ages, and improvement is most striking in babies treated as neonates. Despite improvements in motor function, patients (especially those treated at older ages) continue to experience significant weakness and require continued close monitoring of respiratory and orthopedic symptoms.
SUMMARY
Striking therapeutic advancements have changed the clinical course of SMA dramatically, although supportive care continues to play an important role in patient care.
Topics: Azo Compounds; Biological Products; Genetic Therapy; Humans; Infant; Infant, Newborn; Muscular Atrophy, Spinal; Neuromuscular Agents; Oligonucleotides; Pyrimidines; Recombinant Fusion Proteins; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein
PubMed: 33003005
DOI: 10.1212/CON.0000000000000918 -
Journal of Crohn's & Colitis Jan 2020
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Rectal Fistula; Severity of Illness Index
PubMed: 31711158
DOI: 10.1093/ecco-jcc/jjz180 -
Seminars in Dialysis Nov 2021Extracorporeal blood purification (EBP) techniques provide support for critically ill patients with single or multiple organ dysfunction. Continuous renal replacement... (Review)
Review
Extracorporeal blood purification (EBP) techniques provide support for critically ill patients with single or multiple organ dysfunction. Continuous renal replacement therapy (CRRT) is the modality of choice for kidney support for those patients and orchestrates the interactions between the different artificial organ support systems. Intensive care teams should be familiar with the concept of sequential extracorporeal therapy and plan on how to incorporate new treatment modalities into their daily practices. Importantly, scientific evidence should guide the decision-making process at the bedside and provide robust arguments to justify the costs of implementing new EBP treatments. In this narrative review, we explore the extended indications for CRRT as an adjunctive treatment to provide support for the heart, lung, liver, and immune system. We detail practicalities on how to run the treatments and how to tackle the most frequent complications regarding each of the therapies, whether applied alone or integrated. The physicochemical processes and technologies involved at the molecular level encompassing the interactions between the molecules, membranes, and resins are spotlighted. A clinical case will illustrate the timing for the initiation, maintenance, and discontinuation of EBP techniques.
Topics: Acute Kidney Injury; Continuous Renal Replacement Therapy; Critical Illness; Humans; Renal Dialysis; Renal Replacement Therapy
PubMed: 33711166
DOI: 10.1111/sdi.12963 -
Blood Cancer Journal Feb 2020The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared... (Review)
Review
The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Maintenance Chemotherapy; Multiple Myeloma; Prognosis; Quality of Life
PubMed: 32054831
DOI: 10.1038/s41408-020-0273-x -
Current Oncology (Toronto, Ont.) Feb 2023Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and... (Review)
Review
Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; Quality of Life; Transplantation, Autologous; Neoplasm Recurrence, Local
PubMed: 36826140
DOI: 10.3390/curroncol30020179