Showing papers in "Annual Review of Medicine in 2019"
Journal Article•
TL;DR: Several drugs targeting PI3K/ATK are currently in clinical trials, alone or in combination, in both solid tumors and hematologic malignancies as mentioned in this paper, and these drugs are the focus of this review.
Abstract: Anticancer targeted therapies are designed to exploit a particular vulnerability in the tumor, which in most cases results from its dependence on an oncogene and/or loss of a tumor suppressor. Genes in the phosphoinositide 3-kinase (PI3K)/AKT pathway are the most frequently altered in human cancers. Aberrant activation of this pathway, as a result of these somatic alterations, is associated with cellular transformation, tumorigenesis, cancer progression, and drug resistance. Several drugs targeting PI3K/ATK are currently in clinical trials, alone or in combination, in both solid tumors and hematologic malignancies. These drugs are the focus of this review.
475 citations
TL;DR: This work discusses advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.
Abstract: The therapeutic landscape of prostate cancer has been transformed over the last decade by new therapeutics, advanced functional imaging, next-generation sequencing, and better use of existing therapies in early-stage disease. Until 2004, progression on androgen deprivation therapy for metastatic disease was treated with the addition of secondary hormonal manipulation; in the last decade, six systemic agents have been approved for the treatment of castration-resistant prostate cancer. We review clinical trials and survival benefit for these therapies and assess how the understanding of the disease shifted as these therapies were developed. We also discuss advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.
340 citations
TL;DR: The state of the technology is summarized and how advances in the technology position ASOs to be an important contributor to future medicines is highlighted.
Abstract: The first published description of therapeutic applications of antisense oligonucleotide (ASO) technology occurred in the late 1970s and was followed by the founding of commercial companies focused on developing antisense therapeutics in the late 1980s. Since the late 1980s, there has been steady progress in improving the technology platform, taking advantage of advances in oligonucleotide chemistry and formulations as well as increased understanding of the distribution and safety of ASOs. There are several approved ASO drugs and a broad pipeline in development. In addition, advances in understanding human disease, including the genetic basis for most monogenic diseases and the availability of the full human genome sequence, have created numerous therapeutic applications for the technology. I summarize the state of the technology and highlight how advances in the technology position ASOs to be an important contributor to future medicines.
303 citations
TL;DR: This review focuses on the clinical research that has forged the gene therapy field as it currently stands, and the strategies being translated from the lab to the clinic.
Abstract: Gene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious...
276 citations
TL;DR: Fecal microbiota transplantation is a well-established treatment for recurrent Clostridioides difficile infection and expects that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.
Abstract: Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent Clostridioides difficile infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to C. difficile infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.
145 citations
TL;DR: Clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus, where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity.
Abstract: Enabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineeri...
141 citations
TL;DR: Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD.
Abstract: The ability to efficiently modify the genome using CRISPR technology has rapidly revolutionized biology and genetics and will soon transform medicine. Duchenne muscular dystrophy (DMD) represents o...
125 citations
TL;DR: The benefits and potential harms of treatment, including during breastfeeding, are presented and new understanding of PPD pathophysiology and emerging therapeutics offer the potential for new ways to add to current medications, somatic treatments, and evidence-based psychotherapy.
Abstract: Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is vital to identify best treatments for optimal maternal, infant, and family outcomes. New understanding of PPD pathophysiology and emerging therapeutics offer the potential for new ways to add to current medications, somatic treatments, and evidence-based psychotherapy. The benefits and potential harms of treatment, including during breastfeeding, are presented.
107 citations
TL;DR: Advances in the understanding of the etiology and underlying biology of gastric cancer, as well as the current state of management, are discussed, focusing on the differences between Asia and the West.
Abstract: Regional variation in treatment paradigms for gastric adenocarcinoma has attracted a great deal of interest. Between Asia and the West, major differences have been identified in tumor biology, implementation of screening programs, extent of surgical lymphadenectomy, and routine use of neoadjuvant versus adjuvant treatment strategies. Minimally invasive techniques, including both laparoscopic and robotic platforms, have been studied in both regions, with attention to safety, feasibility, and long-term oncologic outcomes. The purpose of this review is to discuss advances in the understanding of the etiology and underlying biology of gastric cancer, as well as the current state of management, focusing on the differences between Asia and the West.
86 citations
TL;DR: Two transcription factors that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin.
Abstract: The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative,...
81 citations
TL;DR: The rationale to use MRI in general, and abbreviated MRI in particular, for breast cancer screening is described and the way MRI is used in clinical medicine is changed.
Abstract: Given the increasing understanding of cancer as a heterogeneous group of diseases, detection methods should offer a sensitivity profile that ensures perfect sensitivity for biologically important cancers while screening out self-limiting pseudocancers. However, mammographic screening is biased toward detection of ductal carcinoma in situ and slowly growing cancers-and thus frequently fails to detect biologically aggressive cancers. This explains the persistently high rates of interval cancers and high rates of breast cancer mortality observed in spite of decades of mammographic screening. Magnetic resonance imaging (MRI), in contrast, has a sensitivity profile that matches clinical needs. Conventional MRI is not suitable for population-wide screening due to high cost, limited tolerability, and lack of availability. We introduced abbreviated MRI in 2014. Abbreviated MRI will change the way MRI is used in clinical medicine. This article describes the rationale to use MRI in general, and abbreviated MRI in particular, for breast cancer screening.
TL;DR: The measures that enabled rapid progress and the confirmation of their safety and efficacy are discussed and the path forward for successful deployment of ZIKV vaccines are highlighted.
Abstract: Zika virus (ZIKV) emerged at a global level when it spread to the Americas and began causing congenital malformations and microcephaly in 2015. A rapid response by academia, government, public health infrastructure, and industry has enabled the expedited development and testing of a suite of vaccine platforms aiming to control and eliminate ZIKV-induced disease. Analysis of key immunization and pathogenesis studies in multiple animal models, including during pregnancy, has begun to define immune correlates of protection. Nonetheless, the deployment of ZIKV vaccines, along with the confirmation of their safety and efficacy, still has major challenges, one of which is related to the waning of the epidemic. In this review, we discuss the measures that enabled rapid progress and highlight the path forward for successful deployment of ZIKV vaccines.
TL;DR: Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance.
Abstract: Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.
TL;DR: Technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated, and methylation-dependent regulation of transcription is an attractive hypothesis for being a causative factor in ASD etiology.
Abstract: The prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.
TL;DR: This is a time of substantial progress in the evaluation and care of patients with idiopathic pulmonary fibrosis, with the approval and widespread availability of the first IPF-specific therapies and improvements in imaging interpretation and lung biopsy methods to enable more expeditious and more accurate diagnosis.
Abstract: This is a time of substantial progress in the evaluation and care of patients with idiopathic pulmonary fibrosis (IPF). In addition to the approval and widespread availability of the first IPF-specific therapies, there have been improvements in imaging interpretation and lung biopsy methods to enable more expeditious and more accurate diagnosis. Recent advances in identifying genetic factors that underlie susceptibility to IPF and affect prognosis have raised the possibility of personalized therapeutic approaches in the future. Further, evolving work is elucidating novel mechanisms influencing epithelial, mesenchymal, and inflammatory cell responses during the injury-repair process, thus advancing understanding of disease pathogenesis. As analytic approaches mature, the field is now poised to harness the power of rapidly advancing "omics" technologies to further accelerate progress.
TL;DR: Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH, hoping to elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.
Abstract: Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.
TL;DR: CD3 bispecifics may find a key role in addressing tumors with low neoantigen content and/or low inflammation, and this class of therapeutics may productively combine with checkpoint blockade.
Abstract: Bispecific antibodies that recruit and redirect T cells to attack tumor cells have tremendous potential for the treatment of various malignancies. In general, this class of therapeutics, known as CD3 bispecifics, promotes tumor cell killing by cross-linking a CD3 component of the T cell receptor complex with a tumor-associated antigen on the surface of the target cell. Importantly, this mechanism does not rely on a cognate interaction between the T cell receptor and a peptide:HLA complex, thereby circumventing HLA (human leukocyte antigen) restriction. Hence, CD3 bispecifics may find a key role in addressing tumors with low neoantigen content and/or low inflammation, and this class of therapeutics may productively combine with checkpoint blockade. A wide array of formats and optimization approaches has been developed, and a wave of CD3 bispecifics is proceeding into human clinical trials for a range of indications, with promising signs of therapeutic activity.
TL;DR: This review outlines the preclinical and clinical state of individualized cancer vaccine development and the challenges ahead.
Abstract: T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing major histocompatibility complex–bound cancer-specific peptides. Acc...
TL;DR: A review highlights some of the major ethical considerations in human genome editing in light of the committee's recommendations, and recommends allowing experimental germline genome editing to proceed if it is restricted to preventing transmission of a serious disease or condition.
Abstract: Advances in human genome editing, in particular the development of the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 method, have led to increasing concerns about the ethics of editing the human genome. In response, the US National Academy of Sciences and the National Academy of Medicine constituted a multidisciplinary, international committee to review the current status and make recommendations. I was a member of that committee, and the core of this review reflects the committee's conclusions. The committee's report, issued in February 2017, recommends the application of current ethical and regulatory standards for gene therapy to somatic (nonheritable) human genome editing. It also recommends allowing experimental germline genome editing to proceed if ( a) it is restricted to preventing transmission of a serious disease or condition, ( b) the edit is a modification to a common DNA sequence known not to be associated with disease, and ( c) the research is conducted under a stringent set of ethical and regulatory requirements. Crossing the so-called red line of germline genome editing raises important bioethical issues, most importantly, serious concern about the potential negative impact on individuals with disabilities. This review highlights some of the major ethical considerations in human genome editing in light of the report's recommendations.
TL;DR: The potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans is discussed.
Abstract: Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.
TL;DR: The preclinical development of key small molecules that are now being clinically utilized for PCa imaging are highlighted, the roles of PSMA-targeted agents in guiding patient management are discussed, and the role these compounds may play in imaging nonprostate cancers is considered.
Abstract: In recent years, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) labeled with radionuclides that allow for positron emission tomography (PET) imaging have been extensively studied in many clinical contexts in men with prostate cancer (PCa). The high sensitivity and specificity of these agents for identifying sites of PCa has quickly led to their widespread adoption as a de facto clinical standard of care throughout much of the world. PSMA-targeted PET radiotracers have been particularly well-studied in preoperatively staging men with high-risk PCa, evaluating biochemical recurrence following definitive therapy, and guiding metastasis-directed therapy in patients suspected of having oligorecurrent/oligometastatic disease. Furthermore, the expression of PSMA on the tumor neovasculature of many nonprostate malignancies has enabled a burgeoning subfield concentrated on delineating the potential utility of PSMA-targeted PET agents for imaging other cancers. In this review, we highlight the preclinical development of key small molecules that are now being clinically utilized for PCa imaging, discuss the roles of PSMA-targeted agents in guiding patient management, and consider the role these compounds may play in imaging nonprostate cancers.
TL;DR: The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome to render these cancers targetable-and, in theory, rejectable-by the host T cell immune response.
Abstract: The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome t...
TL;DR: For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.
Abstract: Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent exacerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.
TL;DR: Advantages of LDLT include optimization of the timing of transplant, better organ quality, and lower rates of recipient mortality compared to staying on the wait list for deceased donor liver transplant.
Abstract: Adult-to-adult living donor liver transplantation (LDLT) was introduced in response to the shortage of deceased donor liver grafts. The number of adult living donor transplants is increasing due to improved outcomes and increasing need. Advantages of LDLT include optimization of the timing of transplant, better organ quality, and lower rates of recipient mortality compared to staying on the wait list for deceased donor liver transplant. Donor safety remains the major focus when considering LDLT. Recent advancements have supported the increased use of LDLT to help decrease wait list death and improve long-term survival of transplant recipients.
TL;DR: The therapeutic armamentarium, which now consists of alkylating agents, corticosteroids, deacetylase inhibitors, immunomodulatory agents, monoclonal antibodies, and proteasome inhibitors, is expanded and new drugs in these categories are under development that promise to further expand the capabilities and bring us closer to the cure of this plasma cell dyscrasia.
Abstract: Multiple myeloma is diagnosed in over 100,000 patients each year worldwide, has an increasing incidence and prevalence in many regions, and follows a relapsing course, making it a significant and growing healthcare challenge. Recent basic, translational, and clinical studies have expanded our therapeutic armamentarium, which now consists of alkylating agents, corticosteroids, deacetylase inhibitors, immunomodulatory agents, monoclonal antibodies, and proteasome inhibitors. New drugs in these categories, and additional agents, including both small and large molecules, as well as cellular therapies, are under development that promise to further expand our capabilities and bring us closer to the cure of this plasma cell dyscrasia.
TL;DR: It is concluded that active surveillance should be the first line in management of low-risk PMC, because it is safer and less costly than immediate surgery.
Abstract: Papillary thyroid microcarcinoma (PMC) is defined as papillary thyroid carcinoma ≤10 mm. Active surveillance of PMC without high-risk features, such as clinical node metastasis, distant metastasis, and clinical evidence of significant extrathyroid extension, was initiated in two Japanese hospitals in the mid-1990s. This strategy was incorporated into guidelines in Japan in 2010 and in the United States in 2015. In studies conducted by the two hospitals, most PMCs grew very slowly or did not grow, and none of the patients during active surveillance showed distant metastasis or died of thyroid carcinoma. Furthermore, none of the patients who underwent surgery after progression signs were detected showed significant recurrence. Therefore, we conclude that active surveillance should be the first line in management of low-risk PMC, because it is safer and less costly than immediate surgery. Active surveillance helps in avoiding adverse events of surgery and is an economical strategy.
TL;DR: The mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials are summarized.
Abstract: Clinical studies evaluating the cardiovascular safety/impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors demonstrated a reduction in major adverse cardiovascular events driven primarily by a reduced cardiovascular mortality in individuals with type 2 diabetes and previous cardiovascular disease. These somewhat unexpected results are coupled with SGLT-2 inhibitors' known acute effect of improvement in glycemia, reduction in blood pressure, and weight loss. In this review, we summarize the mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials. In addition, we discuss adverse effects associated with these medications and the current recommendations for the use of these agents in the management of diabetes.
TL;DR: Early-stage non-small cell lung cancer is a potentially curable disease, but with relapse rates exceeding 50% with standard treatments, this is a patient population in critical need of therapy innovation.
Abstract: Early-stage non–small cell lung cancer is a potentially curable disease, but with relapse rates exceeding 50% with standard treatments, this is a patient population in critical need of therapy inno...
TL;DR: Shorter, safer regimens for many forms of TB are now available or are in the near-term vision and an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment is provided.
Abstract: Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment.
TL;DR: A clinically focused review describes how new insights gained from natural history studies, improved understanding of pathogenic mechanisms, and appreciation of genetic and environmental modifiers have set the stage for developing personalized approaches to managing both ARVC patients and their at-risk family members.
Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk of ventricular arrhythmias, a...