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Annual Review of Medicine - Volume 70, 2019
Volume 70, 2019
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Arrhythmogenic Right Ventricular Cardiomyopathy: Progress Toward Personalized Management
Vol. 70 (2019), pp. 1–18More LessArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk of ventricular arrhythmias, and progressive ventricular dysfunction. The clinical course is highly variable, and optimal approaches to management remain undefined. ARVC is associated with pathogenic variants in genes encoding the cardiac desmosome. Genetic testing facilitates identification of at-risk family members, but penetrance of ARVC in pathogenic variant carriers is difficult to predict. Participation in endurance exercise is a known key risk factor. However, there remains significant uncertainty about which family member will develop disease and how best to approach longitudinal screening. Our 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.
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Capitalizing on Insights from Human Genetics to Identify Novel Therapeutic Targets for Coronary Artery Disease
Vol. 70 (2019), pp. 19–32More LessCoronary artery disease (CAD) is a major cause of morbidity and mortality. Unfortunately, despite decades of research focused on disease pathogenesis, we still lack a sufficient pharmacopeia for preventing CAD. The failure of many novel cardiovascular drugs to improve clinical outcomes reflects the major substantial challenge of drug development: identifying causal mechanisms that can be therapeutically manipulated to lower disease risk. Identifying genetic variants that are associated with risk of CAD has emerged as a clear path toward improving our understanding of the underlying mechanisms that lead to disease and to the development of new therapies. Here, we review the potential utility and limitations of using human genetics to guide the identification of therapeutic targets for CAD.
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Innovations in Ventricular Assist Devices for End-Stage Heart Failure
Vol. 70 (2019), pp. 33–44More LessThe number of patients with end-stage heart failure (HF) continues to increase over time, but there has been little change in the availability of organs for cardiac transplantation, intensifying the demand for left ventricular assist devices (LVADs) as a bridge to transplantation. There is also a growing number of patients with end-stage HF who are not transplant candidates but may be eligible for long-term support with an LVAD, known as destination therapy. Due to this increasing demand, LVAD technology has evolved, resulting in transformative improvements in outcomes. Additionally, with growing clinical experience patient management continues to be refined, leading to iterative improvements in outcomes. With outcomes continuing to improve, the potential benefit from LVAD therapy is being considered for patients earlier in their course of advanced HF. We review recent changes in technology, patient management, and implant decision making in LVAD therapy.
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New and Emerging Therapies for Pulmonary Arterial Hypertension
Vol. 70 (2019), pp. 45–59More LessPulmonary 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.
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Non–Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation
Vol. 70 (2019), pp. 61–75More LessAtrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non–vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.
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Molecular Diagnostics for Mycobacterium tuberculosis Infection
Vol. 70 (2019), pp. 77–90More LessResistance to antimycobacterial drugs is a major barrier to effective treatment of Mycobacterium tuberculosis infection. Molecular diagnostic techniques based on the association between specific gene mutations and phenotypic resistance to certain drugs offer the opportunity to rapidly ascertain whether drug resistance is present and to alter treatment before further resistance develops. Current barriers to successful implementation of rapid diagnostics include imperfect knowledge regarding the full spectrum of mutations associated with resistance, limited utilization of molecular diagnostics where they are most needed, and the requirement for specialized laboratory facilities to perform molecular testing. Further understanding of genotypic–phenotypic correlates of resistance and streamlined implementation platforms will be necessary to optimize the public health impact of molecular resistance testing for M. tuberculosis.
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Structure-Based Vaccine Antigen Design
Vol. 70 (2019), pp. 91–104More LessEnabled by new approaches for rapid identification and selection of human monoclonal antibodies, atomic-level structural information for viral surface proteins, and capacity for precision engineering of protein immunogens and self-assembling nanoparticles, a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts, clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV), where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens, particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.
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The Global Landscape of Tuberculosis Therapeutics
Vol. 70 (2019), pp. 105–120More LessTuberculosis (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.
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Zika Virus Vaccine Development: Progress in the Face of New Challenges
Vol. 70 (2019), pp. 121–135More LessZika 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.
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Long-Acting HIV Drugs for Treatment and Prevention
Vol. 70 (2019), pp. 137–150More LessAntiretroviral 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.
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DNA Methylation and Susceptibility to Autism Spectrum Disorder
Vol. 70 (2019), pp. 151–166More LessThe 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.
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Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders
Vol. 70 (2019), pp. 167–181More LessFragile 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.
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Postpartum Depression: Pathophysiology, Treatment, and Emerging Therapeutics
Vol. 70 (2019), pp. 183–196More LessPostpartum 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.
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Cystic Fibrosis: Emerging Understanding and Therapies
Vol. 70 (2019), pp. 197–210More LessCystic 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.
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Progress in Understanding and Treating Idiopathic Pulmonary Fibrosis
Vol. 70 (2019), pp. 211–224More LessThis 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.
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Current Status of Living Donor Liver Transplantation in the United States
Vol. 70 (2019), pp. 225–238More LessAdult-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.
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CRISPR Correction of Duchenne Muscular Dystrophy
Vol. 70 (2019), pp. 239–255More LessThe 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 one of the first monogenic disorders that has been investigated with respect to CRISPR-mediated correction of causal genetic mutations. DMD results from mutations in the gene encoding dystrophin, a scaffolding protein that maintains the integrity of striated muscles. Thousands of different dystrophin mutations have been identified in DMD patients, who suffer from a loss of ambulation followed by respiratory insufficiency, heart failure, and death by the third decade of life. Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD. Here, we review recent progress toward the development of possible CRISPR therapies for DMD and highlight opportunities and potential obstacles in attaining this goal.
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Emerging Genetic Therapy for Sickle Cell Disease
Vol. 70 (2019), pp. 257–271More LessThe 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, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, 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. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD.
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Entering the Modern Era of Gene Therapy
Vol. 70 (2019), pp. 273–288More LessGene 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 optimism that effective, durable, and safe therapies will provide benefit to patients—not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands.
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Ethics of Human Genome Editing
Vol. 70 (2019), pp. 289–305More LessAdvances 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.
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Therapeutic Antisense Oligonucleotides Are Coming of Age
Vol. 70 (2019), pp. 307–321More LessThe 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.
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Sodium–Glucose Cotransporter–2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes
Vol. 70 (2019), pp. 323–334More LessClinical 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.
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Clinical Application and Potential of Fecal Microbiota Transplantation
Vol. 70 (2019), pp. 335–351More LessFecal 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.
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Gastric Cancer Etiology and Management in Asia and the West
Vol. 70 (2019), pp. 353–367More LessRegional 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.
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Active Surveillance as First-Line Management of Papillary Microcarcinoma
Vol. 70 (2019), pp. 369–379More LessPapillary 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.
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Expanding Therapeutic Opportunities for Hematopoietic Stem Cell Transplantation: T Cell Depletion as a Model for the Targeted Allograft
Vol. 70 (2019), pp. 381–393More LessAllogeneic hematopoietic cell transplantation is a fundamental part of the treatment of hematologic malignancies and marrow failure syndromes, but complications including graft-versus-host disease, prolonged immune deficiency and infection, and organ toxicities, as well as relapse, remain obstacles to improved overall survival. As the cellular characteristics of the allograft can exert significant impact on outcomes, the development of more strategically designed grafts represents a rich area for therapeutic intervention. We describe the use of ex vivo T cell–depleted grafts as a model for the targeted graft and review evolving knowledge and approaches for further refinement of allografts to improve patient outcomes.
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Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines
Vol. 70 (2019), pp. 395–407More LessT 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. Accumulating evidence suggests that peptides associated with T cell–mediated tumor rejection arise predominantly from somatically mutated proteins and are unique to every patient's tumor. Knowledge of an individual's cancer mutanome (the entirety of cancer mutations) allows harnessing this enormous tumor cell–specific repertoire of highly immunogenic antigens for individualized cancer vaccines. This review outlines the preclinical and clinical state of individualized cancer vaccine development and the challenges ahead.
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New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation
Vol. 70 (2019), pp. 409–424More LessThe 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. In addition, cancers often overexpress tissue-specific and developmental antigens to which immune tolerance is incomplete. Sometimes, virally transferred oncogenes drive malignant transformation and remain expressed throughout the cancer. Despite this state of antigenic sufficiency, cancer grows progressively and overcomes all efforts of the host immune system to contain it. While therapeutic cancer vaccination can mobilize high frequencies of tumor-specific T cells, these responses remain subject to intratumoral attenuation. Antibody modulation of T cell function through checkpoint blockade or costimulatory activation can restore survival, proliferation, and effector function to these tumor-infiltrating T cells and convert otherwise subtherapeutic vaccines into potentially curative cancer immunotherapeutics.
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PD-1 Blockade in Early-Stage Lung Cancer
Vol. 70 (2019), pp. 425–435More LessEarly-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. Immunotherapy with immune checkpoint blockade has revolutionized the treatment strategy for advanced lung cancer. However, the role of this therapy in earlier-stage disease is largely unknown. The study of immunotherapy in earlier-stage disease has many advantages, including assessment of pathologic response and incorporation of translational scientific analyses to evaluate antitumor immune responses. Multiple clinical trials are currently under way, with promising early results.
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Redirected T Cell Cytotoxicity in Cancer Therapy
Vol. 70 (2019), pp. 437–450More LessBispecific 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.
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Prostate Magnetic Resonance Imaging: Lesion Detection and Local Staging
Vol. 70 (2019), pp. 451–459More LessDramatic changes in the use of prostate magnetic resonance imaging (MRI) have occurred in the last decade. The recognition that MRI detects and localizes cancers with reasonable accuracy led to the development of directed biopsies. These image-guided biopsies have a higher sensitivity for clinically significant cancers and a lower sensitivity for indolent disease. Prospective trials provide level 1 evidence supporting the use of prostate MRI. For local staging, while the specificity of prostate MRI is high, its sensitivity is lacking for microscopic extraprostatic extension. Computer-aided diagnosis of prostate MRI promises to bring the diagnostic power of MRI to nonexpert readers and thus further integrate MRI into the diagnostic workup.
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Imaging of Prostate-Specific Membrane Antigen with Small-Molecule PET Radiotracers: From the Bench to Advanced Clinical Applications
Vol. 70 (2019), pp. 461–477More LessIn 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.
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Treatment of Advanced Prostate Cancer
Vol. 70 (2019), pp. 479–499More LessThe 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.
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Abbreviated Magnetic Resonance Imaging (MRI) for Breast Cancer Screening: Rationale, Concept, and Transfer to Clinical Practice
Vol. 70 (2019), pp. 501–519More LessGiven 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.
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New Drugs in Multiple Myeloma
Vol. 70 (2019), pp. 521–547More LessMultiple 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.
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Previous Volumes
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Volume 75 (2024)
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Volume 74 (2023)
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Volume 73 (2022)
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Volume 72 (2021)
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Volume 71 (2020)
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Volume 70 (2019)
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Volume 69 (2018)
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Volume 68 (2017)
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Volume 67 (2016)
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Volume 66 (2015)
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Volume 65 (2014)
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Volume 64 (2013)
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Volume 63 (2012)
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Volume 62 (2011)
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Volume 61 (2010)
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Volume 60 (2009)
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Volume 59 (2008)
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Volume 58 (2007)
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Volume 57 (2006)
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Volume 56 (2005)
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Volume 55 (2004)
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Volume 54 (2003)
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Volume 53 (2002)
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Volume 52 (2001)
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Volume 51 (2000)
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Volume 50 (1999)
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Volume 49 (1998)
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Volume 48 (1997)
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Volume 47 (1996)
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Volume 46 (1995)
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Volume 45 (1994)
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Volume 44 (1993)
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Volume 43 (1992)
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Volume 42 (1991)
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Volume 41 (1990)
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Volume 40 (1989)
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Volume 39 (1988)
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Volume 38 (1987)
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Volume 37 (1986)
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Volume 36 (1985)
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Volume 35 (1984)
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Volume 34 (1983)
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Volume 33 (1982)
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Volume 32 (1981)
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Volume 31 (1980)
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Volume 30 (1979)
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Volume 29 (1978)
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Volume 28 (1977)
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Volume 27 (1976)
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Volume 26 (1975)
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Volume 25 (1974)
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Volume 24 (1973)
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Volume 23 (1972)
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Volume 22 (1971)
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Volume 21 (1970)
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Volume 20 (1969)
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Volume 19 (1968)
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Volume 18 (1967)
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Volume 17 (1966)
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Volume 16 (1965)
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Volume 15 (1964)
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Volume 14 (1963)
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Volume 13 (1962)
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Volume 12 (1961)
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Volume 11 (1960)
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Volume 10 (1959)
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Volume 9 (1958)
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Volume 8 (1957)
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Volume 7 (1956)
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Volume 6 (1955)
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Volume 5 (1954)
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Volume 4 (1953)
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Volume 3 (1952)
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Volume 2 (1951)
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Volume 1 (1950)
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Volume 0 (1932)