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- Volume 71, 2020
Annual Review of Medicine - Volume 71, 2020
Volume 71, 2020
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Bariatric Surgery as a Long-Term Treatment for Type 2 Diabetes/Metabolic Syndrome
Vol. 71 (2020), pp. 1–15More LessMetabolic surgery is increasingly becoming recognized as a more effective treatment for patients with type 2 diabetes (T2D) and obesity as compared to lifestyle modification and medical management alone. Both observational studies and clinical trials have shown metabolic surgery to result in sustained weight loss (20–30%), T2D remission rates ranging from 23% to 60%, and improvement in cardiovascular risk factors such as hypertension and dyslipidemia. Metabolic surgery is cost-effective and relatively safe, with perioperative risks and mortality comparable to low-risk procedures such as cholecystectomy, hysterectomy, and appendectomy. International diabetes and medical organizations have endorsed metabolic surgery as a standard treatment for T2D with obesity.
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Male Hormonal Contraception
Vol. 71 (2020), pp. 17–31More LessThe economic and public health burdens of unplanned pregnancies are evident globally. Since the introduction of the condom >300 years ago, assumptions about male willingness to participate in contraception, as well as concerns about failure rates and side effects, have stagnated the development of additional reversible male contraceptives. However, changing attitudes and recent research advances have generated renewed interest in developing reversible male contraceptives. To achieve effective and reversible suppression of spermatogenesis, male hormonal contraception relies on suppression of testicular testosterone and sperm production using an androgen-progestin combination. While these may be associated with side effects—changes in libido, weight, hematocrit, and cholesterol—recently, novel androgens and progestins have shown promise for a “male pill” with reduced side effects. Here we summarize landmark studies in male contraceptive development, showcase the most recent advances, and look into the future of this field, which has the potential to greatly impact global public health.
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Sex Hormones and Prostate Cancer
Vol. 71 (2020), pp. 33–45More LessThe prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.
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CD40 Agonist Antibodies in Cancer Immunotherapy
Vol. 71 (2020), pp. 47–58More LessCD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 antibodies of varying formulations have been evaluated in the clinic and found to be tolerable and feasible. Administration is associated with mild to moderate (but transient) cytokine release syndrome, readily managed in the outpatient setting. Antitumor activity with or without anti-CTLA4 monoclonal antibody (mAb) therapy has been observed in patients with melanoma, and major tumor regressions have been observed in patients with pancreatic cancer, mesothelioma, and other tumors in combination with chemotherapy. In a recent study of chemotherapy plus CD40 mAb, with or without PD-1 mAb, the objective response rate in patients with untreated, metastatic pancreatic cancer was >50%. Mechanistically, the combination of chemotherapy followed by CD40 mAb functions as an in situ vaccine; in addition, destruction of stroma by CD40-activated macrophages may enhance chemotherapy delivery. Evidence to date suggests that CD40 activation is a critical and nonredundant mechanism to convert so-called cold tumors to hot ones (with prominent tumor infiltration of T cells), sensitizing them to checkpoint inhibition.
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Fecal DNA Testing for Colorectal Cancer Screening
Vol. 71 (2020), pp. 59–69More LessFecal (or stool) DNA examination is a noninvasive strategy recommended by several medical professional societies for colorectal cancer (CRC) screening in average-risk individuals. Fecal DNA tests assay stool for human DNA shed principally from the colon. Colonic lesions such as adenomatous and serrated polyps and cancers exfoliate cells containing neoplastically altered DNA that may be detected by sensitive assays that target specific genetic and epigenetic biomarkers to discriminate neoplastic lesions from non-neoplastic tissue. Cross-sectional validation studies confirmed initial case-control studies’ assessment of performance of an optimized multitarget stool DNA (mt-sDNA) test, leading to approval by the US Food and Drug Administration in 2014. Compared to colonoscopy, mt-sDNA showed sensitivity of 92% for detection of CRC, much higher than the 74% sensitivity of another recommended noninvasive strategy, fecal immunochemical testing (FIT). Detections of advanced adenomas and sessile serrated polyps were higher with mt-sDNA than FIT (42% versus 24% and 42% versus 5%, respectively), but overall specificity for all lesions was lower (87% versus 95%). The mt-sDNA test increases patient life-years gained in CRC screening simulations, but its cost relative to other screening strategies needs to be reduced by 80–90% or its sensitivity for polyp detection enhanced to be cost effective. Noninvasive CRC screening strategies such as fecal DNA, however, have the potential to significantly increase national screening rates due to their noninvasive nature and convenience for patients.
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Genome Editing and Hematologic Malignancy
Vol. 71 (2020), pp. 71–83More LessThe modern genomic era has seen remarkable advancement in our understanding of the molecular basis for disease, yet translation of basic discoveries into new disease treatments has arguably lagged behind. Recently, breakthroughs in genome editing technologies have created hope for their potential to directly treat the genetic causes of disease. Like any therapeutic intervention, genome editing should be considered in light of its potential risks and benefits. In this review, we highlight the promise of genome editing therapies, as well as the conceptual and technical barriers to their clinical application, with a special emphasis on hematologic malignancies.
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Current Approaches to Germline Cancer Genetic Testing
Vol. 71 (2020), pp. 85–102More LessThe prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes.
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The Clinical Spectrum of PTEN Mutations
Lamis Yehia, Emma Keel, and Charis EngVol. 71 (2020), pp. 103–116More LessPTEN is a tumor suppressor gene that classically dampens the PI3K/AKT/mTOR growth-promoting signaling cascade. PTEN dysfunction causes dysregulation of this and other pathways, resulting in overgrowth. Cowden syndrome, a hereditary cancer predisposition and overgrowth disorder, was the first Mendelian condition associated with germline PTEN mutations. Since then, significant advances by the research and medical communities have elucidated how clinical phenotypic manifestations result from the underlying germline PTEN mutations. With time, it became evident that PTEN mutations can result in a broad phenotypic spectrum, causing seemingly disparate disorders from cancer to autism. Hence, the umbrella term of PTEN hamartoma tumor syndrome (PHTS) was coined. Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms.
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Precision Management of Advanced Non–Small Cell Lung Cancer
Vol. 71 (2020), pp. 117–136More LessThe rapid evolution of treatment for advanced lung cancer is a story of how scientists have struggled to move from nonselective cytotoxic chemotherapy to personalized precision medicine. In this century, extraordinary advances have been made in the management of advanced and metastatic non–small cell lung cancer, especially in the development of small molecules targeting specific tyrosine kinase receptors and immune checkpoint inhibitors. These developments have led to a significant improvement in survival for lung cancer patients with metastatic disease. Now, the core guidelines to treat non–small cell lung cancer are based on the identification of targetable driver mutations and immune checkpoints. Continued investigations of newly identified druggable genetic alterations, explorations of biomarkers of immune checkpoint inhibitors, development of next-generation immunotherapy, and optimization of combination therapy are necessary to provide better treatment outcomes for lung cancer patients in the future.
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Microbiome Anomalies in Allogeneic Hematopoietic Cell Transplantation
Vol. 71 (2020), pp. 137–148More LessThe microbiome is an integrated part of the human body that can modulate a variety of disease processes and affect prognosis, treatment response, complications, and outcomes. The importance of allogeneic hematopoietic cell transplantation in cancer treatment has resulted in extensive investigations on the interaction between the microbiome and this treatment modality. These investigations are beginning to lead to clinical trials of microbiome-targeted interventions. Here we review some of these discoveries and describe strategies being investigated to manipulate the microbiome for favorable outcomes, such as the proper selection and timing of antibiotics, type of diet and route of administration, probiotics, prebiotics, and fecal microbiota transplantation.
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A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease
Vol. 71 (2020), pp. 149–161More LessCardiometabolic disease (CMD), such as type 2 diabetes mellitus and cardiovascular disease, contributes significantly to morbidity and mortality on a global scale. The gut microbiota has emerged as a potential target to beneficially modulate CMD risk, possibly via dietary interventions. Dietary interventions have been shown to considerably alter gut microbiota composition and function. Moreover, several diet-derived microbial metabolites are able to modulate human metabolism and thereby alter CMD risk. Dietary interventions that affect gut microbiota composition and function are therefore a promising, novel, and cost-efficient method to reduce CMD risk. Studies suggest that fermentable carbohydrates can beneficially alter gut microbiota composition and function, whereas high animal protein and high fat intake negatively impact gut microbiota function and composition. This review focuses on the role of macronutrients (i.e., carbohydrate, protein, and fat) and dietary patterns (e.g., vegetarian/vegan and Mediterranean diet) in gut microbiota composition and function in the context of CMD.
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Omics and Cardiometabolic Disease Risk Prediction
Vol. 71 (2020), pp. 163–175More LessRisk assessments are integral for the prevention and management of cardiometabolic disease (CMD). However, individuals may develop CMD without traditional risk factors, necessitating the development of novel biomarkers to aid risk prediction. The emergence of omic technologies, including genomics, proteomics, and metabolomics, has allowed for assessment of orthogonal measures of cardiometabolic risk, potentially improving the ability for novel biomarkers to refine disease risk assessments. While omics has shed light on novel mechanisms for the development of CMD, its adoption in clinical practice faces significant challenges. We review select omic technologies and cardiometabolic investigations for risk prediction, while highlighting challenges and opportunities for translating findings to clinical practice.
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Ablation Therapy for Refractory Ventricular Arrhythmias
Vol. 71 (2020), pp. 177–190More LessRecurrent ventricular arrhythmias (VAs) are a leading cause of cardiovascular morbidity and mortality. In the last three decades, important advancements have occurred in the understanding of the mechanisms of recurrent VAs, their prognostic implications in different clinical contexts, and their treatment options. VAs occur in structurally normal hearts as well as in patients with underlying heart disease, but the latter group has a particularly high risk of recurrent VAs. Catheter ablation offers the possibility of cure for a substantial proportion of patients. Research has focused on identifying optimal targets for ablation, correlating the underlying structural abnormalities with the site of origin of VAs, and determining the optimal procedural approach. Ablation therapy can be life-saving in select patients with high burden of repetitive VAs or advanced heart failure syndromes. This article focuses on clinical aspects of catheter ablation of VAs, particularly the selection and clinical management of patients undergoing catheter ablation procedures and expected outcomes.
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Atherosclerosis: Making a U Turn
Vol. 71 (2020), pp. 191–201More LessThe development of potent cholesterol-reducing medications in the last decade of the twentieth century has altered the approach to prevention and treatment of cardiovascular disease (CVD). Initial experience with statins, and more recently with the addition of PCSK9 inhibitors, has proven that human CVD, like that in animal models, can be halted and regressed. Available clinical data show that the lower the achieved level of low-density lipoprotein cholesterol, the greater the regression of disease. Investigative studies are now aimed to understand those factors that both accelerate and impede this healing process. Some of these are likely to be modifiable, and the future of atherosclerotic CVD treatment is likely to be early screening, use of measures to repair atherosclerotic arteries, and prevention of most CVD events.
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Cardiac Amyloidosis: Overlooked, Underappreciated, and Treatable
Vol. 71 (2020), pp. 203–219More LessCardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.
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Contemporary Application of Cardiovascular Magnetic Resonance Imaging
Vol. 71 (2020), pp. 221–234More LessCardiovascular magnetic resonance imaging (CMR) is a comprehensive and versatile diagnostic and prognostic imaging modality that plays an increasingly important role in management of patients with cardiovascular disease. In this review, we discuss CMR applications in nonischemic cardiomyopathy, ischemic heart disease, arrhythmias, right ventricular diseases, and valvular heart disease. We emphasize the quantitative nature of CMR in current practice, from volumes, function, myocardial strain analysis, and late gadolinium enhancement to parametric mapping, including T1, T2, and T2* relaxation times and extracellular volume fraction assessment.
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Postural Orthostatic Tachycardia Syndrome: Mechanisms and New Therapies
Vol. 71 (2020), pp. 235–248More LessPostural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. The three major pathophysiologic mechanisms include partial autonomic neuropathy, hypovolemia, and hyperadrenergic state. Patients often will exhibit overlapping characteristics from more than one of these mechanisms. The approach to the treatment of POTS centers on treating the underlying pathophysiologic mechanism. Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. For hyperadrenergic POTS, beta-blockers and avoidance of norepinephrine reuptake inhibitors is important. Attempts should be made to discern which pathophysiologic mechanism(s) may be afflicting patients so that treatment regimens can be individualized.
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Transcatheter Mitral Valve Replacement: Rationale and Current Status
Vol. 71 (2020), pp. 249–261More LessMitral regurgitation (MR) is the most prevalent form of moderate or severe valve disease in the developed world. MR can result from impairment of any part of the mitral valve apparatus and is classified as primary (disease of the leaflets) or secondary (functional). The presence of at least moderate MR is associated with increased morbidity and mortality. With the goal of avoiding the risks of traditional surgery, transcatheter mitral valve therapies have been developed. The current transcatheter repair techniques are limited by therapeutic target and incomplete MR reduction, and thus transcatheter mitral valve replacement (TMVR) has been pursued. Several devices (both transapical and transseptal) are under development, with both early feasibility and pivotal trials under way. As this field develops, the decision to treat with TMVR will require a heart team approach that takes patient-, disease-, and device-specific factors into account.
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Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation
Vol. 71 (2020), pp. 263–276More LessInterleukin (IL)-11 is upregulated in a wide variety of fibro-inflammatory diseases such as systemic sclerosis, rheumatoid arthritis, pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug-induced liver injury, and nonalcoholic steatohepatitis. IL-11 is a member of the IL-6 cytokine family and has several distinct properties that define its unique and nonredundant roles in disease. The IL-11 receptor is highly expressed on stromal, epithelial and polarized cells, where noncanonical IL-11 signaling drives the three pathologies common to all fibro-inflammatory diseases—myofibroblast activation, parenchymal cell dysfunction, and inflammation—while also inhibiting tissue regeneration. This cytokine has been little studied, and publications on IL-11 peaked in the early 1990s, when it was largely misunderstood. Here we describe recent advances in our understanding of IL-11 biology, outline how misconceptions as to its function came about, and highlight the large potential of therapies targeting IL-11 signaling for treating human disease.
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New Frontiers in Osteoporosis Therapy
Vol. 71 (2020), pp. 277–288More LessCurrent osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone–related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.
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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)