Annual Review of Medicine - Current Issue

The COVID-19 pandemic led to disruption of health services around the world, including cancer services. We carried out a narrative review of the effect of the pandemic on cancer prevention services, including screening. Services were severely affected in the early months of the pandemic, and in some areas are still recovering. Large numbers of additional cancers or additional late-stage cancers have been predicted to arise over the coming years as a result of this disruption. To minimize the effects on cancer outcomes, it is necessary to return as quickly as possible to prepandemic levels of screening and prevention activity or indeed to exceed these levels. The recovery of services should address health inequalities.

Multiple myeloma is a cancer of bone marrow plasma cells that represents approximately 10% of hematologic malignancies. Though it is typically incurable, a remarkable suite of new therapies developed over the last 25 years has enabled durable disease control in most patients. This article briefly introduces the clinical features of multiple myeloma and aspects of multiple myeloma biology that modern therapies exploit. Key current and emerging treatment modalities are then reviewed, including cereblon-modulating agents, proteasome inhibitors, monoclonal antibodies, other molecularly targeted therapies (selinexor, venetoclax), chimeric antigen receptor T cells, T cell–engaging bispecific antibodies, and antibody–drug conjugates. For each modality, mechanism of action and clinical considerations are discussed. These therapies are combined and sequenced in modern treatment pathways, discussed at the conclusion of the article, which have led to substantial improvements in outcomes for multiple myeloma patients in recent years.

Antibody-drug conjugates (ADCs) have become the cornerstone of effective therapeutics in solid and hematological malignancies by harnessing potent cytotoxic payloads with targeted tumoricidal delivery. Since the monumental shift occurred with HER2-targeted ADCs, the discovery of the TROP2 antigen has revolutionized the landscape of ADC development. Moving beyond the traditional ADC design, multiple novel ADCs have successfully shaped and improved survival outcomes in patients with various tumor histologies. Here we review and contrast the clinical impact of the well-known TROP2 ADCs currently in clinical use. We also shed light on upcoming investigational TROP2 ADCs showing promise with novel ADC platforms.

Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of ¹⁷⁷Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.

The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice.

Opioid use disorder continues to drive overdose deaths in many countries, including the United States. Illicit fentanyl and its analogues have emerged as key contributors to the complications and mortality associated with opioid use disorder. Medications for opioid use disorder treatment, such as methadone and buprenorphine, are safe and substantially reduce opioid use, infectious complications, and mortality risk, but remain underutilized. Polysubstance use and emerging substances such as xylazine and designer benzodiazepines create additional treatment challenges. Recent clinical and policy innovations in treatment delivery, including telemedicine, bridge clinics, and expanded models for accessing methadone have the potential to increase access to life-saving care for people living with opioid use disorder.

When the US Food and Drug Administration used the accelerated approval process to authorize the use of the antiamyloid drug aducanumab to treat Alzheimer's disease (AD), many people hoped this signaled a new era of disease-modifying treatment. But 2 years later, aducanumab's failure to launch provides a cautionary tale about the complexities of dementia and the need for a thorough and transparent review of the role that regulatory agencies and various stakeholders play in approving AD drugs. We highlight the events leading to aducanumab's controversial approval and discuss some of the key lessons learned from the drug's failure to deliver the hoped-for benefits. These lessons include the inherent limitations of antiamyloid strategies for a complex disease in which amyloid is only one of several pathological processes, the need for clinical trials that better reflect the diversity of communities affected by AD, the potential pitfalls of futility analyses in clinical trials, the need for greater transparency and other modifications to the approval process, and the dementia field's unreadiness to move from the highly controlled environment of clinical trials to the widespread and chronic use of resource-intensive, disease-modifying drugs in real-world treatment scenarios. People with dementia desperately need effective therapies. We hope that the aducanumab story will inspire changes to the approval process—changes that restore public trust and improve future efforts to deliver disease-modifying therapies to the clinic.

Older adults commonly end up on many medications. Deprescribing is an important part of individualizing care for older adults. It is an opportunity to discuss treatment options and revisit medications that may not have been reassessed in many years. A large evidence base exists in the field, suggesting that deprescribing is feasible and safe, though questions remain about the potential clinical benefits. Deprescribing research faces a myriad of challenges, such as identifying and employing the optimal outcome measures. Further, there is uncertainty about which deprescribing approaches are likely to be most effective and in what contexts. Evidence on barriers and facilitators to deprescribing has underscored how deprescribing in routine clinical practice can be complex and challenging. Thus, finding practical, sustainable ways to implement deprescribing is a priority for future research in the field.

Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.

The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.

Mpox, previously known as monkeypox, is caused by an Orthopoxvirus related to the variola virus that causes smallpox. Prior to 2022, mpox was considered a zoonotic disease endemic to central and west Africa. Since May 2022, more than 86,000 cases of mpox from 110 countries have been identified across the world, predominantly in men who have sex with men, most often acquired through close physical contact or during sexual activity. The classical clinical presentation of mpox is a prodrome including fever, lethargy, and lymphadenopathy followed by a characteristic vesiculopustular rash. The recent 2022 outbreak included novel presentations of mpox with a predominance of anogenital lesions, mucosal lesions, and other features such as anorectal pain, proctitis, oropharyngeal lesions, tonsillitis, and multiphasic skin lesions. We describe the demographics and clinical spectrum of classical and novel mpox, outlining the potential complications and management.

Recent advances in the treatment of tuberculosis (TB) have led to improvements unprecedented in our lifetime. Decades of research in developing new drugs, especially for multidrug-resistant TB, have created not only multiple new antituberculous agents but also a new approach to development and treatment, with a focus on maximizing the benefit to the individual patient. Prevention of TB disease has also been improved and recognized as a critical component of global TB control. While the momentum is positive, it will take continued investment at all levels, especially training of new dedicated TB researchers and advocates around the world, to maintain this progress.

Complement constitutes a major part of the innate immune system. The study of complement in human health has historically focused on infection risks associated with complement protein deficiencies; however, recent interest in the field has focused on overactivation of complement as a cause of immune injury and the development of anticomplement therapies to treat human diseases. The kidneys are particularly sensitive to complement injury, and anticomplement therapies for several kidney diseases have been investigated. Overactivation of complement can result from loss-of-function mutations in complement regulators; gain-of-function mutations in key complement proteins such as C3 and factor B; or autoantibody production, infection, or tissue stresses, such as ischemia and reperfusion, that perturb the balance of complement activation and regulation. Here, we provide a high-level review of the status of anticomplement therapies, with an emphasis on the transition from rare diseases to more common kidney diseases.

Home-based dialysis modalities offer both clinical and practical advantages to patients. The use of the home-based modalities, peritoneal dialysis and home hemodialysis, has been increasing over the past decade after a long period of decline. Given the increasing frequency of use of these types of dialysis, it is important for clinicians to be familiar with how these types of dialysis are performed and key clinical aspects of care related to their use in patients with end-stage kidney disease.

Membranous nephropathy (MN), an autoimmune kidney disease and leading cause of nephrotic syndrome, leads to kidney failure in up to one-third of affected individuals. Most MN cases are due to an autoimmune reaction against the phospholipase A2 receptor (PLA2R) located on kidney podocytes. Serum PLA2R antibody quantification is now part of routine clinical practice because antibody titers correlate with disease activity and treatment response. Recent advances in target antigen detection have led to the discovery of more than 20 other podocyte antigens, yet the clinical impact of additional antigen detection remains unknown and is under active investigation. Here we review recent findings and hypothesize how current research will inform future care of patients with MN.

The MELD (model for end-stage liver disease) 3.0 score was developed to replace the MELD-Na score that is currently used to prioritize liver allocation for cirrhotic patients awaiting liver transplantation in the United States. The MELD 3.0 calculator includes new inputs from patient sex and serum albumin levels and has new weights for serum sodium, bilirubin, international normalized ratio, and creatinine levels. It is expected that use of MELD 3.0 scores will reduce overall waitlist mortality modestly and improve access for female liver transplant candidates. The utility of MELD 3.0 and PELDcre (pediatric end-stage liver disease, creatinine) scores for risk stratification in cirrhotic patients undergoing major abdominal surgery, placement of a transjugular intrahepatic portosystemic shunt, and other interventions requires further study. This article reviews the background of the MELD score and the rationale to create MELD 3.0 as well as potential implications of using this newer risk stratification tool in clinical practice.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD heterogeneity has hampered progress in developing pharmacotherapies that affect disease progression. This issue can be addressed by precision medicine approaches, which focus on understanding an individual's disease risk, and tailoring management based on pathobiology, environmental exposures, and psychosocial issues. There is an urgent need to identify COPD patients at high risk for poor outcomes and to understand at a mechanistic level why certain individuals are at high risk. Genetics, omics, and network analytic techniques have started to dissect COPD heterogeneity and identify patients with specific pathobiology. Drug repurposing approaches based on biomarkers of specific inflammatory processes (i.e., type 2 inflammation) are promising. As larger data sets, additional omics, and new analytical approaches become available, there will be enormous opportunities to identify high-risk individuals and treat COPD patients based on their specific pathophysiological derangements. These approaches show great promise for risk stratification, early intervention, drug repurposing, and developing novel therapeutic approaches for COPD.

Interventional pulmonary medicine has developed as a subspecialty focused on the management of patients with complex thoracic disease. Leveraging minimally invasive techniques, interventional pulmonologists diagnose and treat pathologies that previously required more invasive options such as surgery. By mitigating procedural risk, interventional pulmonologists have extended the reach of care to a wider pool of vulnerable patients who require therapy. Endoscopic innovations, including endobronchial ultrasound and robotic and electromagnetic bronchoscopy, have enhanced the ability to perform diagnostic procedures on an ambulatory basis. Therapeutic procedures for patients with symptomatic airway disease, pleural disease, and severe emphysema have provided the ability to palliate symptoms. The combination of medical and procedural expertise has made interventional pulmonologists an integral part of comprehensive care teams for patients with oncologic, airway, and pleural needs. This review surveys key areas in which interventional pulmonologists have impacted the care of thoracic disease through bronchoscopic intervention.

We review current knowledge on the trends and drivers of global wildfire activity, advances in the measurement of wildfire smoke exposure, and evidence on the health effects of this exposure. We describe methodological issues in estimating the causal effects of wildfire smoke exposures on health and quantify their importance, emphasizing the role of nonlinear and lagged effects. We conduct a systematic review and meta-analysis of the health effects of wildfire smoke exposure, finding positive impacts on all-cause mortality and respiratory hospitalizations but less consistent evidence on cardiovascular morbidity. We conclude by highlighting priority areas for future research, including leveraging recently developed spatially and temporally resolved wildfire-specific ambient air pollution data to improve estimates of the health effects of wildfire smoke exposure.

Diabetic neuropathy is a highly prevalent complication of diabetes. It consists of a broad range of neuropathic conditions, such as distal symmetric polyneuropathy and various forms of autonomic neuropathies involving the cardiovascular, gastrointestinal, and urogenital systems. Prevention or diagnosis in early stages of disease is crucial to prevent symptomatic onset and progression, particularly in the absence of current disease-modifying therapies. In this review, we describe the four main types of diabetic neuropathy. We review current understanding with respect to diagnosis and treatment while highlighting knowledge gaps and future directions.