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IEEE Open Journal of Control Systems

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The IEEE Open Journal of Control Systems covers the theory, design, optimization, and applications of dynamic systems and control. The field integrates elements of sensing, communication, decision and actuation components, as relevant for the analysis, design and operation of dynamic systems and control. The systems considered include: technological, physical, biological, economic, organizational and other entities, and combinations thereof.

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The IEEE Open Journal of Control Systems is a new publication of the IEEE Control Systems Society. The journal aims to publish high-quality papers on the theory, design, optimization, and applications of dynamic systems and control.

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The journal’s main mission is the promotion of open access to all control systems research and education publications, including software, and data.

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Preface to special topic on games in control systems.

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Ji-Feng Zhang, Preface to special topic on games in control systems, National Science Review , Volume 7, Issue 7, July 2020, Page 1115, https://doi.org/10.1093/nsr/nwaa118

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In the past century, we have witnessed the glorious achievements of control science in our daily life, such as industry, transportation, aeronautics and astronautics, and so on. Traditionally, a control system is a set of mechanical or electronic devices, control of which usually deals with objects of passive nature. However, with the development of advanced sensing and communication technologies, ‘intelligent’ agents with not only execution and communication capabilities but also active objects are involved. In this case, traditional control methods may not be applied directly. To deal with active objects in control systems, game concepts and tools may be essential in the control framework. Due to the tremendous application foreground in various fields, including society, economics, artificial intelligence, etc., game-based control has inspired more and more interest among the control community.

To reflect the recent developments in the field of games in control systems, this special topic of the National Science Review presents four timely technical perspectives, a review and an interview.

The first perspective, by Zhang et al ., introduces a new class of control systems referred to as game-based control systems that involve multiple active agents whose behaviours are driven by both physical laws and their own rational pursuits, and points out some new theoretical problems with potential applications, especially to man–machine integration systems. The second perspective, by Shamma, discusses the connections between game theory and control systems with representative examples, especially in the area of game-theoretic learning. The third perspective, by Cheng et al ., shows the application and superiority of game theoretic control in optimization problems using a framework for optimization of networked systems via a game theoretic control-based approach. The fourth perspective, by Cao, discusses merging game theory and control theory in the area of artificial intelligence and autonomy, and expresses great expectations on this emerging research direction.

Modern control systems are featured by their hierarchical structure composed of cyber, physical and human layers. The review ‘Dynamic games for secure and resilient control system design’ by Huang et al . provides a multilayer perspective towards increasingly complex and integrated control systems, and offers an extensive overview of recent research directions on using game-theoretic methods to understand the fundamental trade-offs of robustness, security and resilience.

Control community has recently witnessed a rapidly growing interest in the application of game-theoretic concepts and tools in research on control, multi-agent systems, and networks. In the interview with NSR, Tamer Başar introduces the recently emerging role of game theory in control and networking research, how it broadens the territorial boundaries of control into disciplines outside engineering, and the opportunities and challenges that lie ahead.

As the guest editor, I would like to thank all of the authors, the reviewers, and the editorial staff for their contributions to this special topic. Games in control systems have attracted a great deal of attention in the control community, and there are still many fundamental and challenging problems that need to be investigated. I hope this special topic can provide useful information and promote research in this rapidly developing field.

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Control Applications in Modern Power Systems

Select Proceedings of EPREC 2021

• Conference proceedings
• © 2022
• Jitendra Kumar 0 ,
• Manoj Tripathy 1 ,
• Premalata Jena 2

Electrical Engineering Department, National Institute of Technology Jamshedpur, Jamshedpur, India

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Electrical Engineering Department, Indian Institute of Technology Roorkee, Roorkee, India

• Presents select proceedings of Electric Power and Renewable Energy Conference (EPREC) 2020
• Covers recent developments in the emerging areas of power electronics
• Useful for policy makers and power engineers involved in power generation and distribution

Part of the book series: Lecture Notes in Electrical Engineering (LNEE, volume 870)

Included in the following conference series:

• EPREC: International Conference on Electric Power and Renewable Energy

Conference proceedings info: EPREC 2021.

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About this book

The volume contains peer-reviewed proceedings of EPREC 2021 with a focus on control applications in the modern power system. The book includes original research and case studies that present recent developments in the control system, especially load frequency control, wide-area monitoring, control & instrumentation, optimization, intelligent control, energy management system, SCADA systems, etc. The book will be a valuable reference guide for beginners, researchers, and professionals interested in advancements in the control system.

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The Coming Trends and What to Expect

• Control System
• Optimization
• Industrial Automation
• Intelligent Control
• Wide-Area Monitoring
• Load Frequency Control

Table of contents (49 papers)

Front matter, importance of secondary controller and its parameters optimization using particle swarm optimization technique for agc.

• Hiramani Shukla, More Raju, Prashant Khare

Section of Suitable GRC Structure for Dual Area Thermal System Under 2DOF-PID Controller

• CH. Naga Sai Kalyan, Chintalapudi V. Suresh

Application Hybrid Chaotic Maps and Adaptive Acceleration Coefficients PSO Algorithm for Optimal Integration Photovoltaic Distributed Generation Problem in Distribution Energy Network

• Mohamed Zellagui, Nasreddine Belbachir, Adel Lasmari, Benaissa Bekkouche, Claude Ziad El-Bayeh

A Novel Order Simplification Technique for Large-Scale Linear Dynamic Systems

• Arvind Kumar Prajapati, Sugunakar Mamidala, Rajendra Prasad

Comparative Analysis of Controller Tuning for Multi-area Power System Using Swarm Optimization Techniques

• B. Rajani, Venkatesh Rayapati, Rayudu Srinivas, Koneti Varalakshmi

State Estimation of Power Network Using Phasor Measurement

• Shiv Shankar, Vishal Rathore, K. B. Yadav, Alok Priyadarshi

Optimal Siting of FACTS Controller Using Moth Flame Optimization Technique

• Shweta Kumari, Manoj Kumar Kar, Lalit Kumar, Sanjay Kumar

KNN Based Approach for Transmission Line Outage Detection Using Synchrophasor Data

• Mehebub Alam, Shubhrajyoti Kundu, Siddhartha Sankar Thakur, Sumit Banerjee

Study the Effect of Right-Half Plane Zero on Voltage-Mode Controller Design for Boost Converter

• Subhransu Padhee, Rajesh Murari

Grid-Connected PV System Power Forecasting Using Nonlinear Autoregressive Exogenous Model

• Abrar Ahmed Chhipa, Vinod Kumar, R. R. Joshi

Frequency Regulation of Multi-microgrid Incorporating Hybrid Energy Storage Units

• M. Hamsa Deepika, G. S. Sivasankari, R. Subasri, T. Vigneysh, K. Narayanan, Velamuri Suresh

Voltage Regulator Using Sliding Mode Controller for Inverter Based Islanded Microgrid

• Suhaib Khan, Naiyyar Iqubal, Sheetla Prasad

Design of PID Controller Using Strawberry Algorithm for Load Frequency Control of Multi-area Interconnected Power System with and Without Non-linearity

• Neelesh Kumar Gupta, Idamakanti Kasireddy, A. K. Singh

Dynamic Performance Analysis of Neural Network Based MPPT Under Varying Climatic Condition

• Pushpendra Dangi, Suresh Kr. Gawre, Amit Ojha

Optimum Location of Isolator in Radial Distribution System Using Genetic Algorithm to Improve the System Reliability

• Manish Kumar Madhav, Krishna Bihari Yadav

A Predictive Maintenance Scheme for Solar PV System

• Upendra Pal Singh, Subhash Chandra

Unscented Transform-Based Efficient Energy Management System of a Microgrid for Optimal Heat Power Dispatch

• Debashis Jana, Niladri Chakraborty

A Planning Framework for Reactive Power in Power Transmission System Using Compensation Devices

• Nihar Karmakar, Bishwajit Dey, Biplab Bhattacharyya

Fuzzy Controlled D-STATCOM to Improve the PCC Voltage Profile of a Multi-Microgrid Interconnection Scheme

• Charivil Sojy Rajan, Mabel Ebenezer

Editors and Affiliations

Jitendra Kumar

Manoj Tripathy, Premalata Jena

About the editors

Dr. Jitendra Kumar is currently an Assistant Professor at the Department of Electrical Engineering, National Institute of Technology Jamshedpur, India. He received his B.Tech. from IMS Engineering College, Ghaziabad, India, in 2009, M.Tech from the National Institute of Technology Kurukshetra, Kurukshetra, in 2011, and the Ph.D. degree in electrical engineering from the Indian Institute of Technology (IIT) Roorkee, in 2017. He has over 4 years of experience teaching subjects like power systems, advanced power systems, control systems, control & instrumentation, power system operation, and control, signal & system, power system protection, circuit & network theory. He has many papers in reputed journals. His major areas of research interests include power system protection and restructuring, protection algorithms design in smart grid and microgrid environment, design of protection algorithms in FACTS environment.

Dr. Manoj Tripathy received his B.E. degree in electrical engineering from Nagpur University, Nagpur, India, in 1999; M.Tech degree in instrumentation and control from Aligarh Muslim University, Aligarh, India, in 2002; and a Ph.D. degree from the IIT Roorkee, India, in 2008. He is currently working as an Associate Professor in the Department of Electrical Engineering, IIT Roorkee, India. His fields of interest are wavelets, neural networks, optimization techniques, content-based image retrieval, digital instrumentation, digital protective relays, and digital speech processing. Dr. Tripathy is a reviewer for various international journals in the area of power systems and speech.

Dr. Premalata Jena is currently an Associate Professor at the Department of Electrical Engineering, IIT Roorkee, Uttarakhand, India. She received her B.Tech degree in electrical engineering from the Utkal University, Bhubaneswar, India, in 2001, the M.Tech degree in Electrical Engineering from IIT Kharagpur, in 2006, and the Ph.D. degree from the IIT Kharagpur, India, in 2011. Dr. Jena has seven years of teaching experience. She is an IEEE member and INAE, Young Associate. She received many awards such as the Women Excellence Award and Early Carrier Research Award, SERB, DST, Gov. of India, New Delhi, INAE Young Engineer Award, POSOCO Power System Awards, in 2013. She has published many papers in different reputed journals and conferences. Her fields of interest are Smart Grid, Smart grid technology, and protection, Microgrid, Microgrid Protection, Signal processing application to power system relaying, Power system Protection, Protection Issues with FACTS Devices, Protection Scheme Development for a line with FACTS devices, Disturbance localization, Signal processing application for disturbance localization.

Bibliographic Information

Book Title : Control Applications in Modern Power Systems

Book Subtitle : Select Proceedings of EPREC 2021

Editors : Jitendra Kumar, Manoj Tripathy, Premalata Jena

Series Title : Lecture Notes in Electrical Engineering

DOI : https://doi.org/10.1007/978-981-19-0193-5

Publisher : Springer Singapore

eBook Packages : Energy , Energy (R0)

Copyright Information : The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022

Hardcover ISBN : 978-981-19-0192-8 Published: 28 May 2022

Softcover ISBN : 978-981-19-0195-9 Published: 29 May 2023

eBook ISBN : 978-981-19-0193-5 Published: 27 May 2022

Series ISSN : 1876-1100

Series E-ISSN : 1876-1119

Edition Number : 1

Number of Pages : XIV, 654

Number of Illustrations : 99 b/w illustrations, 311 illustrations in colour

Topics : Energy Systems , Power Electronics, Electrical Machines and Networks , Control and Systems Theory , Energy Policy, Economics and Management

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• Motors and Drives

Hot topics in Control Engineering for 2022

Think again: automation product awards, motors and drives, automation salary and career information, engineering leaders under 40, iiot implementation help, tutorials on hmis, scada and plc programming help were among the hot topics of 2022. see top 3 covers and top 10 articles posted prior to 2022..

Learning Objectives

• Understand how Control Engineering hot topics for 2022 were selected.
• Review top 10 articles posted during and before 2022 at www.controleng.com.
• See top 3 covers as selected by the Control Engineering creative director.

Hot topics during 2022 in Control Engineering include award-winning automation, control and instrumentation products; a variable frequency drive (VFD) tutorial; advanced motor control tutorial; information about engineering salaries and career advice; and “Engineering Leaders Under 40,” based on Google Analytics for www.controleng.com . Other topics, rounding out the top 10 cover use of VFDs with permanent magnet motors; Industrial Internet of Things (IIoT) implementation help; tutorials on human-machine interfaces (HMIs) and supervisory control and data acquisition (SCADA); and programming help for programmable logic controllers (PLCs). Also see top 3 covers below with and top 10 Control Engineering articles posted prior to 2022.

These automation and control topics help Control Engineering subscribers do their jobs better. For future areas of automation coverage based on subscriber research and to contribute articles, see www.controleng.com/2023articles .

Top 10 articles posted in Control Engineering during 2022

Analytics count the number of visits to articles posting during 2022; of course, articles posted earlier in the year have an advantage; just four articles of the 10 were posted after mid-year. Links below the top 10 give a better sense of articles popular in the second half, including digital transformation using the cloud, IIoT for optimization, controller selection advice, alarm management, 5G wireless and MQTT.

• Spotlight on Innovation: 2022 Engineers’ Choice Awards, February 7: Control Engineering announces the best automation, control and instrumentation products in the 19 categories of the annual Engineers’ Choice Awards program.
• VFDs from the inside out, February 1: Variable frequency drive (VFD) vocabulary words: These 50 terms can help properly apply VFDs.
• Understanding the effect of PWM when controlling a brushless dc motor, January 26: Motion system designers can be challenged when selecting or developing electronics using pulse-width modulation (PWM) to drive brushless dc motors. Heed some basic physical phenomena to avoid unexpected performance issues, along with general guidelines for using a PWM driver with a brushless DC motor. See diagrams, equations.
• Control Engineering Career and Salary Survey, 2022, May 17: Solve the workforce challenge: Automate, innovate, hire and retain great workers. Lack of skilled workers, materials and the economy are biggest threats to manufacturing. Lack of available skilled workers jumped from 37% in 2021 to 57% in 2022.
• Engineering Leaders Under 40, Class of 2022, September 6: The future of automation, engineering and manufacturing relies on the younger workforce, and these 36 individuals are here to advance their industries now and for years to come.
• Intro to setting up, tuning a PM motor with a VFD, March 2: A permanent magnet (PM) motor requires a variable frequency drive (VFD) to operate effectively. See motor comparison table, induction motor vs. PM torque curve, and VFD programming and tuning advice.
• Industrial IoT made fast and easy, April 7: With the tools available today, implementing the Industrial Internet of Things (IIoT) is not as hard as people think.
• When designing HMI/SCADA, consider many factors, June 7: User abilities, skill levels, future plans, needs of stakeholders, and other items should be explored. See a system integrator’s advice and seven SCADA system integration/design questions to ask.
• HMI/SCADA systems: Upgrade your migration, November 24: When upgrading human-machine interface (HMI) and supervisory control and data acquisition (SCADA) software, don’t just create a new version of the old. Enable workers with advanced HMI/SCADA capabilities after migration. See five tips for optimizing HMI/SCADA screens.
• PLC programming: What you need to know, July 7: While the programmable logic controller (PLC) is very important, the programming inside the controller is just as critical and can be overlooked.

Hot topics in Control Engineering July through December

Hot topics in the second half of 2022, under-represented in the tally above, include digital transformation using the cloud in July, leveraging IIoT for process optimization, modernization in August, how to find the best controller in September, control system alarm management in October, how AI and machine learning can drive sustainable 5G in November and leveraging MQTT industrial edge devices in automation projects in December.

July: https://www.controleng.com/articles/control-engineering-hot-topics-july-2022/

August: https://www.controleng.com/articles/control-engineering-hot-topics-august-2022/

September: https://www.controleng.com/articles/control-engineering-hot-topics-september-2022/

October: https://www.controleng.com/articles/control-engineering-hot-topics-october-2022/

November: https://www.controleng.com/articles/control-engineering-hot-topics-november-2022/

December: https://www.controleng.com/articles/control-engineering-hot-topics-december-2022/

Top 3 covers of 2022: Edge and AI-enabled IIoT, resolve workforce challenges, industrial wireless

Michael Smith, Control Engineering creative director, explained why January/February edge and AI-enabled IIoT, May resolving workforce challenges and August industrial wireless were his three favorite covers in 2022. Review these and other print/digital editions here: https://www.controleng.com/magazine/

Michael Smith, Control Engineering creative director, chose January/February Edge and AI-enabled IIoT , May Resolving workforce challenges and August industrial wireless as his three favorite covers in 2022. Courtesy: Control Engineering, CFE Media and Technology

January/February print/digital edition of Control Engineering, North American edition

This month’s issue does a splendid job of communicating automation controls with all the various tools and equipment today’s modern engineers have at their fingertips. The artwork displayed shows off some of the technology used for automation in a well-orchestrated cover design. Showing real people in engineering is always the best approach providing a tangible entry point for the reader.

May print/digital edition of Control Engineering, North American edition

The May issue is a perfect snapshot of young engineers from a diverse cultural makeup. The color design works to control the readability, while integrating into the format. Young engineers are in high demand due to a lack of skilled workers entering into the job market today. The well captured photo serves as a visual hook, and is an excellent example of education in the field.

August print/digital edition of Control Engineering, North American edition

The August issue is another great example of people and engineering. The primary subject, followed by cascading coworkers in the background all work together to create a pleasing and engaging format. Colorized type, size, and design are all used to help communicate an integrated wireless message.

Top 10 articles posted in Control Engineering posted prior to 2022

Many articles with the most traffic during 2022 posted in prior years cover tutorial topics including cloud computing, VFDs, permanent magnet motors, PID tuning, PLC programming, virtualized machine advantages, cascade control, and an antenna tutorial.

• Five characteristics of cloud computing ,  2017 : Cloud computing’s characteristics and benefits include on-demand self-service, broad network access, and being very elastic and scalable.
• Top 5 VFD parameter changes explained, 2020: Programming variable frequency drives (VFDs) to fit most industrial applications require only the most basic settings to operate the motor. Understand these 5 VFD parameter changes to optimize VFD programming to fit most motor-drive applications.
• Understanding permanent magnet motors ,  2017 : A permanent magnet (PM) motor is an ac motor that uses magnets imbedded into or attached to the surface of the motor’s rotor. This article provides an elementary understanding behind the terminology, concepts, theory, and physics behind PM motors.
• Understanding PID control and loop tuning fundamentals ,  2016 : PID loop tuning may not be a hard science, but it’s not magic either. Here are some tuning tips that work.
• Free PLC programming software for education, 2021: Available programmable logic controller (PLC) software that is free for users is crucial for users and students who can’t currently access a lab. See table with a breakdown.
• Learning PID loop tuning from an expert, 2014: Hands-on experience helps accelerate the PID learning curve.
• The pros and cons of using a virtualized machine, 2015: A virtualized machine can be a great help in maintaining a system, but the pros and cons of using one should always be taken into consideration.
• Fundamentals of cascade control, 2014 : Sometimes two controllers can do a better job of keeping one process variable where you want it.
• Stepper motor torque basics ,  2018 : Stepper motors remain popular because they are low-cost, rugged, simple, have high torque at startup and low speeds, require little maintenance, and they can operate in an open loop control system.
• Antenna basics, antenna types, antenna functions ,  2014 : Industrial wireless tutorials: What you need to know about industrial antennas, antenna functions, and antenna capabilities.

Mark T. Hoske is content manager, Control Engineering , CFE Media and Technology at [email protected] . Traffic ranking and compliation based on www.controleng.com Google Analytics were performed by Chris Vavra, web content manager, Control Engineering , [email protected] . Cover analysis was by Michael Smith , creative director, Control Engineering.

KEYWORDS: Control Engineering , hot topics in 2022

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A Review on Control System Applications in Industrial Processes

P K Juneja 1 , S K Sunori 2 , A Sharma 3 , A Sharma 4 , H Pathak 5 , V Joshi 5 and P Bhasin 5

Published under licence by IOP Publishing Ltd IOP Conference Series: Materials Science and Engineering , Volume 1022 , 1st International Conference on Computational Research and Data Analytics (ICCRDA 2020) 24th October 2020, Rajpura, India Citation P K Juneja et al 2021 IOP Conf. Ser.: Mater. Sci. Eng. 1022 012010 DOI 10.1088/1757-899X/1022/1/012010

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1 Department of ECE, Graphic Era University, Dehradun, India

2 Department of ECE, Graphic Era Hill University, Bhimtal, Nainital, India

3 Department of PDP, Graphic Era University, Dehradun, 248001, India

4 Department of PDP, Graphic Era Hill University, Dehradun, India

5 Department of EE, Graphic Era University, Dehradun, India

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Present paper attempts to review the literature related to design of P-I-D control for time delayed complex industrial process for single as well as for multivariable process with interaction considerations, their decoupler design and time delay compensators. General instrumentation of the industrial feedback control systems along with control system analysis has been covered. Also it covers, control features of some paper mill sub-processes like headbox operation, basis weight and retention. The importance of eliminating the effects of interactions, among the process control loops inside a multi input multi output industrial control system, has been discussed with the help of literature study. The importance of the process dynamics knowledge for designing a control system has also been investigated. This paper also investigates the significance and effectiveness of PID controllers through various literature studies. The problems of the classical PID controllers such as constraints, presence of disturbances etc.) can be removed by designing in combination with soft computing techniques. Moreover, possibility of further enhancements in the PID controller with the utilization of various schemes available, has been presented. The present status of control systems in industrial processes in terms of various control parameters such as stability, dead time compensation etc. has been presented and the future improvements have been stated.

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A survey of hybrid braking system control methods.

1. Introduction

2. braking torque distribution strategy and coordination control of hybrid braking control methods, 3. primary research challenges in hybrid braking system control, 4. conclusions, author contributions, data availability statement, conflicts of interest, list of abbreviations.

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Share and Cite

Li, W.; Wang, M.; Huang, C.; Li, B. A Survey of Hybrid Braking System Control Methods. World Electr. Veh. J. 2024 , 15 , 372. https://doi.org/10.3390/wevj15080372

Li W, Wang M, Huang C, Li B. A Survey of Hybrid Braking System Control Methods. World Electric Vehicle Journal . 2024; 15(8):372. https://doi.org/10.3390/wevj15080372

Li, Wenfei, Ming Wang, Chao Huang, and Boyuan Li. 2024. "A Survey of Hybrid Braking System Control Methods" World Electric Vehicle Journal 15, no. 8: 372. https://doi.org/10.3390/wevj15080372

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[ This article is part of the 2023 Trends Report ]

The Covid -19 pandemic era ushered in a new set of challenges for youth in the United States, leading to a mental health crisis as declared by the United States surgeon general just over a year ago. But U.S. children and teens have been suffering for far longer.

In the 10 years leading up to the pandemic, feelings of persistent sadness and hopelessness—as well as suicidal thoughts and behaviors—increased by about 40% among young people, according to the Centers for Disease Control and Prevention’s (CDC) Youth Risk Behavior Surveillance System .

“We’re seeing really high rates of suicide and depression, and this has been going on for a while,” said psychologist Kimberly Hoagwood, PhD, a professor of child and adolescent psychiatry at New York University’s Grossman School of Medicine. “It certainly got worse during the pandemic.”

In addition to the social isolation and academic disruption nearly all children and teens faced, many also lost caregivers to Covid -19, had a parent lose their job, or were victims of physical or emotional abuse at home.

All these difficulties, on top of growing concerns about social media, mass violence, natural disasters, climate change, and political polarization—not to mention the normal ups and downs of childhood and adolescence—can feel insurmountable for those who work with kids.

“The idea of a ‘mental health crisis’ is really broad. For providers and parents, the term can be anxiety-provoking,” said Melissa Brymer, PhD, who directs terrorism and disaster programs at the UCLA–Duke University National Center for Child Traumatic Stress. “Part of our role is to highlight specific areas that are critical in this discussion.”

Across the field, psychologists are doing just that. In addition to studying the biological, social, and structural contributors to the current situation, they are developing and disseminating solutions to families, in schools, and at the state level. They’re exploring ways to improve clinical training and capacity and working to restructure policies to support the most vulnerable children and teens.

Psychologists were also behind new mental health recommendations from the U.S. Preventive Services Task Force, a group of volunteer health professionals who evaluate evidence on various preventive health services. The task force now recommends regular anxiety screenings for youth ages 8 to 18 and regular depression screenings for adolescents ages 12 to 18.

“I see these trends in children’s mental health problems as being critical, but there are solutions,” Hoagwood said. “If we refocus our efforts toward those solutions, we could see some of these tides turn.”

Sources of stress

Across the United States, more than 200,000 children lost a parent or primary caregiver to Covid -19 (“ Covid -19 Orphanhood,” Imperial College London, 2022). In the face of those losses, families had to curtail mourning rituals and goodbye traditions because of social distancing requirements and other public health measures, Brymer said. Many children are still grieving, sometimes while facing added challenges such as moving to a different home or transferring to a new school with unfamiliar peers.

The CDC also reports that during the pandemic, 29% of U.S. high school students had a parent or caregiver who lost their job, 55% were emotionally abused by a parent or caregiver, and 11% were physically abused ( Adolescent Behaviors and Experiences Survey—United States, January–June 2021 , CDC ).

“Schools are crucial for keeping kids safe and connecting them with services, but the pandemic completely disrupted those kinds of supports,” Brymer said.

Those extreme disruptions didn’t affect all young people equally. Echoing pre- Covid -19 trends, the CDC also found that girls, LGBTQ+ youth, and those who have experienced racism were more likely to have poor mental health during the pandemic, said social psychologist Kathleen Ethier, PhD, director of the CDC’s Division of Adolescent and School Health.

Contributing factors likely include stigma, discrimination, and online bullying, Ethier said. Female students also report much higher levels of sexual violence than their male peers, which can further harm mental health.

As much hardship as Covid -19 wrought, it’s far from the only factor contributing to the current crisis. Biology also appears to play a role. The age of puberty has been dropping for decades, especially in girls, likely leading to difficulty processing complex feelings and knowing what to do about them ( Eckert-Lind, C., et al., JAMA Pediatrics , Vol. 174, No. 4, 2020 ). In early puberty, regions of the brain linked to emotions and social behavior are developing more quickly than regions responsible for the cognitive control of behavior, such as the prefrontal cortex, Ethier said.

Those developmental changes drive young people to seek attention and approval from their peers . For some, using social media fulfills that need in a healthy way, providing opportunities for connection and validation to youth who may be isolated from peers, geographically or otherwise.

For others, negative messages—including online bullying and unrealistic standards around physical appearance—appear to have a detrimental effect, but more research is needed to understand who is most at risk.

“There is clearly some aspect of young people’s online life that’s contributing [to the mental health crisis], we just don’t know exactly what that is,” said Ethier.

Finally, structural factors that affect millions of U.S. children, including poverty, food insecurity, homelessness, and lack of access to health care and educational opportunities, can lead to stress-response patterns that are known to underlie mental health challenges.

“Even in very young children, prolonged stress can trigger a cycle of emotion-regulation problems, which can in turn lead to anxiety, depression, and behavioral difficulties,” Hoagwood said. “These things are well established, but we’re not doing enough as a field to address them.”

Building capacity in schools

The biggest challenge facing mental health care providers right now, experts say, is a shortage of providers trained to meet the mounting needs of children and adolescents.

“There’s a growing recognition that mental health is just as important as physical health in young people’s development, but that’s happening just as mental health services are under extreme strain,” said clinical psychologist Robin Gurwitch, PhD, a professor in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center.

Schools, for example, are a key way to reach and help children—but a 2022 Pew Research Center survey found that only about half of U.S. public schools offer mental health assessments and even fewer offer treatment services. Psychologists are now ramping up efforts to better equip schools to support student well-being onsite.

Much of that work involves changing policies at the school or district level to provide more support for all students. For example, school connectedness—the degree to which young people feel that adults and peers at school care about them and are invested in their success—is a key contributor to mental health. Youth who felt connected during middle and high school have fewer problems with substance use, mental health, suicidality, and risky sexual behavior as adults ( Steiner, R. J., et al., Pediatrics , Vol. 144, No. 1, 2019 ).

Through its What Works in Schools program , the CDC funds school districts to make changes that research shows foster school connectedness. Those include improving classroom management, implementing service-learning programs for students in their communities, bringing mentors from the community into schools, and making schools safer and more supportive for LGBTQ+ students.

Psychologists are also building training programs to help teachers and other school staff create supportive classrooms and aid students who are in distress. Classroom Wise (Well-Being Information and Strategies for Educators), developed by the Mental Health Technology Transfer Center Network and the University of Maryland’s National Center for School Mental Health (NCSMH), is a free, flexible online course and resource library that draws on psychological research on social-emotional learning, behavioral regulation, mental health literacy, trauma, and more ( Evidence-Based Components of Classroom Wise (PDF, 205KB), NCSMH, 2021 ).

“We’re using evidence-based practices from child and adolescent mental health but making these strategies readily available for teachers to apply in the classroom,” said clinical psychologist Nancy Lever, PhD, codirector of NCSMH, who helped develop Classroom Wise .

The course incorporates the voices of students and educators and teaches actionable strategies such as how to create rules and routines that make classrooms feel safe and how to model emotional self-regulation. The strategies can be used by anyone who interacts with students, from teachers and administrators to school nurses, coaches, and bus drivers.

“What we need is to build capacity through all of the systems that are part of children’s lives—in families, in schools, in the education of everybody who interacts with children,” said psychologist Ann Masten, PhD, a professor of child development at the University of Minnesota.

Other training efforts focus on the students themselves. Given that preteens and teenagers tend to seek support from their peers before turning to adults, the National Child Traumatic Stress Network (NCTSN) created conversation cards to equip kids with basic skills for talking about suicide. The advice, available in English and Spanish, includes how to ask about suicidal thoughts, how to listen without judgment, and when to seek guidance from an adult ( Talking About Suicide With Friends and Peers, NCTSN, 2021 ).

While training people across the school population to spot and address mental health concerns can help reduce the strain on mental health professionals, there will always be a subset of students who need more specialized support.

Telehealth, nearly ubiquitous these days, is one of the best ways to do that. In South Carolina, psychologist Regan Stewart, PhD, and her colleagues colaunched the Telehealth Outreach Program at the Medical University of South Carolina in 2015. Today, nearly every school in the state has telehealth equipment (Wi-Fi and tablets or laptops that kids can use at school or take home) and access to providers (psychology and social work graduate students and clinicians trained in trauma-focused cognitive behavioral therapy). Students who need services, which are free thanks to grant funding or covered by Medicaid, meet one-on-one with their clinician during the school day or after hours ( American Psychologist , Vol. 75, No. 8, 2020 ).

“We learned a lot about the use of technology during the pandemic,” Ethier said. “At this point, it’s very much a matter of having sufficient resources so more school districts can access those sources of care.”

Expanding the workforce

Limited resources are leaving families low on options, with some young people making multiple trips to the emergency room for mental health-related concerns or spending more than six months on a waiting list for mental health support. That points to a need for more trained emergency responders and psychiatric beds, psychologists say, but also for better upstream screening and prevention to reduce the need for intensive care.

“Just as we need more capacity for psychiatric emergencies in kids, we also need an infusion of knowledge and ordinary strategies to support mental health on the positive side,” Masten said.

In New York, Hoagwood helped launch the state-funded Evidence Based Treatment Dissemination Center in 2006, which offers free training on evidence-based practices for trauma, behavioral and attention problems, anxiety, depression, and more to all mental health professionals who work with children in state-licensed programs, which include foster care, juvenile justice, and school settings, among others. The center provides training on a core set of tools known as PracticeWise ( Chorpita, B. F., & Daleiden E. L., Journal of Consulting and Clinical Psychology , Vol. 77, No. 3, 2009 ). It also offers tailored training based on requests from community agency leaders and clinicians who provide services to children and their families.

Hoagwood, in collaboration with a consortium of family advocates, state officials, and researchers, also helped build and test a state-approved training model and credentialing program for family and youth peer advocates. The peer advocate programs help expand the mental health workforce while giving families access to peers who have similar lived experience ( Psychiatric Services , Vol. 71, No. 5, 2020).

Youth peer advocates are young adults who have personal experience with systems such as foster care, juvenile justice, or state psychiatric care. They work within care teams to provide basic education and emotional support to other youth, such as giving advice on what questions to ask a new mental health practitioner and explaining the differences between psychologists, psychiatrists, and social workers. Youth peer advocates in New York can now receive college credit for their training in peer specialist work.

“Making community health work into a viable career can also increase diversity among mental health workers and help us address structural racism,” Hoagwood said.

Pediatricians are another group that can provide a first line of defense, drawing on their relationships with parents to destigmatize mental health care.

“Pediatricians are in many ways uniquely positioned to help address the mental health crisis in youth,” said Janine A. Rethy, MD, MPH, division chief of community pediatrics at MedStar Georgetown University Hospital and an associate professor of pediatrics at Georgetown University School of Medicine. “We have the privilege of building long-term relationships with children and their families over many years,” with at least 12 well-child checkups in just the first three years of a child’s life, followed by annual visits.

During these visits, they can watch for warning signs of social and behavioral problems and screen for maternal depression and other issues in parents, which is now recommended by the American Academy of Pediatrics (PDF, 660KB) . Several new resources provide guidance for integrating mental health care into pediatric practices, including the Behavioral Health Integration Compendium (PDF, 4.1MB) and the Healthy Steps program . But most pediatricians need more education on mental health issues in order to effectively respond, Rethy said—yet another area where psychologists may be able to help. Psychologists can provide direct consultations and training to pediatricians through the Pediatric Mental Health Care Access program.

“The more we can weave mental health knowledge, capacity, and checkpoints into places where parents feel comfortable—like the doctor’s office and at school—the better,” Masten said. “All professionals who work with young people really need the knowledge that’s being generated by psychologists.”

11 emerging trends for 2023

Scientists reach a wider audience

Psychologists take aim at misinformation

Psychological research becomes more inclusive

EDI roles expand

Worker well-being is in demand

Efforts to improve childrens’ mental health increase

Partnerships accelerate progress

Suicide prevention gets a new lifeline

Some faculty exit academia

Venture capitalists shift focus

Psychologists rebrand the field

Further reading

Science shows how to protect kids’ mental health, but it’s being ignored Prinstein, M., & Ethier, K. A., Scientific American , 2022

How pediatricians can help mitigate the mental health crisis Rethy, J. A., & Chawla, E. M., Contemporary Pediatrics , 2022

Review: Structural racism, children’s mental health service systems, and recommendations for policy and practice change Alvarez, K., et al., Journal of the American Academy of Child and Adolescent Psychiatry , 2022

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Why do patients with cancer die?

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Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this Roadmap, we review the proximal causes of mortality in patients with cancer and discuss current knowledge about the interconnections between mechanisms that contribute to mortality, before finally proposing new and improved avenues for data collection, research and the development of treatment strategies that may improve quality of life for patients.

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Causes of death among people living with metastatic cancer

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Introduction.

The phrase ‘metastasis accounts for 90% of cancer deaths’ is one of the most widely used in cancer research, yet it is overly simplistic, imprecise and it is difficult to find any primary analysis supporting the statement. Although patients with metastatic disease are overwhelmingly more likely to die than patients with non-metastatic cancer 1 , 2 , the determinants of cancer mortality are multifaceted and frequently involve dysfunction of multiple interconnected systems within the body. Understanding the mechanisms underpinning the causes of mortality, and subsequently intervening, has the potential to make cancer a less destructive disease, improving both the quality and length of life for patients with cancer. However, systematic analyses of the acute and root causes of mortality in patients with cancer are scarce, in part because death certificates rarely record enough information to understand the exact reason why the patient died beyond them having a malignancy. Causes of death may be simply listed as ‘metastatic carcinoma’ or ‘complications of cancer’, which give little insights into why a patient actually died. Potentially concomitant comorbidities are also not fully recorded. Even in cases in which the cause of death may be attributed to a single event, for example, a  thromboembolism , the underlying cause of that specific event may be complex. Indeed, metastatic cancer leads to perturbed function of multiple organ systems, and importantly, not just the organs to which disease has spread. This is probably due to the exuberant activation of local and systemic inflammatory, tissue repair and immune-suppressive programmes.

A simple view would be that death from metastatic disease correlates with the burden of disease. However, evidence suggests that the situation is more complex, with many factors influencing how metastases impact vital functions and ultimately lead to death. First, metastases to different organs will lead to different impacts on overall health. For example, brain metastases can lead to dysfunction of the central nervous system 3 , whereas peritoneal metastases may cause obstruction of the bowel 4 . In addition, the size or extent of metastases may not necessarily correlate with dysfunction of the organ where it is located 5 . Second, the production of the molecular mediators of organ dysfunction can vary between metastases and cancers of different origins. Third, individual patient characteristics such as age, sex, overall health, pre-existing comorbidities, genetics and socio-economic status vary 6 . Together, these factors directly influence the course of and physiological response to metastatic disease and can have profound indirect effects by limiting available treatment options and/or the ability of patients to tolerate or complete all intended treatment 7 , 8 . To understand why patients with cancer die, a closer examination of the factors contributing to mortality in patients with cancer and a dissection of the intricate web of causes that shape the frequency and dynamics of death are required.

Death may be related to an acute event, but the underlying mechanisms which trigger it may be modifiable or even preventable. In addition, other deaths may be the end stage of a continuum of deterioration, allowing the possibility of targeted intervention to improve quality of life. Moreover, it has been noted that early palliative care improves survival 9 . Ultimately, increased understanding of the processes occurring in patients with advanced disease should lead to improved strategies to minimize ill-health and suffering at the end of life. Coupled to this, patients and those around them should be enabled to have essential discussions about their wishes and preferences, minimizing potentially inappropriate treatments and maximizing quality of life 10 . Therefore, in this Roadmap, we briefly review data considering the immediate causes of mortality, highlight the intricate interconnections between different aspects of patient deterioration and conclude with recommendations for future studies of late-stage cancer that may shed new light on this important aspect of cancer biology and medicine.

Acute events leading to mortality

Although some cancers can be considered a chronic condition, with many patients living with their disease for years, the immediate cause of mortality can often be an acute event. Here, we briefly summarize common acute events leading to death in patients with cancer (Fig.  1 ). Although it is not possible to precisely determine, it is likely that the acute causes discussed subsequently may account for up to half of cancer deaths 11 , 12 . Immediate causes of mortality in other patients are less clear, with a more gradual deterioration typically occurring in vital organ systems (Fig.  1 ).

This schematic shows organs that frequently become dysfunctional in patients with late-stage cancer.

Vascular coagulation and cardiac failure

Patients with cancer are at an elevated risk of thromboembolism, which may trigger respiratory failure, fatal strokes, heart failure or myocardial infarction 13 . In some cases, disseminated intravascular coagulation can lead to thrombotic obstruction of small and midsize vessels leading to organ failure 14 . Haemorrhagic complications from depletion of platelets, via either immune or non-immune mechanisms 15 , 16 , and reduced levels of coagulation proteins can also be life-threatening 14 .  Congestive heart failure can also be a proximal cause of mortality, although the underlying causes are complex and include loss of cardiac muscle (associated with cachexia), shifts in intravascular fluid status and thromboembolic events 17 . Interestingly, bone metastases are particularly associated with cardiovascular problems, although the underlying mechanism remains unclear 18 . Comorbidities affecting the cardiovascular system may also make patients more prone to such events. Spatial occlusion of or invasion into vessels by cancer metastases can also lead to failure in blood supply or catastrophic haemorrhage 19 , 20 , 21 , 22 .

Displacement, functional impairment or obstruction of vital organs

The volume of disease may impair the function of a vital organ. This can be the case with brain metastases and glioblastoma or other primary brain cancers, with extensive invasion, brain herniation or oedema resulting in  midline shift or increased intracranial pressure irreversibly compromising brain function 22 , 23 , 24 . In addition, patients may develop seizures, which, if uncontrolled, can result in death 25 , 26 . However, this does not apply to all brain metastases, with  leptomeningeal metastases having minimal impact on intracranial pressure and brain structure; instead, these commonly obstruct cerebrospinal fluid flow and/or affect nerve function resulting in  hydrocephalus , deterioration of neurological function and death 26 .

Large lung metastases may impair the essential function of gas exchange. However, patients with miliary-like disease — characterized by nodules too numerous to count — can live with extensive disease in an organ with surprisingly little impact on function until a hard-to-predict tipping point is reached, which is then followed by rapid deterioration 27 . As with brain metastases, the volume of disease is often not sufficient to account for organ failure, as even a relatively small volume (<100 ml lung metastases volume compared with 4–5 l total lung volume) can be fatal 28 .  Lung oedema and pleural effusion are additional common contributors to death. Oedema may be caused by other pathologies such as infection or heart failure, whereas pleural effusion may be related to the presence of disease within the pleura as opposed to total tumour volume 28 , 29 .

Bowel obstruction can be a cause of mortality, especially in patients with peritoneal disease as found in particular in ovarian, colorectal and gastrointestinal cancers 30 . Both liver and kidney failure will also cause death in patients with cancer. Reasons for the failure of these organs include obstruction of the bile duct or ureters by metastases, therapy-induced toxicity leading to compromised normal organ function (discussed subsequently) and reduced tissue perfusion owing to hypotension or dehydration 31 , 32 , 33 , 34 . In addition, sepsis can result from obstruction of the bile ducts or ureters, which occurs unpredictably and often progresses rapidly leading to multiple organ failure and ultimately death.

Bacterial infections are the most common infection in patients with cancer, owing to impaired immune systems resulting from both the cancer itself and certain cancer treatments (discussed in detail subsequently), which induce myelosuppression and leukopenia. Patients with cancer can have an elevated risk of opportunistic viral, fungal and protozoal infections, which would typically be considered mild in healthy individuals, but which can cause serious life-threatening complications in those with cancer. Pneumonia and other lung infections leading to respiratory failure are often listed as causes of mortality in patients with cancer 35 , 36 . One of the most striking recent examples of this is the increased mortality observed in patients with cancer, particularly those with haematological cancers, who succumbed to COVID-19 compared with the general population 36 , 37 .

Paraneoplastic syndromes

Paraneoplastic syndromes are a group of rare disorders that can occasionally cause irreversible damage to critical organs and death. They are most associated with lung, breast, ovarian and lymphatic cancers, causing tissue or organ dysfunction at sites distinct from the location of the tumour 38 . Various mechanisms underpin paraneoplastic syndromes, including the inappropriate production of cytokines, hormones and antibodies. For example, excess parathyroid hormone-related protein (PTHRP) production by tumours can lead to hypercalcaemia 39 , 40 . Inappropriate anti-diuretic hormone production is commonly associated with small-cell lung cancer resulting in  hyponatraemia 41 . Furthermore, some neuroendocrine pancreatic tumours (insulinomas) secrete large amounts of insulin 42 . Tumours can also trigger the aberrant production of autoantibodies leading to disorders such as  Lambert–Eaton myasthenic syndrome (LEMS) or anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis and myasthenia gravis 43 . Although treatment can usually manage the symptoms, in a subset of cases the syndromes cannot be controlled and are fatal 38 .

Therapy-induced toxicity

Although therapies are developed and administered with the intent of primarily targeting the tumour, almost all have some detrimental impact on normal tissue function. In some cases, the unintended consequences of therapy can be life-threatening. Autoimmune reactions resulting from targeting immune checkpoints can have fatal consequences, including  myocarditis and encephalitis 44 , 45 , 46 . Chemotherapy can lead to death as a result of acute neutropenic sepsis 47 . Depletion of platelets because of therapy can lead to fatal bleeding 16 . Arrhythmias, cardiomyopathy and coronary vasospasm are also a cause of death related to some anticancer treatments such as 5-fluorouracil and capecitabine 48 , 49 , 50 . The long-term detrimental effects of some therapies are discussed in detail subsequently.

Underlying causes

Determination of the proximal cause of mortality prompts further questions around the underlying factors giving rise to lethal pathology and ultimately how metastatic cancer triggers or accelerates those factors. In this section, we consider how chronic disruption of three major physiological organ systems is perturbed in patients with cancer and how these might contribute to mortality.

The immune and haematopoietic systems

In patients with cancer, the immune system becomes progressively less able to mount effective responses to infectious challenge, a phenomenon often generically termed ‘immune exhaustion’ (this usage is distinct from the more specific usage of immune exhaustion as a failure of tumour-reactive T cells to function). As a result, patients with metastatic disease have increased susceptibility to a wide range of infections and typically suffer more severe consequences than would otherwise be observed in healthy individuals 51 . Multiple mechanisms contribute to the reduced capability of the immune system to respond to infection. The presence of cancer cells in diverse organs triggers similar cellular and molecular events to wound responses 52 . The production of cytokines including interleukin 6 (IL-6), granulocyte colony-stimulating factor (GCSF) and granulocyte–macrophage colony-stimulating factor (GM–CSF), both by tumour cells and by other cells of the tumour microenvironment (TME), perturbs haematopoiesis leading to altered subsets of leukocytes 53 . Although, in the short term, this may have limited consequences on the ability of the body to respond to other challenges, prolonged disruption to haematopoiesis can strain the ability of haematopoietic stem cells (HSCs) to generate sufficient cells of the right type to cope with infections, with increased myeloid-to-lymphoid cell ratios.  Clonal haematopoiesis can be increased in patients with cancer, with myeloid skewing of immune cells and overall myeloid-mediated immune suppression and diminished naive T cell reservoirs 53 . Reduced production of platelets and altered iron metabolism leading to compromised oxygen carrying by red blood cells is also observed in many patients 54 . Other problems such as  immunoparesis can arise, with a high frequency observed in patients with multiple myeloma 55 .

T cell responses to infection are impaired in the presence of cancer with decreased proliferation and expression of granzyme B typically observed 56 . The chronic stimulation of T cells with neoantigens arising from ongoing mutational processes may also contribute to their weakened functionality. Moreover, immune surveillance of tumours inevitably selects for the production of immune suppressive factors by cancer cells, which further compound the issue 57 . Once again, comorbidities leading to either immune suppression or autoimmunity can intersect with the detrimental effects of cancer on the immune system.

Other consequences of cancer can indirectly result in an increased likelihood of infection. For example, vessel obstruction from cancer results in decreased flow of fluids such as bile, urine and lymph, creating environments in which bacteria can thrive 58 . Blockage of the bronchial tree can lead to pneumonia 59 . The invasive phenotype of cancer can result in  fistula formation (for example, rectovaginal in colorectal cancer), which enables bacteria to invade 60 . Furthermore, patients are often rendered bedbound or have limited mobility as cancer progresses, resulting in an increased chance of infections through decreased respiratory ventilation and atelectasis , as well as pressure sores and oedema 61 .

Disruption to haematopoiesis can also contribute to defects in coagulation and haemostasis . Elevated platelet numbers, termed thrombocytosis, are found in patients with cancer and are correlated with higher mortality 62 . The altered inflammatory cytokine milieu caused by the tumour may promote megakaryopoiesis, potentially through increasing thrombopoietin (TPO) production by the liver, and leading to higher platelet numbers. The risk of clotting can be further increased by the production of  tissue factor , which is responsible for initiating the clotting cascade, by tumour cells 63 . These mechanisms increase the likelihood of fatal thromboembolisms 63 .

Iatrogenic effects also have a role in the reduced immune function in patients with cancer. Cytotoxic therapies interfere with the proliferation and division of haematopoietic stem cells and can leave the immune system unable to mount effective responses to pathogens, leading to mortality 64 . In severe cases, pancytopenia results, marked by a substantial decrease in all three major blood cell lineages (red cells, white cells and platelets) 65 . This can lead to severe anaemia, increased infection susceptibility and increased likelihood of bleeding 47 , 66 , 67 . In other cases, more limited subsets of haematopoietic cells are affected. Thrombocytopenia — low platelet levels — leads to hypocoagulation and elevates the likelihood of haemorrhage 66 . Therefore, during cancer development and treatment, haemostasis mechanisms may be either augmented or attenuated; in both cases, the result is less predictable and less well-controlled coagulation. Neutropenia — low neutrophil levels — renders patients less able to fight infection and contributes to cancer mortality from infections that in many cases are thought to arise from resident mucosal flora 68 . Treatments, including chemotherapy and radiotherapy, often result in the breakdown of mucosal barriers (for example, oral mucositis) resulting in higher numbers of infections from pathogens, which normally reside on these surfaces 69 . In addition, corticosteroids, which are often given to alleviate symptoms or manage toxicity, can also contribute to the suppression of immune responses and compound the risk of infections in patients 70 . Clonal haematopoiesis, which as mentioned earlier is already more frequent in patients with cancer, can be further increased by chemotherapy 71 . More generally, cancer therapies can increase ageing-associated processes and reduce organ function 72 . Opioid pain relief administered to those with late-stage disease can also suppress the function of various bodily systems 73 . Finally, infections can arise owing to the insertion of drains and stents, or central venous catheters (CVCs; also known as lines) for the delivery of therapies. Infections from such lines are estimated to be around 0.5–10 per 1,000 CVC-days 74 , 75 .

Immunotherapies present a different set of immune complications from conventional therapies. These primarily relate to over-activation of the immune system leading to autoimmunity and, in some cases, cytokine storms that are treated with anti-cytokine therapies such as tocilizumab, anakinra and ruxilitinib, all of which can further suppress the immune response 76 . However, deaths attributable to autoimmune side effects of immune checkpoint inhibitors are rare (<1% in an analysis of more than 8,000 patients) especially if toxicity is managed promptly 77 , 78 . Colitis is a frequent problem, with disruption to colonic barrier function leading to increased susceptibility to perforation, which can be life-threatening.  Guillain–Barré syndrome , hepatitis and myocarditis are also causes of immune checkpoint inhibitor-related deaths 79 , 80 , 81 . Once again, high-dose corticosteroids are the main first-line treatment to manage autoimmune side effects in patients receiving immunotherapy and can lead to suppression of the immune system.  Hyperprogressive disease is observed in some patients following immunotherapy, the reasons for which are still being delineated, but there is probably a role for innate lymphoid cells releasing pro-growth cytokines 82 . Cell-based immunotherapies can also lead to disrupted bone marrow function and subsequent myelosuppression 83 .

The nervous system

The brain serves as a central nexus, orchestrating all vital functions. It is the hub of thought processes, emotions and sensory perception and regulates, directly or indirectly, everything from heartbeat and breathing to appetite. In addition to physical disruption of brain structure and intracranial pressure (discussed earlier) 84 , brain metastases impact the nervous system in multiple ways. Tumours in the brain or its surrounding tissues can substantially impair neural connections, leading to cognitive deficits, motor and sensory dysfunction, and even personality changes 84 , 85 , 86 . Interactions between brain metastases and neurons lead to changes in cortical function 87 , 88 , 89 . Even in regions of the brain without overt metastases, neuro-excitability can be increased, leading to changes in cognition, alertness and mood 90 . Tumours can slow the posterior dominant rhythm, leading to reduced alertness, loss of working memory and deterioration of quality of life 91 . Circadian rhythms are also impacted, leading to problems in memory and sleep, which is vital for the repair processes of the body that are essential for overall health and functioning 92 . Ultimately, many of these changes are not sustainable long-term. How these changes may lead to death is unclear, but they may follow similar trajectories to those in patients with dementia.

Brain function can also be disrupted in patients without brain metastases, with autonomic nervous system dysfunction often reported 93 . Intriguingly, anhedonia — a lack of ability to experience pleasure — occurs in many patients 94 . The mechanistic causes of this are unclear, but it is not restricted to patients with brain metastasis suggesting that circulating systemic factors may play a role. The wider effects of metastatic cancer on the mental well-being of a patient are discussed in Box  1 . However, beyond an effect on well-being, the disruption of brain function can contribute to anorexia, and reduced nutrition can influence many other physiological and pathophysiological processes 95 , 96 .

The role of the  peripheral nervous system in cancer-related death is not well described. Although the burgeoning field of cancer neuroscience provides evidence that the efferent system can support local and metastatic tumour growth 97 , 98 , 99 , at this time, it is unclear whether the reverse is also true. As mentioned earlier, there is clear evidence of autonomic nervous system dysfunction in patients with cancer 93 , raising the possibility that cancer-mediated interruption of afferent impulses might impact overall survival. Further studies are needed to explore this possibility.

Box 1 Psychosocial and societal factors contributing to the deterioration of patients with late-stage cancer

Psychological and social factors can have major and wide-ranging impacts on patients with incurable cancer. This manifests in more than threefold higher suicide rates 145 , 146 , 147 . Of note, these rates were further exacerbated in less advantaged sociodemographic groups 148 , arguing that financial issues and possibly health-care access are linked to suicide in patients with cancer. However, psychological symptoms are far more extensive than those captured in studies of suicide. Anhedonia and depression are frequent in patients with cancer, impacting their overall well-being, treatment adherence and outcomes including mortality 149 . These psychological challenges often intertwine with physical symptoms, compounding the burden of each 150 . Several studies have linked stress-related psychosocial factors to cancer mortality 151 , with recent work beginning to uncover the cellular and molecular mechanisms at play 152 .

Research on the psychosocial aspects of cancer care, including emotional and cognitive well-being, remains under-emphasized. Barriers to the integration of psychosocial care into cancer care include stigma, difficulty identifying substantial distress, limited access to evidence-based psychosocial treatments and concerns about cost 153 . Yet, an integrated system of psychosocial care including population-based screening and targeted treatment and access to good-quality palliative care improves emotional wellbeing 154 and physical symptoms 155 and is likely to be cost-saving 156 . A deeper understanding of the mechanisms underlying neuropsychological systems and insights into how metastatic disease impacts the physiological and chemical axes of the brain will be crucial. Such insights could inform tailored interventions, therapies and support structures that address the emotional toll of cancer, enhancing the holistic care approach and improving quality of life. Expanding psychosocial research can help bridge gaps in addressing mental health in patients with cancer, ultimately improving quality of life of patients during and after treatment 146 , 147 .

Metabolism and cachexia — catabolic effects of cancer

The presence of metastases presents altered energetic and anabolic demands on the body, leading to detrimental imbalances in metabolism 100 . Progressive and involuntary loss of body weight — termed cachexia — is a widespread multiorgan phenomenon commonly seen in patients with metastatic cancer 100 , 101 . This complex syndrome is characterized by a net negative energy balance, driven by the combination of increased energy expenditure and catabolism, with reduced appetite and caloric intake. A persistent decrease in nutrient intake is a key component across patients with many different cancer types, leading to breakdown of host tissues, with the degree of loss of adipose tissue and muscle mass varying between patients and among different cancer types 102 . However, the contribution of increased energy expenditure (as a result of tumour burden) is less clear.  Sarcopenia may be particularly prominent in some patients, possibly representing an independent pathology from other more global tissue wasting phenotypes, and in extreme cases, loss of cardiac or intercostal muscle mass can be fatal owing to insufficient cardiac or respiratory function, respectively 103 , 104 . These events have also been observed in the context of extreme starvation in patients with non-cancer conditions; for example, anorexia nervosa, in which cardiac dysfunction, in particular bradycardia and sinus pauses, can cause pulseless electrical activity and death 105 , 106 . Electrolyte disturbances and hypoglycaemia that are often observed in cases of severe malnutrition may exacerbate the risk of such arrhythmias 105 . Cachexia also has effects on other organs and tissues, including the brain and immune system 107 . Compromised immune function is a major consequence of starvation-induced tissue wasting 108 and suggests that altered systemic metabolism leading to, or associated with cachexia, may be a contributor to the immune dysfunction present in some patients with cancer 108 . Conversely, several studies have shown that both the brain and immune system can contribute to cachexia 100 , 101 .

Cachexia is multifactorial and has many potential causes. In some limited cases, tumour metabolism leads to systemic changes that increase energy usage. For example, high levels of lactate secretion by tumours can trigger the liver to convert lactate back to glucose, which requires energy input — termed the Cori cycle 109 . Such cycles can increase metabolic demand on the liver leading to further perturbation of liver function. However, cachexia does not correlate with disease volume in many cancer types 110 . Therefore, it is hard to reconcile a model in which the energetic and anabolic demands of the volume of disease are the main trigger for cachexia. Numerous studies have begun to reveal the possible molecular underpinnings of cachexia in some cancer types. Disruption of signalling by transforming growth factor-β (TGFβ) and related ligands is a recurring theme 111 , 112 , 113 . For example, circulating growth/differentiation factor 15 (GDF15; also known as MIC1), a highly conserved member of the TGFβ superfamily, is a known mediator of anorexia and weight loss, and increased circulating levels of this molecule in patients with lung cancer have been shown to correlate with cachexia development 114 . Clinical trials are currently underway to determine whether blockade of GDF15 ameliorates cachexia 115 . TGFβ itself can also promote muscle loss via the induction of myostatin 116 , and the induction of signalling by activin — another TGFβ superfamily ligand — can also have similar effects on muscle mass 117 , 118 . Furthermore, modulation of ryanodine receptor 1 (RYR1) downstream of TGFβ can perturb sarcomere organization and thereby lead to muscle weakness 111 . As such, preclinical studies have demonstrated the potential utility of TGFβ blockade in preventing cachexia 112 .

Elevated levels of cytokines, including tumour necrosis factor (TNF), IL-1 and IL-6, can also have roles in cachexia 119 , 120 , 121 . TNF induces multiple aspects of cachexia 122 . Muscle wasting is promoted through increased TNF and downstream nuclear factor-κB (NF-κB)-dependent ubiquitin-mediated proteolysis of muscle protein 123 , 124 . IL-6 triggers muscle loss through both NF-κB-dependent and JAK/STAT-dependent mechanisms 120 . Lipid metabolism is impacted by TNF reducing the expression of lipoprotein lipase and free fatty acid transporters, thereby reducing the accumulation of fat 125 . TNF can also reduce appetite through the production of  corticotropin-releasing hormone (CRH). IL-1, which triggers similar proximal changes in cell signalling to TNF, can activate many of the same processes 125 . It is also interesting to note that TGFβ, IL-1 and IL-6 are associated with programmes in cancer cells that drive metastasis, which could potentially explain why metastatic disease is linked to cachexia more strongly than the presence of primary disease alone.

Whole body dysfunction

Although consideration of different organ systems is useful for highlighting some of the key events contributing to cancer mortality, the interconnected nature of body systems and the pleiotropic characteristics of the molecular mediators at play mean that it is essential to consider whole body dysfunction when thinking about causes of cancer mortality. Furthermore, such analyses may explain cancer deaths without an acute proximal cause. As discussed earlier, cytokines with potent effects on the immune system, as well as effects on appetite, can be contributors to cachexia. Therefore, it is unsurprising that tumours impact both immune and metabolic function. The immune and nervous systems are highly sensitive to metabolite availability; for example, the brain has a high demand for glucose 108 , 126 . Several factors, including lactic acid production and kidney dysfunction, can lead to life-threatening systemic acidosis in patients with cancer, particularly haematological malignancies with high cell turnover 127 . These can be further exacerbated upon initiation of cytotoxic therapy resulting in  tumour lysis syndrome which can be fatal 128 . Consequently, metabolic perturbations and cachexia impact these systems. Over time, the cumulative stress of metabolic alterations caused by metastases, chronic changes in the level of cytokines, constant generation of tumour (neo)-antigens, aggressive therapies and incidental infections lead to exhaustion of the adaptive immune system and hamper the regenerative capacity of many organ systems with debilitating effects 18 . This multifaceted burden can ultimately trigger a body-wide shutdown leading to death.

Are mortality causes cancer-specific?

Although a subset of mortality causes are cancer-specific, such as metastatic invasion compromising specific organ function, the progressive and interconnected deterioration of multiple organ systems probably underlies many cancer-related deaths. This may be further influenced by interaction with other comorbidities. Of note, similar progressive deterioration is sometimes observed in the context of chronic infection and inflammation, with both cachexia and immune exhaustion associated with diseases such as tuberculosis (TB) and human immunodeficiency virus (HIV) infection 129 , 130 , 131 . This raises the question of whether the causes of death in patients with cancer are specific to cancer, or whether cancer (or any other chronic disease) is simply an accelerant of ageing processes occurring in healthy individuals. This hypothesis has practical implications because, if proven, it would suggest that lessons and approaches from other disease contexts could be readily transferable to patients with metastatic cancer. For example, the targeting or modulation of senescent cells is an active area of anti-ageing research, and numerous preclinical studies have indicated that similar strategies can attenuate the systemic effects of cancer 132 , 133 , 134 .

Recommendations

One goal of this Roadmap is to propose ways to improve our understanding of why patients with cancer die and thereby develop better strategies to ameliorate symptoms and prolong life with good quality. To this end, we propose that the following steps would be useful (Fig. 2 ).

This scheme shows how recommendations can interlink to provide both an improved understanding of the underlying biology behind late-stage cancer and strategies to improve quality of life of patients.

Improved records and reporting

It is notable that systematic reviews of the precise causes of cancer mortality are infrequent. This gap in knowledge, and recognition that this is often simply not known, is a major hindrance to learning and progress. Although improved accuracy of reporting on death certificates would be desirable, it would require a shift in longstanding clinical habits and may not be easily achievable in health-care systems under strain. Nonetheless, we advocate for locally enacting more consistency in death certificates, with specific acute causes included in addition to the underlying cause of cancer where known. Palliative care primarily focuses on symptom control for patients while balancing the potential benefits and burdens of additional diagnoses. Nevertheless, to address the gaps in our knowledge, it would be desirable to fund and establish prospective studies that continue active monitoring of patients as they transition from active disease treatment to palliative care. If possible, monitoring should be non-invasive as to not compromise patient comfort at the end of life. The great advances being made in patient monitoring with  wearable technologies might facilitate this and could be used for earlier detection of infections enabling quicker intervention. Caregiver involvement in reporting of symptoms may also play a role. Furthermore, consent to obtain more detailed information from the community and palliative care teams on the contributing factors to death would provide further insight. Patient and public engagement in this type of research will be critical, with studies indicating patient desire to participate in the right context 135 , 136 . In addition to information gathered before death, research autopsies have the potential to shed further light on the aetiology of death, such as thromboembolic events that may not have been detected in the absence of symptoms or diagnostic testing — discussed in Box  2 . Moreover, the availability of post-mortem samples can aid research into the biological underpinnings of metastases and processes leading to death. The greatest amount of information would be gained from cohorts additionally enrolled into warm autopsy programmes (Box  2 ).

Box 2 Research Autopsy Programmes and their optimization

Research autopsies are initiatives that involve the prompt collection of tissues from deceased individuals shortly after death, whereas tissue morphology is intact, and cells and tissues have not undergone substantial post-mortem changes. Research autopsy studies can be labour-intensive, and care is required in their logistical planning. The post-mortem interval (PMI) to autopsy can vary depending on the infrastructure available and can have implications for the utility of samples collected after death. For example, shorter PMIs achieved in rapid warm autopsy studies can more effectively facilitate in vitro (for example, cell line) and in vivo (for example, organoid and xenograft) models and can derive better quality RNA 157 , 158 . However, such studies are not easily established in the absence of out-of-hours facilities and expert input. Autopsies performed with longer PMIs, for example, up to several days after death, have been shown to have maintained tissue morphology and adequate DNA and RNA to facilitate cellular imaging techniques and genomic sequencing approaches 159 , 160 . Therefore, there is merit and general scientific value with autopsies regardless of the PMI, provided that consideration is given to the question being addressed, and the experimental approach.

The most powerful data are obtained from patients already involved in clinical studies before death. Information about disease course, longitudinal scans and tissue and blood analysis (cell counts, electrolytes, cytokines, metabolites and possibly circulating tumour DNA (ctDNA)) greatly enhances what can be learnt from post-mortem tissues. However, sensitivity is required to align the desire to acquire data with the wishes of the patients and their families, such that ultimately each autopsy has the potential to be meaningful and shed light on the biological processes leading to death.

More detailed observational clinical studies

Disease burden is not well correlated with survival; however, we propose that the accurate identification of prognostic factors correlating with survival should provide important insights into what ultimately precipitates mortality. As the cost of both targeted and non-targeted analyses of proteins and metabolites decreases, it should also become more feasible to explore molecular predictors of survival. Once identified, such factors could then be monitored in a targeted way prospectively with the potential to intervene where possible. In this setting, both the tumour and patient trajectory would receive precision-tailored treatments, the impact of which would need to be studied in randomized controlled trials. Even in the context of early phase trials, additional data could be obtained about patient symptoms in addition to safety considerations and tumour burden. Clinical imaging could also be exploited. Many patients receive computed tomography (CT) and positron-emission tomography (PET) scans, which contain abundant information about the burden and location of metastases and offer the opportunity to study changes in extent of adipose and muscle tissue and therefore body composition in relation to cachexia. Machine learning and artificial intelligence can be capitalized on to accurately measure these parameters, meaning that what would have previously been prohibitive owing to hours of radiologist time being required is now feasible 137 , 138 . In addition to the analysis of scans, the application of machine-learning approaches to metabolite, cytokine, immune cell and wearable technology-derived multimodal and multidimensional data may also uncover previously unknown parameters that correlate with mortality 139 . As outlined in Box  1 , incorporating psychosocial metrics into the study of late-stage cancer could also enable improvements in mental well-being of patients.

Increasing the relevance of model systems

Preclinical models will also have a place in determining the linkage between events found to precede death and cause of death; however, there should be an emphasis on reverse translation of questions from human studies to preclinical models. By way of example, this could involve modelling how metastases impinge on the ability of the body to respond to infection by challenging metastatic mouse models with a pathogen. Animal ethics and husbandry considerations mean that mice are housed in controlled environments in which exposure to pathogens is rare and the types of pathogen exposure are very narrow, so this type of information is currently lacking. To be optimally informative, practical and ethical complications around studying end-of-life physiology seen in patients need to be considered. Most models are chosen for their rapid progression, often with less than a month between primary or metastatic tumour seeding and death. These are not optimal for studying longer timescale chronic changes in patients. The development of slower progressing models, implementation of multiple lines of treatment and mimicking presence of other comorbidities should enable models to more accurately recapitulate observations made in patients. Furthermore, most preclinical cancer research currently uses young mice that fail to accurately mirror the interplay between ageing and cancer seen in humans 140 , with differences between chronological and immunological age providing a further confounding factor 141 . Researchers need to recognize the importance of and adopt more age-appropriate mouse models to better understand cancer mortality. In addition, most studies focus solely on tumour burden (which may only be possible at the point of death rather than longitudinally) or tumour size as a marker of disease, owing to the technical challenges of accurately quantifying organ impairment. Furthermore, tumour volume response and progression are poor surrogates of mortality in patients 142 ; therefore, better modelling of other metrics of tumour activity and impact on the body system may lead to better drug development. Minimizing and alleviating suffering in experimental animals is critical; hence ethical considerations limit the ability to study mortality in mice. Therefore, an expanded repertoire of analysis would help to understand how metastases impact specific systems and events, including the haematopoietic and nervous systems, as well as whole-body physiology and metabolism. Analysis of small volumes of blood can provide data on metabolites and cytokines, as well as complete blood counts (red blood cells, white blood cells and platelets), whereas increasingly sophisticated and automated technology is available to monitor mouse behaviour 143 . It is worth noting that weight loss is frequently used as a humane end point, which indicates that many cancer models trigger cachexia and that with appropriate measurements there is an opportunity to learn more about this phenomenon in existing models. We advocate more detailed reporting of why mice were culled in experimental studies — for example, tumour volume, weight loss, laboured breathing, complete blood cell counts and blood chemistry.

Clinical trials

The types of analyses detailed earlier will provide correlation between different factors and mortality, but not causative linkage. Ultimately, this information depends on testing in the context of clinical trials. Many of the mediators of immune dysfunction and cachexia can now be targeted with function blocking antibodies or forms of receptor traps and are being actively explored in clinical trials 115 , 144 . Several of these interventions were originally developed for chronic inflammatory conditions, which further highlights links between cancer and inflammation. The use of appropriately chosen secondary end points would provide an opportunity for testing whether correlative associations have a causal basis. In addition, many cancer drug trials stop providing an intervention at the point where a cancer progresses. The mechanisms behind cancer cachexia suggest that trials should be adapted to additionally consider clinical benefit in terms of weight, muscle loss and other specific determinants of efficacy, rather than solely monitor cancer progression.

Concluding remarks

Although efforts at cancer prevention and the development of curative treatment rightly receive considerable attention, we argue that understanding the precise events leading to cancer mortality should not be overlooked by funding bodies. Understanding the causes of dysfunction across multiple organ systems may provide novel strategies to manage symptoms of advanced cancer. Furthermore, better knowledge of the processes leading to death could enable patients and those around them to have essential discussions about their wishes and preferences, minimizing potentially inappropriate treatments and maximizing quality and enjoyment of life. In addition, more precise biomarkers of the likely timing of death may enable patients and their families to better utilize the time that is left. In the longer term, strategies to prevent organ dysfunction should offer considerable benefits to both patients with high tumour burden and those who have low disease burden but die from factors produced by cancer.

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Acknowledgements

A.B. is funded by National Institutes of Health/National Cancer Institute P30 CA008748 and R01-CA245499. K.B. is employed by the UK National Health Service. T.R.C. acknowledges funding support from the National Health and Medical Research Council (NHMRC) Ideas (2000937), Project (1129766, 1140125), Development (2013881) and Fellowship (1158590) schemes, a Cancer Institute NSW Career Development Fellowship (CDF171105), Cancer Council NSW project support (RG19-09, RG23-11) and Susan G. Komen for the Cure (CCR17483294). T.G. is funded by the Cancer Prevention and Research Institute of Texas Grant 00011633. M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. T.J. acknowledges funding from Cancer Grand Challenges (NIH: 1OT2CA278690-01; CRUK: CGCATF-2021/100019), the Mark Foundation for Cancer Research (20-028-EDV), the Osprey Foundation, Fortune Footwear, Cold Spring Harbour Laboratory (CSHL) and developmental funds from CSHL Cancer Center Support Grant 5P30CA045508. R.K. is funded by the Intramural Research Program, the National Cancer Institute, NIH Clinical Center and the National Institutes of Health (NIH NCI ZIABC011332-06 and NIH NCI ZIABC011334-10). R.L. is supported by a Wellcome Early Career Investigator Award (225724/Z/22/Z). E.S. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2040), the UK Medical Research Council (CC2040) and the Wellcome Trust (CC2040) and the European Research Council (ERC Advanced Grant CAN_ORGANISE, Grant agreement number 101019366). E.S. reports personal grants from Mark Foundation and the European Research Council. C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). His work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041) and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (ERC Advanced Grant PROTEUS Grant agreement number 835297). M.G.V.H. reports support from the Lustgarten Foundation, the MIT Center for Precision Cancer Medicine, the Ludwig Center at MIT and NIH grants R35 CA242379 and P30 CA1405141.

Author information

These authors contributed equally: Adrienne Boire, Katy Burke, Thomas R. Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G. Vander Heiden, Erik Sahai.

Authors and Affiliations

Memorial Sloan Kettering Cancer Center, New York, NY, USA

Adrienne Boire

University College London Hospitals NHS Foundation Trust and Central and North West London NHS Foundation Trust Palliative Care Team, London, UK

Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia

Thomas R. Cox

School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Theresa Guise

Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK

Mariam Jamal-Hanjani

Department of Oncology, University College London Hospitals, London, UK

Mariam Jamal-Hanjani & Charles Swanton

Cancer Research UK Lung Centre of Excellence, University College London Cancer Institute, London, UK

Cold Spring Harbour Laboratory, Cold Spring Harbour, New York, NY, USA

Tobias Janowitz

Northwell Health Cancer Institute, New York, NY, USA

Paediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Rosandra Kaplan

Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK

Rebecca Lee & Erik Sahai

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Rebecca Lee

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK

Charles Swanton

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

Matthew G. Vander Heiden

Dana-Farber Cancer Institute, Boston, MA, USA

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Contributions

All authors researched data for the article. A.B., K.B., T.R.C., T.G., T.J., C.S., M.G.V.H, R.K., M.J.-H. and E.S. contributed substantially to discussion of the content. T.C., R.L. and E.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Thomas R. Cox or Erik Sahai .

Ethics declarations

Competing interests.

A.B. is an inventor on pending patents 63/449,817, 63/052,139 as well as awarded patents 11,305,014 and 10,413,522; all issued to the Sloan Kettering Institute. She has received personal fees from Apelis Pharmaceuticals and serves as an unpaid member of the Evren Technologies SAB. K.B., T.R.C., T.G., T.J. and R.K. declare no competing interests. M.J.-H. reports support from Achilles Therapeutics Scientific Advisory Board and Steering Committee, Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster and Bristol Myers Squibb outside the submitted work. R.L. reports personal fees from Pierre Fabre and has research funding from BMS, Astra Zeneca and Pierre Fabre outside the submitted work. E.S. reports grants from Novartis, Merck Sharp Dohme, AstraZeneca and personal fees from Phenomic outside the submitted work. C.S. reports grants and personal fees from Bristol Myers Squibb, AstraZeneca, Boehringer-Ingelheim, Roche-Ventana, personal fees from Pfizer, grants from Ono Pharmaceutical, Personalis, grants, personal fees and other support from GRAIL, other support from AstraZeneca and GRAIL, personal fees and other support from Achilles Therapeutics, Bicycle Therapeutics, personal fees from Genentech, Medixci, China Innovation Centre of Roche (CiCoR) formerly Roche Innovation Centre, Metabomed, Relay Therapeutics, Saga Diagnostics, Sarah Canon Research Institute, Amgen, GlaxoSmithKline, Illumina, MSD, Novartis, other support from Apogen Biotechnologies and Epic Bioscience outside the submitted work; in addition, C.S. has a patent for PCT/US2017/028013 licensed to Natera Inc., UCL Business, a patent for PCT/EP2016/059401 licensed to Cancer Research Technology, a patent for PCT/EP2016/071471 issued to Cancer Research Technology, a patent for PCT/GB2018/051912 pending, a patent for PCT/GB2018/052004 issued to Francis Crick Institute, University College London, Cancer Research Technology Ltd, a patent for PCT/GB2020/050221 issued to Francis Crick Institute, University College London, a patent for PCT/EP2022/077987 pending to Cancer Research Technology, a patent for PCT/GB2017/053289 licensed, a patent for PCT/EP2022/077987 pending to Francis Crick Institute, a patent for PCT/EP2023/059039 pending to Francis Crick Institute and a patent for PCT/GB2018/051892 pending to Francis Crick Institute. C.S. is Co-chief Investigator of the NHS Galleri trial funded by GRAIL. He is Chief Investigator for the AstraZeneca MeRmaiD I and II clinical trials and Chair of the Steering Committee. C.S. is cofounder of Achilles Therapeutics and holds stock options. M.G.V.H. is a scientific adviser for Agios Pharmaceuticals, iTeos Therapeutics, Sage Therapeutics, Faeth Therapeutics, Droia Ventures and Auron Therapeutics on topics unrelated to the presented work.

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Nature Reviews Cancer thanks Vickie Baracos, Clare M. Isacke, who co-reviewed with Amanda Fitzpatrick and Erica Sloan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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An autoimmune encephalitis characterized by complex neuropsychiatric features and the presence of immunoglobulin G (IgG) antibodies against the NR1 subunit of the NMDA receptors in the central nervous system.

Partial collapse or incomplete inflation of the lung.

Pressure-induced movement of brain tissue.

An ageing-associated process in which haematopoiesis becomes dominated by one or a small number of genetically distinct stem or progenitor cells. Clonal haematopoiesis is linked to an increased risk of haematological malignancies.

Inability of the heart to pump blood properly.

Constriction of the arteries that supply blood to the heart.

(CRH). One of the major factors that drives the response of the body to stress.

(DIC). A rare but serious condition in which abnormal blood clotting occurs throughout the blood vessels of the body.

Inflammation of the brain.

An abnormal connection that forms between two body parts, such as an organ or blood vessel and another often unrelated structure in close proximity.

A rare disorder in which the immune system of a body attacks the nerves, which can lead to paralysis.

The stopping of flow of blood, typically associated with the bodies response to prevent and stop bleeding.

A build-up of fluid within the cavities of the brain.

Elevated calcium levels in the blood, often caused by overactive parathyroid glands. Hypercalcaemia is linked to kidney stones, weakened bones, altered digestion and potentially altered cardiac and brain function.

(HPD). Rapid tumour progression sometimes observed during immune checkpoint inhibitor treatment.

The condition that occurs when the level of sodium in the blood is low.

Harm, which is often unavoidable, caused by cancer treatments.

The marked suppression of polyclonal immunoglobulins in the body.

(LEMS). A neuromuscular junction disorder affecting communication between nerves and muscles, which manifests as a result of a paraneoplastic syndrome or a primary autoimmune disorder. Many cases are associated with small-cell lung cancer.

When cancer cells spread to the tissue layers covering the brain and spinal cord (the leptomeninges).

Also known as pulmonary oedema is a condition caused by excess fluid in the lungs. This fluid collects in the alveoli compromising function and making it difficult to breathe.

The observation of displacement of brain tissue across the centre line of the brain, suggestive of uneven intracranial pressure.

Decreased blood flow to the myocardium, commonly called a heart attack.

Inflammation specifically of the middle layer of the heart wall.

A group of rare disorders that occur when the immune system reacts to changes in the body triggered by the presence of a neoplasm.

A dense network of nerves that transmit information from the brain (efferent neurons) to the periphery and conversely transmit information from the periphery to the brain (afferent neurons). A component of the peripheral nervous system is the autonomic nervous system.

A build-up of fluid between the tissues that line the lungs and the chest wall.

A condition characterized by loss of skeletal muscle mass and function.

The lodging of a circulating blood clot within a vessel leading to obstruction. Thromboembolisms may occur in veins (venous thromboembolism) and arteries (arterial thromboembolism).

A key component of the pathway regulating blood clotting, specifically the receptor and cofactor for factor VII/VIIa.

A syndrome occurs when tumour cells release their contents into the bloodstream, either spontaneously or more typically, in response to therapeutic intervention.

Devices worn on the body, typically in the form of accessories or clothing, that incorporate advanced electronics and technology to monitor, track or enhance various aspects of human life. Examples include smartwatches and fitness trackers.

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Boire, A., Burke, K., Cox, T.R. et al. Why do patients with cancer die?. Nat Rev Cancer 24 , 578–589 (2024). https://doi.org/10.1038/s41568-024-00708-4

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Accepted : 15 May 2024

Published : 19 June 2024

Issue Date : August 2024

DOI : https://doi.org/10.1038/s41568-024-00708-4

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