The Invisible Hand of Cancer: The Complex Force of Socioeconomic Factors in Oncology Today 3031457730, 9783031457739

Table of contents :
Foreword
Preface
About the Editor
Contents
Contributors
The Blame Game
1 Nobody’s Fault
2 Brave Old World—and What Aldous Huxley, Cancer, and CO2 Emission Have in Common
3 The Butterfly in Cancer
References
Life and Death Are Made of Five Letters: A, T, C, G, and U
1 The Alphabet of Life
2 The Alphabet of Death
References
Chaos and Complexity in Cancer
1 Complexity in Cancer
2 The Chaos We Love
3 The Chaos We Hate and the Chaos We Love
4 The Disease of Chaos
5 Fractals
References
Cancer as a Taboo
1 Belonging
2 Cancer and Death
3 Breast Cancer as a Taboo
4 Oppression and How It Makes Healthcare Become a Taboo
References
Cancer as a Taboo: Part 2
1 Cancer Treatment in Transgender People
2 Pointe Shoes and Cancer
References
Childhood Cancer Survivorship in Germany
References
Healthy and Fit: To Be, or Not to Be, that Is the Question
1 An Ode to Butter
2 If It Is Bayer, It Is Good
3 To Read During Your Free Time
References
Men Tend to Avoid the Doctor: And Why It Can Be Deadly
1 Why Do Men Avoid the Doctor?
2 Avoiding the Doctor Can Be Deadly
References
Pharmaceutical Industry: Good and Bad
1 Who Is the Pharmaceutical Industry?
2 How Are Medicines Developed and Registered?
3 What Is the Process of Making Medicines?
4 Why Are Prices for Medicines So High? Why Some Patients Are Covered by Insurance and Others Are Not?
5 Conclusions
6 About the Author of this Chapter
References
Panem et Circenses
1 Bread and Circus
2 Collective Hallucination
3 Adapt, Adapt, and Adapt Once Again to Survive
References
Homing
1 The Big Picture
2 Origin
3 Science Is Not as Glamorous as the Red Carpet
4 Homing in a Metaphorical Way
5 Dying at Home
6 A Stem Cell Transplantation Can Have Some Bizarre Side Effects … Like HIV Negative
References
Financial Toxicity in Cancer
1 B of Billion, B of Burden
2 That Depends a Good Deal on Where You Want to Get to
References
Poverty and Cancer
References
Cancer and Incarceration
1 How Long Do I Have to Live?
2 Lung Cancer and Incarceration
3 Skin Cancer and Incarceration
4 Stress, Cancer, and Incarceration
5 The Future of Cancer and Incarceration
6 Remedies of Cancer and Incarceration
References
Matilda and Matthew Effects and Sexism in Science
1 Disclosing the Matilda Effect: Acknowledging Women’s Contributions to Science
2 The Matthew Effect of Accumulated Advantage: A Closer Look at Sexism in Science
References
Against All Odds, Creating My Own Plan for Survival
Index

Citation preview

Carola Schmidt  Editor

The Invisible Hand of Cancer The Complex Force of Socioeconomic Factors in Oncology Today

The Invisible Hand of Cancer

Carola Schmidt Editor

The Invisible Hand of Cancer The Complex Force of Socioeconomic Factors in Oncology Today

Editor Carola Schmidt Curitiba, Paraná, Brazil

ISBN 978-3-031-45773-9    ISBN 978-3-031-45774-6 (eBook) https://doi.org/10.1007/978-3-031-45774-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Foreword

There was not much hope that I would get the job. I was thrilled (and terrified) to have made it as far as the tryout—an unexpected chance to make the leap from small-town reporter to a medical journalist. I had been writing for the lay press—meaningful but general health news for a general audience, and features and fluff pieces with local appeal—but this was a whole new level. The laser medicine conference where I was dispatched to cover plenary sessions and try my hand at writing a few clinical stories on key presentations was a whirlwind of jargon and technical terms I could not begin to decipher. Conference faculty, taking turns at the podium to share complex new techniques and dazzling before-and-after slides, spoke what seemed to me a foreign language. If only Carola Schmidt and her friends who contributed to this insightful and compelling collaboration had been there, as they are in these pages, to unravel an intimidatingly tangled topic, to respect science while giving comfort and hope, and to gently guide me away from clinical minutia so I could see the “big picture.” The big picture for me, at the time, was a view from the starting blocks. I landed the job despite my inexperience; it was potential that opened the door. I slowly but steadily learned the ropes of writing for a physician audience and never looked back until about two decades later when my focus turned mainly to writing about unprecedented, mind-boggling advances in cancer medicine. How far we had come! Precision medicine, immune checkpoint inhibition, and gene therapies like chimeric antigen receptor (CAR) T-cell therapy were ushering in a new era in oncology. Potential. The potential for these advances to change the face of cancer care and patient outcomes—to soften the harshness of the “C” word and steal its power— drew me in. Potential is a driving theme for Dr. Schmidt and her colleagues, as well. They carefully and courageously venture through the darkness of the cancer journey, shining light in places where fear still hides, where the “least of these” are left behind, and where hope is lost. They reveal the potential for overcoming the darkness and conquering the chaos by tearing down walls and embracing humanity. Oh, how easy it is to get lost in the fascination of the science while neglecting the human suffering—the guilt, the anguish, the despair, and the costs to heart and spirit, body, and bank account—but the authors lead us to a brighter place where we v

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can better maneuver around the bumps and boulders blocking our path. They channel their vast expertise and striking life experiences to guide the reader through history and across cultures—nearer to a place where facts and feelings coexist, where fear can be faced head-on and thereby diminished, where economic and social justice reign, and where cancer is conquerable. Indeed, this book should serve as a road map for practitioners, researchers, writers, and all who want to be part of the conversation and part of solutions, and for those who need to find their way back to a place where they can take it all in and see the big picture. It is the starting point for a worthwhile journey—a step in the right direction. The views expressed here are my own. Birmingham, AL, USA

Sharon Worcester Medical Journalist and Author

The views expressed here are those of the author and do not necessarily reflect official policies or positions of her employer or associates.

Preface

The province of scientifically determined fact has been enormously extended, theoretical knowledge has become vastly more profound in every department of science. But the assimilative power of the human intellect is and remains strictly limited. Hence it was inevitable that the activity of the individual investigator should be confined to a smaller and smaller section of human knowledge. Worse still, as a result of this specialization, it is becoming increasingly difficult for even a rough general grasp of science as a whole, without which the true spirit of research is inevitably handicapped, to keep pace with progress. A situation is developing similar to the one symbolically represented in the Bible by the story of the Tower of Babel. — Albert Einstein, in The World As I See It

Get your coffee, or maybe a glass of wine or bourbon, and join us in this discussion. Although The Invisible Hand of Cancer is entirely science based, with thoughts and analyses originated from the most trusted and reputable sources that, as professionals, we depend on to develop our abilities, we the authors of this book are a group with specialties in different areas, with different backgrounds, discussing what is going on in our home countries and analyzing what is in the news and the quality of information people receive, as well as the sociological, financial, and biological components that put us where we are in the timeline of cancer treatment. Our purpose was not to publish this book as an exhaustive analysis. We intended to open a discussion, scrutinize facts, and ponder where we are and why, in regard to cancer prevention and treatment. We need to do better. We want to do better, as a society, as professionals, and as humankind. We have known for a long time that patients should be looked at with all their fantastic individuality and individual needs. But how far have we come to look at the patient as a single, extraordinary universe, and how specialized have we become in very specific areas so that we cannot see the big picture anymore? It is important to step back to see the whole, looking back to see how far we have come and looking ahead to move in the right direction. Cancer is considered a disease of high complexity not only because it is divided into more than a hundred diseases, and the treatment for each “subtype of a subtype of a subtype” of cancer can be focused on very different proteins or mechanisms, including long and complicated treatments. The many variants that intersect lead to vii

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a nearly infinite number of possibilities for cause and effect. Cancer is not only biological, but also political. The treatments are expensive. The production of new drugs is expensive. There is not one cure for cancer, because cancer is not one disease. As we move forward in science, more mechanisms of the microenvironments of cancer are explained, basing new treatments and conducts. It is a complex system that needs many specialists to analyze each part of it. The scientific community needs to join these people and enable them to see the bigger picture. Based on the concept of an invisible hand introduced by Adam Smith in 1759 (in regard to the natural force that markets have on the economy), it is natural to talk about the invisible hand of cancer when seeing the big picture, and how we cannot see and understand every little piece of this puzzle and all the possibilities of every interaction before making decisions. Like any complex system, cancer is also a mathematical model in which patterns operate within. Analyzing these patterns can help us make better choices, of course, to go ahead. The entire biological system of cancer, excluding other factors like economy and politics, forms a nonlinear system that crosses over the edge of chaos, becoming a chaotic system. Like other chaotic systems in mathematics, it presents patterns, interconnections, and its own self-­ organization. And sometimes, to come upon a new drug or new treatment, being able to see the whole picture is not necessary. We just need a pattern. Once a new drug or new treatment is discovered, though, until it is commercialized and standardized as a treatment for certain patients, we must depend on the big picture for all the variables rather than those present in the biology of a particular cancer. And that is what we are discussing in this book. Considering the broad view of this public healthcare puzzle, the big picture of scientific knowledge in cancer, and all the discussions present here, the goal is for it to serve professionals in cancer healthcare (and even people that are not professionals), as well as those who do not have time to dig into the whole biological and pharmacological world of cancer in detail. Healthcare professionals often need to learn pharmacoeconomics, business, and administration, and the opposite is also true; professionals in these industries have to learn healthcare. One of the hardest things for scientists to do can also be the most rewarding: taking a step back from their area of knowledge to write about it in journalistic style and make the information publicly accessible. I have many scientific books published, all for practicing pharmacists like myself, physicians, and other healthcare professionals who are specialists in very specific areas, such as pediatric oncology and hematology and stem cell transplantation in pediatrics. It has been fascinating to walk freely between popular science and clinical medicine in writing. I have written in the most extreme of the two very different styles. I contributed a section about homing of stem cells, a subject that fascinates me, for a scientific book entitled Pediatric Hematopoietic Stem Cell Transplantation for Pharmacists (Springer, 2020), with all the complex biochemistry involved in the migration process of stem cells to the bone marrow, and, a short period before that, I explained homing to kids in a book entitled Chubby’s Tale: The True Story of a Teddy Bear Who Beat Cancer. Doctor Doll tells Chubby that stem cells will be collected from Bearnard’s bone marrow, and he will receive them into his vein through a little prick in his arm

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because the cells know the way home, and they will find his bone marrow and fix it. As a writer and also a scientist, I am mesmerized by the different ways we can use words to communicate science, for different needs. That is something many scientists are passionate about. Einstein wrote many times about communicating science in a more accessible way: We have all suffered under this evil, without making any effort to mitigate it. But Berliner has come to the rescue, as far as the German-speaking world is concerned, in the most admirable way: He saw that the existing popular periodicals were sufficient to instruct and stimulate the layman; but he also saw that a first-class, well-edited organ was needed for the guidance of the scientific worker who desired to be put sufficiently au courant of developments in scientific problems, methods, and results to be able to form a judgment of his own. Through many years of hard work he has devoted himself to this object with great intelligence and no less great determination, and done us all, and science, a service for which we cannot be too grateful. It was necessary for him to secure the co-operation of successful scientific writers and induce them to say what they had to say in a form as far as possible intelligible to non-specialists. He has often told me of the fights he had in pursuing this object, the difficulties of which he once described to me in the following riddle: Question: What is a scientific author? Answer: A cross between a mimosa and a porcupine. Berliner’s achievement would have been impossible but for the peculiar intensity of his longing for a clear, comprehensive view of the largest possible area of scientific country. This feeling also drove him to produce a text-book of physics, the fruit of many years of strenuous work, of which a medical student said to me the other day: ‘I don't know how I should ever have got a clear idea of the principles of modern physics in the time at my disposal without this book.’(From The World How I See It)

This book is not in the extremes. It is in the middle of them. It is not as simple as science for kids, and it is not as overwhelming as a scientific book. It is a friendly union where you are a part. It is a discussion that does not mean to be exhaustive because it will be reflected in yourself and will eventually bounce back to us with your personal view, your knowledge, and your own analysis. This book is an open door. It is the start of a discussion that we hope will not end here. And I would like to say a huge thank you to my friends who contributed with their areas of expertise. These people were selected as the people I would invite to have a bourbon here at my home, if they all did not live so far away, and have a good talk, or to work with me on almost any project (in fact, we have worked on other projects together). A huge thank you as well to my acquisition editor, Vanessa Shimabukuro, for the wonderful partnership that has been ongoing for several years and many extraordinary books. Thank you to Henry Rogers, my clinical medicine editor, who believed that this project was right for popular science. Thank you to my production editors Nishantini Vetriel and Vijayasankara Gomathy, and their teams. And thank you to Chris Roy, my personal editor, who goes to tremendous efforts to edit all my chapters, one by one, so my Brazilian English reads like American English with so much respect for science and my style. Curitiba, Paraná, Paraná

Carola Schmidt Pediatric Oncology Pharmacist & Writer kidscancerbooks.com

About the Editor

Carola Schmidt Pediatric Oncology Pharmacist and Writer • Springer Nature author of books in pediatric oncology • Reycraft Books children’s author • Writer of children’s books about cancer Carola has extensive experience in chemotherapy and stem cell transplantation—an area that she loves—for children and has handled thousands of doses for kids of all ages, including babies. She is an oncological hospital pharmacy specialist with an MBA in Planning and Business Management and has experience with adult oncology, as well. Her education began at home, reading medical science books as a hobby. Her academic studies include experience in pharmacy, pediatrics, oncology, and hematology and teaching at the Pediatric Oncology Hematology program in the biggest pediatric hospital in Brazil. After college, she gained a wealth of experience at hospitals, clinics, and pharmacies, working with drug interactions, pediatrics, oncology, hematology, stem cell transplantation, neonatology, intensive healthcare, and infectology. Carola has the experience of working in huge medical centers in Brazil, some of them without resources, demanding a lot of creativity, research, and knowledge. Her research and treatments are used in the very best hospitals, and she continues to develop and publish guidelines to help healthcare professionals worldwide. “Belonging” is a subject that has always fascinated her and directs her writing for children’s books. She believes that each of us has our own stories, history, and the desire to belong. As she explains her understanding of it, our memories are like a living tissue that intersects with other people and their lives. It is not something static or even physical. These intersections encompass the people we meet, all of our experiences, and feelings about the places we have been—all of it forms who we really are, with our families, friends, and our homes. That is the meaning of belonging to her. Her favorite word is “homing.” When she learned about homing of stem cells, she fell in love with the complex biochemical processes that make stem cells (that are collected from a donor’s bone marrow) able to be infused into a receptor’s arm vein—they can find their way home to the receptor’s bone marrow! Homing, for her, is highly related to belonging. These themes gave her the idea to write Chubby’s Tale: The True Story of a Teddy Bear Who Beat Cancer, which entered BookAuthority’s

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list of the “Best Leukemia Books of All Time.” And it was the reason she dedicated an entire chapter about homing of stem cells in her book Pediatric Stem Cell Transplantation for Pharmacists, which is among the Springer Nature 2020 Highlights. Carola loves business. She wants to make a difference in science and education. An impact. If you are a company or organization interested in collaborating, please get in touch.

Contents

The Blame Game����������������������������������������������������������������������������������������������    1 Carola Schmidt  Life and Death Are Made of Five Letters: A, T, C, G, and U����������������������    9 Carola Schmidt  Chaos and Complexity in Cancer������������������������������������������������������������������   15 Carola Schmidt Cancer as a Taboo��������������������������������������������������������������������������������������������   23 Carola Schmidt  Cancer as a Taboo: Part 2 ������������������������������������������������������������������������������   33 Carola Schmidt  Childhood Cancer Survivorship in Germany ����������������������������������������������   41 Christian Müller  Healthy and Fit: To Be, or Not to Be, that Is the Question��������������������������   45 Carola Schmidt  Men Tend to Avoid the Doctor: And Why It Can Be Deadly ����������������������   55 Gogs Gagnon  Pharmaceutical Industry: Good and Bad������������������������������������������������������   61 Marius-Călin Cherecheș Panem et Circenses������������������������������������������������������������������������������������������   83 Carola Schmidt Homing��������������������������������������������������������������������������������������������������������������   89 Carola Schmidt Financial Toxicity in Cancer ��������������������������������������������������������������������������  101 Carola Schmidt

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Poverty and Cancer ����������������������������������������������������������������������������������������  107 Camila Witchmichen Penteado Cancer and Incarceration ������������������������������������������������������������������������������  111 Chris Roy  Matilda and Matthew Effects and Sexism in Science ����������������������������������  121 Carola Schmidt  Against All Odds, Creating My Own Plan for Survival ������������������������������  135 Steve Rubin Index������������������������������������������������������������������������������������������������������������������  141

Contributors

Marius-Călin Cherecheș  Faculty of Pharmacy, Drug Industry and Pharmaceutical Management Department, George Emil Palade University of Medicine, Târgu Mureș, Romania Gogs Gagnon  Writer for Health Union and CURE Media, Member of the Prostate Cancer Foundation Canada Support Groups, and Author, Vancouver Island, BC, Canada Christian Müller  Gert and Susanna Mayer Foundation, Wuppertal, North RhineWestphalia, Germany Camila  Witchmichen  Penteado  Master of Law and Teacher, Curitiba, Paraná, Brazil Chris Roy  Writer and PR Manager, Biloxi, MS, USA Steve Rubin  Author at The Other (C) Word Blog, Diagnosed with osteosarcoma in 2016, New York, NY, USA Carola Schmidt  Pediatric Oncology Pharmacist & Writer, Curitiba, Paraná, Brazil Sharon Worcester  Medical Journalist and Author, Birmingham, AL, USA

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The Blame Game Carola Schmidt

1 Nobody’s Fault Everybody knows someone who has cancer—or knows someone who has had it. When a diagnosis is shared with family and friends, along with support, the patient receives tips, opinions, and comments. The gifted housewife saying that her friend with metastatic breast cancer ate too much frozen food is a common story. And there is always someone that will share an article about a juice that promises to “cure” cancer. The blame is never ending: cigarettes, alcohol … People enjoy discussing the causes and “cures” for cancer. To blame is so ingrained in language and culture that people do not realize that they do it. In 2010, a study [1] with 1620 British women determined how much they would blame someone—blame cancer patients for getting cancer—who had a diagnosis of breast cancer, cervical cancer, bowel cancer, lung cancer, and leukemia, as well as chlamydia and obesity. The results were that 9% of these women blamed (citing numerous reasons) a patient with leukemia for getting leukemia, 15% blamed breast cancer patients, 23% if it was bowel cancer, and 37% if it was cervical cancer, and the winner of the cancer blame game was lung cancer, with 70% of these women admitting that they would blame a lung cancer patient for getting cancer. (For the other diseases mentioned, 87% of these women said that they would blame patients for their chlamydia infections, and 96% for obesity.) It is not difficult to imagine why patients are blamed for their lung cancer. Probably, one of the first correlations of smoking and cancer was a study published in 1795 pointing out the relation between pipe smoking and cancer of the lower lip [2]. Massive anti-smoking campaigns were implemented, to bring awareness to the cellular mutations caused by smoking tobacco, but the way this theme was approached led people to make an C. Schmidt (*) Pediatric Oncology Pharmacist & Writer, Curitiba, Paraná, Brazil e-mail: [email protected]; kidscancerbooks.com © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Schmidt (ed.), The Invisible Hand of Cancer, https://doi.org/10.1007/978-3-031-45774-6_1

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inseparable link between lung cancer and smoking tobacco. In the same research, women who knew that cervical cancer can be caused by chlamydia infection were more inclined to think that a person with cervical cancer deserved to be blamed than those who did not know about this correlation. The conclusion of the study showed that knowledge of how to prevent cancer seemed to be associated with perceived responsibility. Maybe when we increase awareness of cancer prevention, we should also increase, in as many ways as possible, the reminder that cancer is not the patient’s fault. That may sound contradictory to some people. It is difficult to promote awareness of cancer-causing habits, such as smoking and too much sun, and at the same time remind people not to blame the patient. The study raises three important matters to think about: Lung cancer attracts more blame than other cancers; cancer— with the possible exception of lung cancer—attracts less blame than conditions strongly associated with personal behaviors, such as obesity or sexually transmitted infections, and awareness of the link between cervical cancer and sexual activity is followed by blame attributions. The blame study also made a correlation with education and the likelihood of someone blaming cancer patients for getting cancer. Older women were less likely to attribute blame for leukemia or breast cancer. People with a higher education were more likely to blame cancer patients for getting bowel, cervical, and lung cancer. The significance—the differences between levels of education—varied between cancers. There were also some ethnic differences, with non-White participants more likely to attribute some blame to leukemia and breast cancer. The effects of age, education, and ethnicity are probably independent of one another. It is easier to point out what can cure cancer, and what cannot, than what can cause cancer and what cannot. Worldwide, cancer specialists are often saying, repeatedly: Food does not cure cancer … No … Food cannot cure cancer. Science is not made of opinion but data. In the twenty-first century, with the incredible amount of scientific information available to the general public, scientists still have to remind people that vaccines work, the world is not flat, and food cannot cure cancer. Cancer can be treated and cured. The cure can involve combinations with chemotherapy, other drugs such as monoclonal antibodies, radiation, surgery, stem cell transplantation, and/or therapies with modified cells, such as CART cells. But what can cause cancer, to what extent and probability, is a much more complicated matter to decipher. It is a complex subject that involves many variables. The most important ones are biology, genetics, and habits. Back to the blame game, genetics play a crucial role not only in DNA codification but also in addictions that can cause genetic abnormalities. Cancer is always a genetic disease. But “genetic” does not necessarily mean “hereditary,” since the genetic alterations that cause cancer are sometimes acquired, not always hereditary, and here is where the habits can have participation. Many studies were performed to find the genetic alterations that smoking can cause, as well as to find the genetic conditions that are associated with nicotine dependence. Smoking is the most established risk factor for lung cancer, with strong evidence that even passive smoking

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increases the risk of lung cancer. After this was concluded, the researchers started to search whether genetics can contribute to the habit [3–6]. Studies suggest that “smoking genes” exist. CYP2A6 is a gene that encodes a superfamily of enzymes (which are also called CYP2A6) and is present in the liver. CYP2A6 enzymes are responsible for metabolizing nicotine. CYP2A6 enzymes vary between individuals, and this enzyme is responsible for metabolizing not only nicotine but also several medicines. In general, medicines are metabolized by more than one type of enzyme in complex orchestrated processes. There is an ethnic variability in CYP2A6 levels and activity, which can be attributed to polymorphisms (alterations) in the CYP2A6 gene. Inactivating mutations, leading to inactive alleles, are low in European populations, which means that there will be few poor CYP2A6 metabolizers in this population. In contrast, 15–20% of Asians have CYP2A6 gene deletion (we call this CYP2A6*4), resulting in a generally reduced CYP2A6 activity in this population. People who lack the CYP2A6 gene, such as many Asians, cannot activate the compounds N-nitrosamines contained in tobacco smoke (and are carcinogens). All of this indicates that smokers carrying this alteration might have less risk of tobacco-related cancers, such as lung cancer. Since there are other carcinogens in cigarettes, and other enzymes that metabolize them, the risk still exists [3–6]. A study showed that smokers with a lack of CYP2A6, CYP2A6*4, smoked fewer cigarettes per day. It shows that genetics influence not only the risk to develop cancer but also the habit of smoking [6]. It is almost impossible, if not utterly impossible, to be sure of all the factors that cause cancer development. But people have curiosity and necessity driving them to explain the disease. Curiosity and dissatisfaction move humanity. They are great qualities when the balance is maintained. Dissatisfaction leads people to have a constant need to invent and discover new things, improving their lives and of others, while curiosity leads them to question everything and then return to dissatisfaction, as a kind of vicious circle. Why cancer? Why her? The brain is quick in bringing up what we heard, what we care about, and our habits, in making a transposition of the cancer victim to our own lives and habits. On the other hand, there is a motivation from an instinct to take care of ourselves, an instinct that screams in our subconscious that we need to live. This instinct, this bio-mechanism, forces us to take care of ourselves, to think about the consequences of the choices we make, and to balance the happy moments with the happiness that lasts. Together with our capacity for reflection, it makes us feel guilty when we do not take care of ourselves and makes us vow to be more responsible for our decisions. When we think that our choices were not the correct ones, the blame comes to light. Cancer is never somebody’s fault. It does not matter how many cigarettes a person smoked (although it is proven to cause genetic abnormalities, so please do not smoke!); if they are diagnosed with cancer, we cannot affirm that the cancer was caused by smoking cigarettes. We cannot measure that. Probably, most cancers can be avoided with healthy habits. Even the preventive exams, which are essential and help to diagnose cancer in time to treat with better success rates, are not a guarantee.

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There is no procedure to measure exactly how a cancer is caused. But even if there was, the patient is not in a cancer court. People who judge are so far from being experts that they burn the first principle of the health professionals’ code of ethics: primum non nocere. First, do no harm. And the only thing more harmful than suggesting alternative, nonscientific cures to a person who received a cancer diagnosis is to judge them. Looking at the big picture of blaming, it is not exclusive to patients’ social circles. It is an issue that often starts with visits to the doctor. It is something that, unfortunately, can occur among healthcare professionals. The lung cancer stigma is well known among healthcare professionals who research quality of life regarding cancer. It is responsible for the higher levels of psychological distress, and lower quality of life, of lung cancer patients compared with patients who have other types of cancer. A greater perception of lung cancer stigma can be directly related to higher levels of depression and a lower quality of life. The screening of lung cancer stigma is recommended for psychologists who have patients with lung cancer [7, 8]. There is something vitally important to tell kids who are dealing with cancer: Cancer is not their fault. And when a child asks what they did to cause cancer, the answer is so obvious. Not only is it not their fault, but also it is nobody’s fault. So why is it when an adult has cancer, there should be someone to blame? It is their fault. It is the doctor’s fault. It is the researchers’ fault. It is God’s fault. It is the last incarnation, karma, whatever. Like in the movie Good Will Hunting, we should adopt the blameless message and tell cancer patients with love: It is not your fault.

2 Brave Old World—and What Aldous Huxley, Cancer, and CO2 Emission Have in Common I went quickly into the cupboard in the other room where Dr. Bernstein was, and the TV which had just announced the shooting of Kennedy. I took the LSD and said, “I am going to give him a shot of LSD, he asked for it.” The doctor had a moment of agitation because you know very well the uneasiness about this drug in the medical mind. Then he said, “All right, at this point what is the difference.” — Laura Huxley, in a letter to a friend [9]

In the first reading, I am sure that most will agree that it has a strange atmosphere. With the right context, however, we can feel the concern of a wife standing in the face of death, attending to the needs of her husband, in an attempt to help him make peace with his death by cancer. The reconciliation was done, and Aldous went “forward and up, light and free, forward and up towards the light, into the light, into complete love ….” Laura wrote as some of her last words to him. Cancer is no longer a mortal disease, as it was in the past. In contrast, we talk much more about death nowadays than when cancer had only the prognosis of death. The news today in Brazil was about a Nordic adolescent who lives in one of the best developed countries in the world. She blames several developing countries for their neglectful attitude towards climate change, saying that the smog is their fault.

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The analysis of a Brazilian to the economic organization that published it? The girl’s discourse was nonsense. Regardless of who is right or wrong, the motivations of everyone involved should be considered—and this has everything to do with Aldous and cancer. While it is obvious to a Nordic girl born in a country where poverty does not exist that the whole world should take care of the planet and control CO2 emissions, it is just as obvious to a man living in Brazil that a country with people dying of malaria and hunger has other priorities, such as employment and medicine. The discrepancy of interests is very personal, socialized from cultural heritage over generations. When the Portuguese navigator and explorer Pedro Álvares Cabral arrived in Brazil in 1500, and the colonization of the country started, Europe was already using arsenic, largely, to treat cancer. History points to reasons why some countries have cancer as their focus and why others do not. The degree of evolution in past cancer research seems to be only one of the many factors determining where countries are today in their ability to prevent and treat cancer. It is especially evident in India, where cancer is not a national priority, even though India had cancer treatment with arsenic described in the year 500 BCE [10]. The first documented observation of cancer in Brazil was done only in 1872, by an ophthalmologist named Hilário de Gouveia. Although now access to the healthcare system is universal in Brazil (there are free treatments for everyone), the development of health research and discoveries is typical of a country in development. Probably, that is because of the relatively recent colonization of the country, as a colony of exploration. From then to now, a lot has happened to contribute to its development in healthcare. The fact is that in a country where people die from malaria, and the government often struggles to keep tuberculosis under control, cancer will not be a priority. Nor will CO2 emissions. The country is simply not developed enough to have its priorities changed. It is an old saying often ignored, and people should be mindful of this: To know where you will go, you should first know where you are. It seems obvious when we think about places, and even when it is about science. But it is not so obvious when we talk about history, ethics, and sociology [11, 12]. Before climate change, Aldous, and Linda—but after Brazilian colonization and Europe’s first treatments for cancer—a new scientific field arose. It was called thanatology. Élie Metchnikoff, a Russian zoologist, concluded that those who were dying of cancer had little or nothing to read about it; therefore, there was a need for this new field. This scientist had an important idea, thanatology, that became an essential field commonly used by healthcare professionals. There is a strong relationship between the development of countries and research/discussion of the late effects of cancer, mental health, and thanatology. Think of the Nordic girl vs. the Brazilian man. The same is also true for thanatology vs. studies on diseases, or oncology as a national priority vs. contagious diseases as a national priority. In countries with a high rate of poverty, such as some countries of the African continent, where children have not received vaccination and are hungry, oncology certainly will take a long time to be a national priority. In parallel, there are always philanthropists and scientists who can improve people’s

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lives beyond the highest necessity of the moment and can anticipate resolutions of future problems. These political, sociological, and ethical issues in healthcare can be more difficult than the complex, orchestrated biochemical mechanisms of cancer; instead of biochemistry and pharmacology, there is no “right or wrong” when the subjects are social sciences. The only right thing is, like a mirror, trying to see the whole big picture knowing that it is only a reflection and not the truth. And the more knowledge you have about what is happening, where you are, and where you should go, the less assurance you have about the world around you. That is positive. Everyone should express themselves, but not about everything. When people can see the big picture and think about where they are and where they want to go, they can see what is their business to advocate and what is not. Pseudo-intellectuals in oncology—and also other areas—have been advocating for a cascade of harmful pseudo-cures, diets, and even supposed new drugs. It is always important to take a few steps back to see the whole. On the other hand, it is also essential to know who we can trust about a subject. Who said that? Who published this information? What are their credentials? Delicate subjects such as cancer can make people more vulnerable to believe in any answer to a question they have. It is important to take control of the anxiety and what information is surrounding us.

3 The Butterfly in Cancer The flap of a butterfly’s wings might ultimately cause a tornado. — Butterfly Effect Theory, Edward Lorenz

It is not because cancer is composed of more than a hundred diseases, and all of those have very complex biological and biochemical mechanisms that it is not as logical as a machine. The whole human body is as logical as a machine even in its smallest unit: the atom. We do not have the ability to control everything, but observing the mechanisms is the first action to try to control some parts. And it was this first action that Edward Lorenz, a meteorology professor at MIT, took to discover a tiny alteration that drastically transformed the entire pattern of his simulated weather program. Once more, let us think about the idea of knowing where we are before knowing where we should go for a while, and the idea of taking a few steps back to see the big picture. Now we can proceed with Professor Lorenz’ conclusion: This kind of effect is sensitive and dependent on initial conditions. It is no different from cancer. Just as everything in the world is made of atoms, everything in our bodies is made of cells. A human being begins formation with embryonic stem cells. Stem cells have two essential abilities that distinguish them from a common specialized cell, like a skin cell: self-renewal and differentiation. The essential feature of self-­ renewal allows stem cells to make copies with the same or very similar potential. That characteristic is unique, and all other cells cannot make copies with the same

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or even similar potential. The other ability, differentiation, means that they can differentiate into various types of cells with specialized functions. Stem cells are the origin of every cell that composes a human body, including every specialized cell, such as white blood cells and nerve cells [13]. The term “stem cell” seems to have first appeared in scientific literature in 1868, written by the German biologist Ernst Haeckel. The search for stem cells probably came about in 1945, during the aftermath of the bombings in Hiroshima and Nagasaki. People exposed for a prolonged period to lower doses of radiation could not regenerate their blood function (hematopoiesis) with blood transfusion, and they died. People who were in contact with higher doses of radiation had a more rapid death, and it was observed that the radiation killed the stem cells of their intestinal tract. Based on these observations, researchers started to reproduce radiation effects in mice. They irradiated mice and demonstrated that after radiation exposure that should be lethal, these mice could be rescued from blood (hematopoietic) failure with injections of cells collected from blood-forming organs, such as the bone marrow. In 1956, it was demonstrated that injected bone marrow cells directly regenerate the blood-forming system, rather than releasing factors to cause the repairing of irradiation damage. These miraculous bone marrow cells are the stem cells. All of this led to the only known treatment, currently, for hematopoietic failure following whole-body irradiation (and other malignancies as well), which is stem cell transplantation [13]. The clockwork universe, as Isaac Newton said when comparing the universe with a mechanical clock, is a good way to think about cells. A cell is like a mechanical clock, in which every piece, or organelle, has its own partial but essential function. An embryonic stem cell can be found on the blastocyst stage of an embryo, and this cell is “the most elaborate of all mechanical clocks.” They can generate every cell type in the human body except extraembryonic cells, such as those in a placenta. However, if we go back in time for a while, from the blastocyst stage of the embryo to the stage of morula, the stem cells there can spawn every type of cell in a human body, including placenta cells. Because of these differences in their capacities to differentiate into other cells, stem cells of an embryo at the morula stage are called totipotent, while those from the next stage, blastocyst, are called pluripotent [13]. But what makes stem cells from the morula stage of the embryo lose a few capabilities on the next (blastocyst) stage? On their way to create specialized cells, stem cells lose their differentiation ability, and each further stage of stem cell development has less differentiation capacity, up to the point that they form cells that are not stem cells anymore. When they get to the point in which they are very specialized (for example, a skin cell), they can only make cells just like them. Skin cells only originate from other skin cells; gut cells only originate from gut cells. If you look at your skin through the microscope, you will see many specialized cells with the same characteristics, and if you see gut cells, you will see many cells with the same characteristics that are unique to gut cells. Or … that is how it was supposed to happen. Because everything changes with cancer. Abnormal, misshapen, and even giant cells can be found on a biopsy. Cells not fully developed, which should be only in

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bone marrow, can be seen circulating in blood in an absurd quantity when seen through a microscope. Cells specialized for one organ (say, a kidney) can be seen through a microscope in a biopsy of another organ, because of metastasis [13]. Everything in cancer starts and ends with cells. And that is why the affirmation that cancer is as old as humanity is wrong. Cancer came up much before humans. Evidence of cancer was found in dinosaur fossils dating 70–80 million years ago. However, while a gene can have hereditary mutations or acquire a mutation throughout its lifetime, it can be fixed by systems of repair that we have in our bodies before it causes cancer [13].

References 1. Marlow LAV, Waller J, Wardle J. Variation in blame attributions across different cancer types. Cancer Epidemiol Biomarkers. 2010;19:1799–805. 2. Hajdu S. A note from history: landmarks in history of cancer, part 3. Cancer. 2012;118:1155–68. 3. Verde Z, Santiago C, González-Moro JMR, et al. ‘Smoking genes’: a genetic association study. PLoS One. 2011;6(10):e26668. 4. Liu YL, Xu Y, Li F, Chen H, Guo SL.  CYP2A6 deletion polymorphism is associated with decreased susceptibility of lung cancer in Asian smokers: a meta-analysis. Tumor Biol. 2013;34(5):2651–7. 5. Oscarson M.  Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. Drug Metab Dispos. 2001;29(2):91–5. 6. Styn MA, Nukui T, Romkes M, et  al. CYP2A6 genotype and smoking behavior in current smokers screened for lung cancer. Subst Use Misuse. 2013;48(7):490–4. 7. Lisa W, McDonnell KK, et al. Lung cancer stigma among African-American survivors of lung cancer in South Carolina. 8. Maguire R, Lewis L, et  al. Lung cancer stigma: a concept with consequences for patients. Cancer Rep (Hoboken). 2019;2:e1201. 9. Usher S (compilator). Letters of note: correspondence deserving of a wider audience. Alexandria: Spectator. 2013. 10. canceratlas.cancer.org/history-­cancer/. 11. Cruz F. História do Controle do Câncer no Brasil. http://www.historiadocancer.coc.fiocruz.br/ linhadotempo/. 12. History of cancer. The cancer atlas. http://canceratlas.cancer.org/history-­cancer/. 13. Schmidt CWP. Hematopoietic stem cell transplantation for pharmacists: the gold standard to practice. Cham: Springer; 2020.

Life and Death Are Made of Five Letters: A, T, C, G, and U Carola Schmidt

1 The Alphabet of Life In the beginning was the Word, and the Word was with God, and the Word was God. — 2 Corinthians 10:3–6

In molecules that contain nitrogen, nitrogenous bases form the code of life. Able to donate hydroxide (OH−) in aqueous solutions, they are the properties in the chemistry base. They can be purines (adenine and guanine) or complementary nitrogenous bases, pyrimidines (cytosine, thymidine, and uracil—this last one is only present in RNA). Nitrogenous bases form the double strand of DNA through weak hydrogen bonds between A and T, C and G, and, when it is RNA, A and U instead of A and T. That difference makes DNA more stable than RNA. The beautiful and fascinating story of the four nitrogenous bases that compound the DNA—A, T, C, and G—that we learn in basic biology at school becomes uglier and much more fascinating in the study of oncology genetics. There, we discover that besides these four nitrogenous bases, there are modified nitrogenous bases, like 5mC, and also the base modified from the modified base, 5hmC.  Both 5mC and 5hmC are created in a very important process called methylation, which helps us understand fantastic subjects like humans, dinosaurs, cancer, and evolution. It is suggested that the genetic alphabet, composed by “only” A, T, C, G, and U, was not always like this. The alphabetic composition seems to be the product of a continual process of refinement that evolved to this current state. Thymine shows evidence of being the result of a chemical modification that replaced uracil in early DNA evolution. Uracil-based DNA is one of the most common native base substitutions found in bacteriophage DNA.  Altered bases, such as 5-methylcytosine (5mC), 5-­hydroxymethylcytosine (5hmC), and 5-hydroxymethyluracil (5hmU), completely C. Schmidt (*) Pediatric Oncology Pharmacist & Writer, Curitiba, Paraná, Brazil e-mail: [email protected]; kidscancerbooks.com © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Schmidt (ed.), The Invisible Hand of Cancer, https://doi.org/10.1007/978-3-031-45774-6_2

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replace some of the native bases in bacteriophage DNA. 5-Formylcytosine (5fC) and 5-carboxylcytosine (5caC) were revealed in genomic DNA of mouse embryonic stem cells and mouse organs [1–7]. 5mC is considered “the 5th base of DNA,” and it is a modified cytosine, which has an addition of a methyl group to its fifth carbon. It has many functions, contributing to the dynamic control of gene expression in mammals. And it was found that 5hmC is an enzymatic oxidation product of 5mC. These altered bases, like 5mC and 5hmC, have everything to do with cancer: DNA methylation patterns in human cancer cells are highly abnormal. There is often DNA hypermethylation in tumors where there should not even be methylation. Several genes coding for proteins involved in the 5mC oxidation reaction are mutated in human tumors, and 5hmC is substantially reduced in many types of cancer. Studies with solid tumors showed losses of 5hmC ranging from 50% to over 90% in lung cancer, breast cancer, colorectal cancer, prostate cancer, liver cancer, glioma, ovarian cancer, melanoma, and several other tumor types. It is not completely clear why there is a loss of 5hmC in cancer, but it is possible that one of the reasons is because tumor cells proliferate more rapidly than corresponding normal cells of the same tissue and cannot maintain 5hmC.  Since cancer cells are immature and do not work properly, they can divide faster. This reduction of 5hmC is also associated with decreased expression of TET enzymes, which are the enzymes that convert 5mC to 5hmC [1–7]. For many decades, 5mC has been recognized as the only confirmed mammalian modified DNA base. Then, in 2009, the second modified cytosine base, 5hmC, was observed in cells of the nervous system and embryonic stem cells. An enzyme that converts 5mC to 5hmC was identified as a protein encoded by the ten-eleven translocation 1 (TET1) gene, a gene previously implicated in a chromosomal translocation in leukemia patients [6]. Methylation is also an indication of evolution and was the first evidence of selection found at the epigenome level. Epigenome means genetic regulation, a process of determining when and to what extent genes are activated, a process that can happen for tens of millions of years. That finding subverted the notion that natural selection acts exclusively on variation in the genome sequence itself. The yeast Cryptococcus neoformans contains a particular epigenetic imprint in its DNA, which should have disappeared from the species during the age of the dinosaurs. The methylation mark has managed to stick around for at least 50 million years, maybe as long as 150 million years. Different epigenetic mechanisms have been maintained or not maintained during the evolution of the species. Methylation can undergo natural variation and can be selected for over million-year timescales to drive evolution not based on changes in the DNA sequence of the organism. DNA methylation is found in all vertebrates and plants, and many fungi and insects [8].

2 The Alphabet of Death Meanwhile, at the Hall of Justice … — Hanna-Barbera’s Super Friends

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Death is an interesting process. The absence of blood circulation and its oxygenation allows space for metabolic acidosis. Hypoxia, the absence of O2 in the blood, seems to be the tipping point of all reactions caused after death. Although everything seems to be disintegrating when life is not in a body anymore, some genes become more active. Some genes are activated as a cell reaction to the body’s death, and there is still some activity at the level of transcription sometime after death. In a relatively short time frame, the cascade of events after death finishes in cell death and autolysis (their autodestruction). DNA is relatively stable over long postmortem periods, and RNA is much more labile in nature and sensitive to degradation in a tissue-specific manner [9]. But forget about hypoxia, and let us continue the macabre conversation by focusing on the methylation. That same methylation turned us into wonderfully evolved human beings who still fear death. We have an epigenetic clock, and methylation can predict someone’s lifetime. Nature published an article about the DNA methylation profiles from 712 known-age bats (from 26 species) to identify epigenetic changes associated with age and longevity, and it was demonstrated that DNA methylation accurately predicts chronological age. Longevity is negatively related to the rate of DNA methylation change at age-associated sites. Analyzing several bat genomes, the researchers also found that hypermethylated age- and longevity-­ associated sites are disproportionately located in promoter regions of key transcription factors, enriched for histone and chromatin features associated with transcriptional regulation. Age-related methylation change is influenced by developmental processes, while longevity-related DNA methylation change is related to innate immunity or oncogenesis, suggesting that bat longevity results from augmented immune response and cancer suppression [10]. The ability of apoptosis, cell suicide, is an important feature for cancer prevention. It is the body working as a machine doing what is best for the whole. Cancer seems to work as a segregated unity, a factory of cells that starts to have its own rules and organization and ways to break rules to obtain nutrients by developing new blood vessels, through the angiogenesis process, and one of the mechanisms cancer can develop to trick the body and survive is to turn off the apoptosis. Malignant melanoma is a master of that. It is highly metastatic and resistant to chemotherapy [11]. p53 genes encode p53 proteins, which are mechanisms to repair the DNA or induce apoptosis if they cannot fix it. Hypoxia, DNA damage, and absence of nutrients can all be recognized by p53 protein. p53 protein is very important for the body to prevent cancer development. Many types of cancer lack p53 protein. The weird thing is that malignant melanoma, the king of avoiding apoptosis, has functional p53 genes, unlike other types of cancer. They master the technique to avoid apoptosis by working on a gene before the p53 gene in the apoptosis pathway. This type of cancer switches off the Apaf-1 gene. Apaf-1 gene is not mutated or lost, only switched off. The Apaf-1 transcript genes APAF-1XL and APAF-1XL have also been linked to poor response to chemotherapy. Lower expression of APAF-1XL and APAF-1LN is associated with a poor response to chemotherapy in acute myeloid leukemia [11, 12].

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Since the Apaf-1 gene is not mutated or lost in the malignant melanoma pathway to trick the body system, just switched off, it can be turned on again by inhibitors of DNA methylation or histone deacetylation. Histone acetylation and deacetylation are essential parts of gene regulation, cell cycle progression, and cell differentiation. Histone acetylation is an epigenetic modification that changes chromatin architecture and regulates gene expression by opening or closing the chromatin structure. The epigenetic gene that silences melanoma with Apaf-1 is a common example of how cancer cells inactivate cancer-related genes [11, 13]. CpG (when C lies next to G in the DNA sequence, connected by a phosphodiester bond) islands are DNA methylation regions in promoters and are known to regulate gene expression through transcriptional silencing of genes. DNA methylation at CpG islands is crucial for gene expression and tissue-specific processes. Genes become silent when CpG islands are methylated and changes associated with histone deacetylation have occurred. For example, the abnormal methylation of the promoter of the p14ARF gene downregulates the gene, resulting in degradation of p53, disabling the apoptosis pathway [11, 13]. Methylation was discovered in 1948. Rollin Hotchkiss found modified cytosine in the preparation of calf thymus using paper chromatography, a laboratory technique to segregate mixtures that nowadays is very complex and useful in industries. In 1965, Barnett Rosenberg and his team, who at the time thought platinum had no effect on biology, added platinum electrodes into a solution containing the most common laboratory bacteria, feces bacteria E. coli, and turned on the power. The bacterial cells stopped dividing as soon as the current started, but they kept growing up to 300 times their normal length. The original intention of using chemotherapy was to act on the edge of the chaos, the exponential cellular growth, so this all seemed very promising to develop treatments. That experiment with platinum was the beginning stages of development for a drug formed of highly reactive, charged, platinum complexes called cisplatin. We still use it a lot, even for kids, to treat many types of cancer. This drug, which became widely used in 1965, was actually discovered by Italian scientist Michele Peyrone, who first synthesized it in 1844, which is why it was at first called Peyrone’s chloride. In the 1980s, another platinum compound (now a class of drugs) was approved by the FDA, carboplatin, a derivative of cisplatin with a similar mechanism of action but different in structure and toxicity. This drug is largely used for many types of cancer, including pediatrics. Carboplatin is fascinating for many reasons, and one of them is that the dose is calculated based on an area under the curve. Oncology and hematology become otherworldly when we enter this area; it is like stepping into Alice’s Wonderland. Kids receive doses of chemotherapy much higher than adults. This is definitely not common for almost all other classes of drugs. I say almost because I worked with amphotericin B doses in neonatal intensive healthcare before I worked with oncology and hematology for adults and kids. This drug also has higher doses for smaller kids. The standard rule for other drugs is that adults need much higher doses of drugs than kids, but since kids have a faster cellular renewal, they can and should receive protocols with higher doses of chemotherapy to be

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efficient for their treatments. Most of the doses, both in pediatric and adult oncology, are prescribed in mg/m2 instead of mg/kg. And more than any other area, we have doses that are measured in international units, μg, administered in the body in the most creative ways you can imagine, as if in surgery, in the spinal canal (intrathecal injections), and intravesical. The dose, at least for carboplatin, is calculated based on the area under the curve of the patient’s glomerular filtration rate, meaning the rate at which the patient’s kidneys work to achieve the therapeutic dose in the blood, without extensive harm. This therapy is customized based on how well the patient’s kidneys function. Life and death are art. The treatment should not be different [14–16].

References 1. Rios AC, Tor Y. On the origin of the canonical nucleobases: an assessment of selection pressures across chemical and early biological evolution. Isr J Chem. 2013;53(6–7):469–83. https:// doi.org/10.1002/ijch.201300009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181368/. 2. Ito S, Li S, Dai Q, et  al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-­ carboxylcytosine. Science. 2011;333(6047):1300–3. https://doi.org/10.1126/ science.1210597. 3. Epigenie. 5-methylcytosine (5mC). https://epigenie.com/key-­epigenetic-­players/ important-­dna-­methylation-­factors/5-­methylcytosine-­5mc/. 4. Vincenzetti L, Leoni C, Chirichella M, Kwee I, Monticelli S. The contribution of active and passive mechanisms of 5mC and 5hmC removal in human T lymphocytes is differentiation- and activation-dependent. Eur J Immunol. 2019;49(4):611–25. https://doi.org/10.1002/ eji.201847967. 5. Jonasson NSW, Daumann LJ. 5-Methylcytosine is oxidized to the natural metabolites of TET enzymes by a biomimetic iron(IV)-Oxo complex. Chemistry. 2019;25(52):12091–7. https:// doi.org/10.1002/chem.201902340. 6. Pfeifer GP, Xiong W, Hahn MA, Jin SG. The role of 5-hydroxymethylcytosine in human cancer. Cell Tissue Res. 2014;356(3):631–41. https://doi.org/10.1007/s00441-­014-­1896-­7. 7. Misawa K, Yamada S, Mima M, et  al. 5-Hydroxymethylcytosine and ten-eleven translocation dioxygenases in head and neck carcinoma. J Cancer. 2019;10(21):5306–14. https://doi. org/10.7150/jca.34806. 8. Science Daily: Science News. ‘Living fossil' may upend basic tenet of evolutionary theory. Natural selection's reach extends beyond genome into epigenome, study suggests. 2020. From University of California; originally written by Jason Alvarez. https://www.sciencedaily.com/ releases/2020/01/200116121837.htm 9. Ferreira PG, Muñoz-Aguirre M, Reverter F, et al. The effects of death and post-mortem cold ischemia on human tissue transcriptomes. Nat Commun. 2018;9:490. https://doi.org/10.1038/ s41467-­017-­02772-­x. 10. Wilkinson GS, Adams DM, Haghani A, et  al. DNA methylation predicts age and provides insight into exceptional longevity of bats. Nat Commun. 2021;12(1):1615. https://doi. org/10.1038/s41467-­021-­21900-­2. 11. Jones P. Death and methylation. Nature. 2001;409:141–3. https://doi.org/10.1038/35051677. 12. Benites BD, Fattori A, Hackel C, et al. Low expression of APAF-1XL in acute myeloid leukemia may be associated with the failure of remission induction therapy. Braz J Med Biol Res. 2008;41(7):571–8. https://www.scielo.br/j/bjmbr/a/vYSYM8kSpK3cLRrxfGHBLWL /?lang=en.

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13. Gurjal P, Mahajan V, Lissaman AC, Ponnampalam AP. Reprod Biol Endocrinol. 2020;18(1):84. https://rbej.biomedcentral.com/articles/10.1186/s12958-­020-­00637-­5. 14. Flanagan JM, Wilson A, Koo C. Platinum-based chemotherapy induces methylation changes in blood DNA associated with overall survival in patients with ovarian cancer. https://clincancerres.aacrjournals.org/content/clincanres/23/9/2213.full.pdf. 15. National Cancer Institute. The “accidental” cure—platinum-based treatment for cancer: the discovery of cisplatin. https://www.cancer.gov/research/progress/discovery/cisplatin. 16. Sousa GF, Wlodarczyk SR.  Carboplatin: molecular mechanisms of action associated with chemoresistance. Braz J Pharm Sci. 2014;50(4):693. https://doi.org/10.1590/ S1984-­82502014000400004.

Chaos and Complexity in Cancer Carola Schmidt

1 Complexity in Cancer Complexity is your enemy. Any fool can make something complicated. It is hard to keep things simple. — Richard Branson

Comprised of more than a hundred diseases, cancer is complex and chaotic. It is complex because, like any intricate system, it has many components that can interact, changing the course of the disease. Genetic variants, mutations, and characteristics that form each human body—and each cancer—can form unique systems, even though they present common characteristics. The genes codify many different proteins relevant to oncology, like p53 protein—which is a mechanism to identify and repair wrong genetic mutations—and human epidermal growth factor receptor 2 (HER2) protein—which affects cancer growth and spread of cancer cells in breast and ovary cancer. Years ago, genetic screenings were not standard in cancer diagnosis and monitoring. The analysis of HER2 oncogene (which codifies HER2 protein) is now standard practice for patients with invasive or recurrent breast cancer, as well as the test to measure the amount of HER2 protein. We call HER2+ the result of the test when carcinogenic cells have increased levels of HER2. Noncarcinogenic cells also have HER2 but in smaller amounts. It is so important to know if the invasive or recurrent breast cancer is HER2+ because the protocols of treatments vary a lot according to the characteristics of the tumor, its stage, tolerance of the patient to drugs, age, sex, ethnicity, and individual genetics. If the patient is diagnosed as HER2+, they have extra copies of the HER2 gene (because of a mutation called amplification), and with those copies come excessive amounts of HER2 protein, which makes the cancer more aggressive. HER2+ patients can receive a specific monoclonal antibody C. Schmidt (*) Pediatric Oncology Pharmacist & Writer, Curitiba, Paraná, Brazil e-mail: [email protected], kidscancerbooks.com © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Schmidt (ed.), The Invisible Hand of Cancer, https://doi.org/10.1007/978-3-031-45774-6_3

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for HER2+ tumors, such as trastuzumab, which would not make sense to administer in the treatment of an HER2− patient. Trastuzumab is selective for HER2 receptors, which are transmembrane. The drug links to the side of the receptors located over the cell membrane. Trastuzumab then blocks the signal of these receptors. It can also inhibit cell proliferation and promote cell death (by apoptosis). Trastuzumab also flags the tumor cell, which the immune system will then destroy; we call that antibody-dependent cellular cytotoxicity. For that process to occur, natural killer cells expressing the Fc gamma receptor bind to the Fc domain of trastuzumab. Another effect of the drug is that it prevents HER2 shedding. High extracellular levels of HER2 are correlated with poor prognosis and decreased responsiveness to endocrine therapy and chemotherapy in patients with advanced breast cancer. Since typical cells also have HER2 receptors, trastuzumab will also act in healthy cells, but much less since there is not a hyperexpression of HER2 in healthy cells. That mechanism has a lot of complexity involved, and it is just one of the drugs a patient with HER2+ breast cancer would probably receive. Patients with invasive or recurrent breast cancer can receive trastuzumab alone, but, more likely, they will need other treatments in combination, in a protocol designed specifically for them. This can include a mixture of chemotherapy drugs with trastuzumab—or another monoclonal antibody (and sometimes more than one monoclonal antibody)—radiotherapy, and/or surgery. The ramifications in the treatment of cancer are boundless. The combination of drugs is chosen based on different mechanisms of action. A drug’s ability to block key points of the diseased area and inhibit or eliminate the progression of cancer is vital, as is destroying as little of the healthy tissue around it as possible. Over the years, scientists have been discovering patterns and publishing about new proteins, genes, enzymes, or cytochemical processes of relevance. Cancer complexity is certainly better explained now, and the advancements call for more specialists, from diverse areas, to add specific knowledge to treat each person with all their individuality. Treatment of cancer is all about finding key points, those tipping points, and acting there [1]. Many times, the protocols are giant and act in many key points of the disease. Pediatric oncology is more complex than adult oncology, and the protocols are much more extensive. The doses are, in general, higher, since kids have faster cellular multiplication than adults. An acute lymphocytic leukemia treatment protocol has several pages. Any protocol to treat this kind of leukemia in kids is a big organogram with many possible paths available. The treatment path is chosen according to the results of the bone marrow examination, sex, age, evolution of the disease, individual response, genetic tests, and more. Groups of pediatric oncology healthcare professionals often join to discuss the results of treatments and propose changes in the protocols, so that research is started, formally, and these protocols are constantly improved. Such protocols are never definitive. Even the gold standards can change completely with the advance of science. We cannot fight against complexity in its entirety, but we can understand it, break it down little by little, and act on the right key points. Sometimes, something very small can change the course of the disease.

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As the mathematician Edward Lorenz said, “When a butterfly flutters its wings in one part of the world, it can eventually cause a hurricane in another.”

2 The Chaos We Love The fragile wants tranquility, the antifragile grows from disorder, and the robust doesn’t care too much. — Nicholas Nassim Taleb

I worked in one of the worst places a healthcare professional could work in the world. OK, maybe it was the second or third worst place. But until I know someone who worked in a worse job, I will keep thinking it was the worst place in the world. After I graduated from college, I began working at a philanthropic hospital in Brazil. The pharmacy attended to the entire hospital. From neonates to elderly, my responsibility—together with a very small team—was to deliver doses at the prescribed times. We managed drug therapies for patients being treated by every specialist in the hospital. Overwhelmed resident physicians were issuing prescriptions without the oversight of their mentors, who were also overwhelmed. It was my duty as a pharmacist to check all the doses and contact doctors about drug interactions and tell them about changes needed in the prescriptions. A multitask operation, at the same time I needed to ask the warehouse to send or restock drugs, check if the pharmacy had everything it needed, and if not contact pharmacists at other hospitals to borrow it. Because of serious budget issues, we were often short on common medications. People were always complaining, asking why the drugs did not come earlier. “It’s just to inject the drug inside the bag, after all,” they would whine. Like an octopus, I needed eight arms to make sure that the pharmacy was well cleaned and the waste was discarded properly—has the cleaning team been here today???—and manage the technicians and schedule their shifts and … I must not forget, I needed to sort all the sedatives for 15 patients that needed to be sent at 14 h. I worked 12-h shifts almost every weekend because there were not enough pharmacists to take turns. But those 12 h used to become 14, 16, or even 21 h. Lunch? What is that? If I got a chance to have lunch, it was at about 16 h. I had to call the canteen and ask them to save food. They served juice with it, and I just ignored the expiration date because there was a 50/50 chance it was expired. The hospital did not even have enough money for chairs; for much of my time there, I worked sitting on a trash can. Why would a recently graduated professional, who is finishing her MBA in Planning and Business Management—and who has enough money to not have to work—want to work in this madhouse? That is what people asked me. Something got me stuck there. The sharp psychological pressure, the gaslighting, put the weight of the world on my shoulders. Even more immense was the feeling that the patient would die if I go home. It would be my fault because I needed to stay there for them. Whew. After about a year working at this hospital, I realized that there was a high

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rate of suicide among the staff. The hospital’s bathroom was notorious because professionals wanting to end their suffering would often do it there with ketamine or fentanyl. That is a talk to have with a therapist someday. What held me there was something fascinating in the chaos. Imagine yourself as a healthcare professional: in your mind, you know that you can make the difference. You sacrifice and volunteer and see people getting better. You see people who were almost dead get up and go home because you gave them the best medication—you borrowed it, you gave everyone hell, and you did not go to lunch so you could call every hospital. You did great. You have anemia, but you did something that changed the course of a life. They survived. You survived. You feel like you are doing something significant in your life, serving a meaningful purpose. But you find that the sacrifice carries a high price: People call you to say that you have not been there for them. You missed their wedding or the funeral of their dad. And they will never understand that you really could not call them. When you do not have 5 min to go pee during 12 h, you really do not have 5 min to call and say that you feel sorry for their loss. And you feel so much angst and resentment by the need to hold everything together that maybe you do not really feel sorry for their loss. You are too busy, and too hungry, to feel anything outside of the job. You know you will not be there forever. Chaos is too unstable to go on and on forever. It will end. And you feel that. So, you absorb all the madness and keep going. You dive headfirst into the disorder, because you know you are learning things there that you will never learn working in a comfortable office somewhere. You learn to be creative; you learn to adapt yourself; you learn things that no school or other job in the world would ever teach you. The chaos holds you in fascination.

3 The Chaos We Hate and the Chaos We Love It is not the strongest of the species that survives, nor the most intelligent; it is the one most adaptable to change. — Charles Darwin

Normal, healthy cellular tissue is characterized by order. Within this order, cancer is a chaotic system; it has crossed the edge of chaos, which is exponential cellular growth. Between the organized, predictable system and the chaos can exist an edge. The location of it, and the point of transition, can sometimes be predicted. It is the edge of chaos, and it can change the course of the cancer system. Inside the chaos, it is impossible to make accurate and secure predictions, so infinite are the possibilities of interactions [2, 3]. Although normal tissues are characterized by order, the immune system is quite the opposite. Normal and abnormal hematopoiesis works as a complex adaptive system. Hematopoiesis, the process of commitment and differentiation that leads to the formation of all blood cells from hematopoietic stem cells, happens in adults, and mainly in the bone marrow (medullary). In a stem cell niche that is composed of specialized cells that play an essential role in regulating adult stem cell self-renewal

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and differentiation, the cells are released into the blood. Adult hematopoiesis also occurs, even to a much lesser degree, in other tissues, such as the liver, thymus, and spleen (extramedullary). In the fetus, hematopoiesis occurs in the yolk sac, liver, spleen, and eventually bone marrow. Complex adaptive systems are a subset of nonlinear systems. They are self-­ organizing systems. The immune system has nonlinear interactions among its elements, and the elements can evolve over time or change their specification. Complex adaptive systems present unanticipated global properties, often resulting from interactions. Agents adapt their behavior to other agents and environmental constraints. Controlled by the immune system and the influence of hereditary and environmental events, the development and behavior of hematopoietic cell lineages balance between normal and abnormal hematopoiesis in the setting of a functioning or malfunctioning microenvironment. Normal hematopoiesis and immunity can operate between equilibrium and chaos. In a state of equilibrium, the hematopoietic system would fail because its internal dynamic would not allow enough responses to its microenvironment. This system would also fail if it only operated in chaos; it would cease to function as a system. The most productive state of an immune system is always at the edge of chaos—this is where the most creativity, the maximum number of possibilities, is generated to evolve the system. Like the order and chaos of the hospital I worked at, an antifragile system grows from disorder [4–9].

4 The Disease of Chaos When will I start the treatment? Today. While you receive chemotherapy, we’ll find a teddy bear with matching bone marrow. Then, you’ll have some rest days before you have to repeat the chemotherapy. You can play in the store on your rest days, but for now you should wait in your bed. The pharmacist will prepare the chemotherapy especially for you, and the nurse will bring it soon. — Chubby and Doctor Doll, from Chubby’s Tale: The true story of a teddy bear who beat cancer

Leukemia is a disease of chaos. It is more than just abnormal cells; it is a breakdown of order in bone marrow. The disorder happens when the many and complex controls, typically present, malfunction. Leukemia formation is a complicated process. With multiple alterations of cells and their physiologic control mechanisms, it is probably best illustrated by whole-genome and -exome sequencing studies, which show the extent of genetic changes in the molecular heterogeneity of acute leukemia. Leukemia stem cells, rather than the bulk leukemia cell population, may be the objects of genetic alteration and clonal selection. The clonal descendants of the “favorable” mutated cell dominate because the other cells lack this mutation, resulting in a clonal expansion [4–6].

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Multiple equilibrium states exist in the immune system. Someone can have leukemia cells and not have leukemia. The states can be transitory or stable and might be as different as: • • • •

Normal and functional hematopoiesis Presence of abnormal cells easily controlled by the immune system Preleukemic stages without any consequences on normal hematopoiesis Preleukemic stages with inhibition of normal cell lineages without a major expansion of abnormal cells • Development of an abnormal clone without significant infiltrative and proliferative abilities • Development of an aggressive leukemia clone taking absolute control of the bone marrow leading to the disease [6] The number of events necessary to affect the equilibrium depends on its stability. Massive events are required to modify a stable state, while minor events can change a less stable equilibrium. Just as in Darwin’s evolution theory, if one system emerges, it is the system that is better than its competitors, and this system will trade off increased efficiency every time in favor of greater effectiveness. The system’s strength is proportional to its variety, and contradictions are used by the hematopoietic cells, like every complex adaptive system. They are required to create new possibilities to coevolve with their microenvironment [6]. Leukemia, lymphoma, and myeloma cells are monoclonal, which means that they are derived from a single cell or clone (group of identical cells with the same ancestry). They present a relative morphologic, immunophenotypic, and genetic uniformity. The homogeneity is not absolute, and, if it was, chemotherapy for hematological diseases would be less complex and would have better results. The leukemic clone retains a certain degree of chaos and can eventually adapt to new conditions, even resulting in resistance. Normal hematopoiesis with cytotoxic damage by chemotherapy recovers in a matter of weeks because of its versatility, resulting from increased chaos. In contrast, the resistance of a neoplastic clone appears in months or years. Some patients who can be cured by chemotherapy never develop resistance. During leukemogenesis (the leukemic hematopoiesis), leukemia stem cells can hijack bone marrow niches and signaling molecules from normal hematopoietic cells. In a niche, leukemia stem cells can be more therapy resistant and provide important cellular markers of clinically relevant minimal residual disease. Clonal evolution is common in a leukemia relapse, through the acquisition of new mutations [4, 6] .

5 Fractals My life seemed to be a series of events and accidents. Yet when I look back, I see a pattern. — Benoît B. Mandelbrot

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The geometry of a fractal is an intriguing mathematical construct. A fractal surface repeats its geometry periodically at different scales. Cancer tissues look random and chaotic. Fractals typically occur as geometry formed from chaos or in a state far from equilibrium. Cancer-specific fractal geometry can be found in tumors on the tissue scale. Fractal geometry can also be found in the structure of tumor antiangiogenesis, which is the inhibition of tumor vascularization. When a solid tumor grows, it needs more blood supply, and the tumor can start a process called angiogenesis to develop more blood vessels to have more supply. There are chemotherapy drugs that work as antiangiogenic drugs, targeting and blocking the activity of proangiogenic factors, such as vascular-endothelial growth factor (VEGF). The use of fractal image analysis techniques shows that tumor vascular architecture is determined by heterogeneity in the cellular interaction with the extracellular matrix, instead of gradients in diffusible angiogenic factors. This finding changed the treatment approaches [10, 11]. The characteristics of fractal geometry are defined by an infinite range of scales, from infinitely small to infinitely large. Cells derived from cancer and normal tissues both demonstrate this almost ideally. Since an image with infinite resolution and unlimited cell size is not plausible, the geometric scale is limited by the cell size (of approximately 10 μm) and the resolution of the imaging technique. The fractal definition is limited to these scales when studying individual cells. Fractals can be used to help with cancer diagnosis and decide the best treatments. The parameter describing deviation from a fractal can be used to identify new physical biomarkers. Fractals can also help cancer modeling and targeting of points of instability to develop new treatments. Pharmacological treatment of solid tumors relies on the ability of the blood to carry the agents to the tumor. Ionizing radiation also works best in well-oxygenated tumors. Tumor vasculature often expands rapidly and has a high vascular density and relatively dilated blood vessels. Because of that, it may be surprising that drug and oxygen transport to tumors is difficult. That can be explained using fractal, percolation-based computer models. In the absence of the controlled release of growth factors that would arise in normal tissue from oxygen gradients, the tumor vasculature thrives wherever and whenever it can through a heterogeneous extracellular matrix, a process known as invasion percolation [10, 11]. The transport of drugs and oxygen to tumors was investigated with computer models of tumor vasculature based on percolation processes. It was discovered that as a network deviates from the regular patterns of a normal capillary bed and behaves like a percolation network, the transportability of the network is impaired. Percolation processes produce stagnant flow regions and highly variable intravascular distances, making large tumor regions far from the nearest blood vessel. Tumor vascular networks lack the network optimization of normal tissues, and high-molecular-weight drugs have little chance of reaching all of the tumor cells. The most efficient transport of drugs by an internal network, such as the vasculature, should have a minimum path dimension of unity [10, 11].

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References 1. Roche. Product monography: herceptin (trastuzumab). 2021. https://www.rochecanada.com/ PMs/Herceptin/Herceptin_PM_E.pdf. 2. Pinho MSLP. Proteína p53: Algum valor clínico ou apenas pesquisa? Uma revisão da literatura. Rev Bras Coloproctol. 2000;20(4):258–60. 3. Janecka IP. Cancer control through principles of systems science, complexity, and chaos theory: a model. Int J Med Sci. 2007;4:164. 4. Cucuianu A. Chaos in cancer? Nat Med. 1998;4:1342. 5. Puca A, Russo G, Romano G, Giordano A.  Chaotic dynamic stabilities and instabilities of hematopoietic stem cell growth plasticity. J Cell Physiol. 2007;213(3):672–8. https://doi. org/10.1002/jcp.21181. 6. Thomas X.  Understanding leukemic hematopoiesis as a complex adaptive system. World J Stem Cells. 2015;7(9):1145–9. 7. Grilo A, Caetano A, Rosa A. Immune system simulation through a complex adaptive system model. In: Roy R, Köppen M, Ovaska S, Furuhashi T, Hoffmann F, editors. Soft computing and industry. London: Springer; 2002. https://doi.org/10.1007/978-­1-­4471-­0123-­9_57. 8. Yin T, Li L. The stem cell niches in bone. J Clin Invest. 2006;116(5):1195–201. 9. Nature portfolio: haematopoiesis. https://www.nature.com/subjects/haematopoiesis. 10. Sokolov I.  Fractals: a possible new path to diagnose and cure cancer? Future Oncol. 2015;11(22):3049. 11. Baish J, Jain R. Cancer, angiogenesis and fractals. Nat Med. 1998;4:984.

Cancer as a Taboo Carola Schmidt

1 Belonging Fernando Silva ran the children’s hospital in Managua. On Christmas Eve, he worked late into the night. Firecrackers were exploding, and fireworks lit up the sky when Fernando decided it was time to leave. They were expecting him at home to celebrate the holiday. He took one last look around, checking to see that everything was in order, when he heard cottony footsteps behind him. He turned to find one of the sick children walking after him. In the half-light, he recognized the lonely, doomed child. Fernando recognized the face already lined with death and those eyes asking for forgiveness, or perhaps permission. Fernando walked over to him, and the boy gave him his hand. “Tell someone, …” the child whispered. “Tell someone I’m here.” — Christmas Eve, in The Book of Embraces, by Eduardo Galeano, translated by Cedric Belfrage

While writing Chubby’s Tale: The True Story of a Teddy Bear Who Beat Cancer— now in its second edition—I met several other writers that were willing to exchange manuscripts for beta reading. We read each other’s books and provided feedback, a common step among writers to make a book stronger. Chubby is a teddy bear with a wool pullover and no pants. He felt ill. After talking to his friend Superhero, he decided that there was one thing to do: go on an adventure through La La Land Toy Store. The journey begins with Chubby taking off in a toy Volkswagen Beetle, to find Dr. Doll. Along the way, he learns about leukemia, chemotherapy, hair loss, and stem cell transplantation, and he is cured. Returning to his shelf, Chubby is given the best Christmas gift a teddy bear can have. Chubby is the favorite of all my books because it explains complex subjects, like homing of stem cells and leukemia, in a very simple and cute way. A beta reader suggested that I cut out everything about cancer from the book and leave just the book’s core, which for her was Chubby’s journey in the toy store to find a home. I completely ignored her advice. This was C. Schmidt (*) Pediatric Oncology Pharmacist & Writer, Curitiba, Paraná, Brazil e-mail: [email protected], kidscancerbooks.com © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Schmidt (ed.), The Invisible Hand of Cancer, https://doi.org/10.1007/978-3-031-45774-6_4

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not another Christmas-themed picture book. It was for cancer patients and has a particular purpose for those patients. In my experience, most patients want to talk about their condition, cancer, health, and feelings, and the immediate caregivers (parents, partner, etc.) want it as well. Taboo thinking generally comes from friends and family members who do not live in the same house as the patient. That is what I have seen in Brazil, both in pediatric oncology and adult oncology, and in the USA (which is the best market for my books) where it is common to hear patients complain about friends “ghosting” them or saying inappropriate things like “I’m so happy you are alive.” Having experienced this so many times, and knowing of the negative impact it has on kids with cancer, I wanted to do something about it. Show parents and kids how to recognize these situations and think about them differently. I wrote a picture book titled Cancer Daily Life for teenagers and young adults, classified as 12+, that is full of bittersweet humor. It has frames of illustrations showing situations that are awkward and strange to anyone that has not experienced cancer, such as people stalking a patient with green juices. We need to talk more about cancer, and these awkward situations are the conversation that needs to be had. Belonging is a subject that is always present in my children’s books. Everybody wants to belong and feel welcomed as a whole. How can we do this? When people are receiving cancer treatment, they generally do not want to ignore it, to stay away from everyone, or to pretend that nothing different is happening. It is reality. Ignoring it does not make it disappear. By pointing out a handful of common awkward situations, people become aware of them and more, and the awkwardness goes away. What is left is the old feeling of belonging that cancer patients need. Yesterday, I had an appointment with a neuropsychologist—a pleasant, sharp lady with a Ph.D. in near-death experience—as research for a children’s book I am writing about grief. We talked about many exciting things, and I remember that she said, “The tear that doesn’t go out, goes in.” What she meant was that we need, as a society, to let people express themselves better and more. Sometimes, kids express themselves in ways that we adults would consider inappropriate, like with anger. It is hard to understand the language of the feelings and what someone’s attitude communicates, and sometimes we do not even need to try to understand but to welcome. After harmful advice, such as “food to treat cancer,” the worst answer someone can give to a cancer patient is no answer at all. Ghosting can be very harmful and usually happens because a person fears the situation and of saying something wrong. Patients can facilitate the relationship by communicating what they need and how they feel. And friends and family members can ask how they can help. Sometimes, it is with food, house cleaning, a ride to chemotherapy, or just listening with an open mind. There are many books out there to help with this. If you do not know what to say, buy a good book with the message you want to transmit.

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2 Cancer and Death People try to hide their pain. But they’re wrong. Pain is something to carry, like a radio. You feel your strength in the experience of pain. It’s all in how you carry it. That’s what matters. Pain is a feeling. Your feelings are a part of you. Your own reality. If you feel ashamed of them, and hide them, you’re letting society destroy your reality. You should stand up for your right to feel your pain. — Jim Morrsion

In Brazil and the USA, countries with open-minded communities, cancer is still a delicate subject. And countries with small communities governed by traditions see cancer as an even bigger taboo. Although cancer is a highly curable disease nowadays, it can still be stigmatized as a death sentence by people with a cultural heritage of traumatic experiences. A psychology thesis about palliative care and anticipatory grief of kids with terminal cancer, researched in Brazil, is a good example of terminal cancer from the point of view of kids. When cancer has no cure, the kid and the family still need treatment, maybe chemotherapy for the kid to have a better quality of life, pain management, and a lot of what we call “acolhimento” in Brazil, which means to host, to give shelter (in the metaphorical meaning), to welcome the person, and to make them feel belonging. Psychological treatment helps immeasurably on that. Dying can be a process, sometimes a long one, and it can be a blessing to have time to make peace with your life and prepare for death. A cathartic experience for sure. When a kid will die, some families opt for telling the kid, together with psychological support, using the techniques that allow the kid to have a sincere, respectful experience of dying. In that thesis, a psychologist interviewed kids who would die of cancer. The imaginative process of those kids was described, as well as their plans for the future. A 7-year-old girl had as her immediate future the wish to work in the church. She said that she needed to take care of her bald head for her hair to grow straight. A 9-year-old girl, who used the verbs in the past to talk about cancer, said that she lost her hair because she complained it was bad. She also said that she was kicked in the belly, and that originated the tumor, and her body just stays with the disease if it wants, and her body wanted it because she did not eat well. Regardless of cancer, and because of it, she planned to study and become a cuisine chef. When we do not talk about the disease, feelings, pain, and problems, they do not disappear. They grow. And, as people, we give meaning to what we do not understand to try to make sense of the half-information we have. That is why we need to talk about cancer. A 10-year-old boy with terminal cancer said, in the same research study, that God cured him. A 14-year-old boy said that his goal was to find a cure so he could then go back to his daily routine. The imaginative process is a mechanism to separate a person from the here and now and put them into distant experiences. The imagination permits us to concentrate on the past or future instead of the present and be focused on concrete or abstract thoughts that can be plausible or not plausible. The imagination can prepare kids for experiences in the future. Like the kid that wanted his daily routine back, they were interrupted, and they sought a

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solution to go back to their projects. Imagination can amplify kids’ capacities for future events. All of the participants interviewed talked about their perspectives for the future without mentioning the possibility of aggravation from the disease or death. The girl who said that she wants to be a cuisine chef wanted to create healthy food and go to the beach. Another girl showed her wish to be a doctor and work in oncology. Unfortunately, these two girls will not realize their wishes in adult life because their cancer was terminal, and even with new possibilities coming all the time—even though healthcare professionals fight up to the last minute—it was too late for them to achieve the cure. But they could have made their wishes more plausible and acted on them, by attending a cooking course for kids, for example. The study mentions that the lack of communication on the part of the team and the family and the difficulty of facing dying reinforce the idea of death as a taboo in the Western society. This is intensified when dealing with children and adolescents who are considered unable to understand life’s experiences. As a citation in the study mentioned, Kellehear said, “The dying experience is the most commonly ignored measure of our wider history as human beings” [1]. The reframing process is fundamental and a sincere way to deal with the psychological impact of cancer. In that same thesis with Brazilian kids with terminal cancer, a 17-year-old patient said, “You can have cancer. But you can’t let cancer have you.” This girl mentioned death as a possibility, something that she is not afraid of but does not want at that time in her life. At the same time that she recognized herself as a new person, the girl learned new ways of acting and thinking, reflected in her ability to face the problems arising from the illness and the difficulties faced with the treatment. An intense construction of meanings occurred to her, such as the realization of being strong, able, and giving a new value to life and everyday experiences, softening the ambivalences experienced, and allowing the continuity of the self, reframing the experiences [1]. A culture of avoiding the subject of death brings anxiety for families of children with terminal cancer. Grief is heavy and isolating, and families consistently report feeling abandoned by the medical system after their child dies. The feeling of the world moving on while their inside world stops can make them feel depersonalized. Grief is a highly personal experience and often lonely. When it is about palliative care and supporting families that are grieving, one person cannot do everything, but everyone can do something meaningful for each grieving person, and the care should be done in the anticipatory grief, grief around the time of death, and grief after death. Many families face several losses at once: the loss of support systems, jobs, financial security, mental and physical well-being, etc. These secondary losses exacerbate the stress of a terminal diagnosis. The feeling of safety fades away, and the person holds themself on what is good and meaningful [2]. Definitely, not all children will be highly anxious in the period immediately preceding death, and death-related anxiety can be triggered by restricted or veiled information about one’s health status, limited involvement in medical decision-­ making, and fear of poorly controlled physical symptoms, like pain management. Death anxiety may trigger or make anxiety disorders worse, such as panic disorder

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or generalized anxiety disorder. Adolescents are more likely than younger children to experience anxiety and depressive symptoms. According to terminal patients, one of the most common and troubling symptoms of suffering during the time of the end of life is poorly managed anxiety, which reflects on parents’ psychological states after the death of the kid. The palliative care team can offer the building of a legacy, providing the option to create items like hand impressions, ink prints, and heartbeat recordings, which are tangible keepsakes that have proven beneficial for caregivers and siblings in their grieving process. Since families can tend to deny memories related to hospitals, even more if the offering of keepsakes is closer to the time of death, the emphasis should remain on honoring the child and family. Beyond tangible keepsakes, the wishes of the child and the family should be focused on, the favorite activities or milestones of importance to them should be considered, and the kids’ autonomy should be respected. Art is wonderful for kids to express themselves and their feelings in this critical period [2].

3 Breast Cancer as a Taboo On the first night they approach and steal a flower from our garden. And we don’t say anything. On the second night, they no longer hide: step on the flowers, kill our dog, and we don’t say anything. Until one day, the weakest of them enter alone and our house, steals our light and, knowing our fear, rips the voice out of our throats. And we can no longer say anything. —Eduardo Alves da Costa

Some of my favorite Brazilian writers are the marginal ones. Alive enough to share thoughts and be reached and to not have their work recognized by most of the world and to fear that someone will make thousands or maybe millions by discovering them after their death. Not different from many of the classic writers and painters who are famous and valued today that died poor and misunderstood and now are everywhere on store shelves. Another parcel of my favorite Brazilian writers is composed of authors from dictatorship times—the literature of the 1960s–1970s. Some are still alive, and others not. Artists were heavily punished during those times. Tortured and killed by the military government, sometimes. Silenced, always. The poem that introduces this section was written at that time. And many times attributed to the wrong person. There is a famous saying adopted from a Virginia Woolf phrase, “For most of history, Anonymous was a woman.” And the same is valid for

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OwnVoices writers, including men. It is an everyday fight to keep your name, keep your place, and be recognized depending on where you live, which is your ethnicity and history, how you were born, what happened to you, and the choices you made. At the time of that dictatorship in Brazil, writers and musicians were using metaphors to express what they could not properly say and homophone words and even expressed themselves in children’s literature. A book entitled Raul da Ferrugem Azul, which means Raul of the Blue Rust, by Ana Maria Machado, was refused by several publishing houses at the time of the dictatorship because the book could cause trouble. Raul realized that he had some blue rust spots, and then he finds out that only he can see them. He takes off to find the reason for this and the cure. The book is about being silenced when facing daily struggles. To prefer to stay comfortable instead of to act. And then, because of so much ignoring what cannot be ignored, he starts to rust [8]. To wait for the results of a biopsy can be brutal. To hear the results of the exams and the word cancer directed at you for the first time is a very hard experience. This experience comes with fear of all kinds. And even after a successful treatment, the fear can still be present. Fear of cancer recurrence is commonly experienced. Studies show that it is common for Caucasian women in America, who were cured of breast cancer, to fear recurrence, and communication with family members contributes to the administration of this feeling. Chinese women in America who were cured of breast cancer have the same fear. According to researchers, similar to Chinese families in China, cultural expectations that encourage concealing emotions to maintain interpersonal harmony are also prominent among Chinese Americans. These studies have suggested that Chinese American families are more comfortable providing practical support rather than what concerns the cancer patient’s emotions. Cancer is often a taboo topic in Chinese American families. It is rare for Chinese American breast cancer survivors to discuss feelings and concerns openly with significant others. The study examined the association between social constraints, such as barriers from significant others inhibiting cancer-related disclosure in relation to fear of recurrence, among 136 Chinese Americans who were cured of breast cancer—while proposing that self-stigma, such as internalized feelings of shame about having cancer, together with body pain and ambivalence over emotional expression (like the conflict between the desire to express emotions and the fear of its consequences) would mediate the association. The study suggested that sharing thoughts and concerns with supportive and empathic people can facilitate the cognitive process of the experience of cancer and its adjustment, while an unsupportive network, such as significant others’ disinterest, unavailability, or disapproval, would block the cognitive processing and adjustment. It concluded that family-based psychosocial interventions to promote effective communication among family members, strengthen positive aspects of the patients’ identity, encourage culturally appropriate ways of emotional expression, and train the patients with pain management skills might help in reducing those survivors’ fear of recurrence [3]. A recent study about breast cancer as a taboo in Ghana exposed several important concerns about cultural beliefs and stigma. In northern Ghana, breast cancer is perceived as a taboo, and women who detect abnormalities in their breasts often

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keep their symptoms secret for months before seeking healthcare. Or, first, they try to be healed in a church. The study pointed to another sad situation: women afflicted with breast cancer refusing to mention it to keep the respect of their families. Daughters of women who have breast cancer find it difficult to get married in their communities. Some cultures in Ghana think that breast cancer is a contagious disease and segregate clothing, bowls, cups, and spoons. Financial constraints and long distances to healthcare facilities are also challenging. Most women in Ghana work in the informal sector and are homemakers who are supposed to care for children, do household chores, and engage in low-income jobs to keep the home. The relatively few women in the Ghanaian corporate world earn a lower income than their male peers. All of this makes women in Ghana lack the financial independence necessary to make treatment decisions for breast cancer. And breast cancer treatment is not covered by national health insurance. Of course, the emotional well-being of a person is an essential goal, but while we discuss the fear of recurrence and to welcome American women and talk about how they feel, in other countries, like Ghana, breast cancer in young women comes with a lot more social and economic challenges. Women in Ghana have financial burdens when they are unable to work because of treatment side effects. At the same time, they need to cope with their community’s erroneous and harmful beliefs that make them feel stigmatized and, because of that, isolate themselves [4].

4 Oppression and How It Makes Healthcare Become a Taboo So, I want to encourage you to do what I only started to do later in my life: take time to learn about the lives of women around the world—and try to play a small part in their fight to create the future they deserve. — Melinda Gates

Shukria Barakzai had never been assaulted before. Some men jumped out of a truck and started whipping her with a rubber cable until she fell out, and they continued whipping her after she was unconscious. During this time in Afghanistan, there were no laws preventing violence against women. In an extreme absence of respect for women, sharia, a law the Taliban forces Afghan people to follow, makes clear that women cannot even go outside without a mahram, a male guardian. Some countries have a well-defined law about not only the physical violence against women but also psychological, financial, and emotional violence (emotional abuse can be as hurtful as physical violence, and often it even represents an open door for physical violence). That day, Shukria’s husband was at work, and she woke up feeling dizzy and feverish. She could not walk the street herself being a woman, to visit the doctor, so she shaved her 2-year-old daughter’s head and dressed her in boys’ clothes since with a 2-year-old “boy” she would be allowed to walk the street. She was wearing a burka with blue folds that hid her fingertips, painted red. The Taliban forbids nail polish. She asked her neighbor, another woman, to walk with her to the doctor in central Kabul. They left the doctor’s office with a prescription and were going to the

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pharmacy when Taliban militants, who regularly drove around Kabul looking for Afghans to shame and punish for violating their moral code, decided, as a way to justify sadism, that there was something wrong about her. She was shocked and humiliated. Afterwards she said, “Are you familiar with something we call sadism? Like they don’t know why, but they are just trying to beat you, harm you, disrespect you. This is now (what) they enjoy. Even they don’t know the reason” [5]. Shukria could have gone home and stayed there with a false sense of security and tried to leave her country, or she may have had other responses to the oppression that, even though it is so wrong, would be very natural and comprehensive from a victim’s point of view. But she decided to organize underground classes for girls instead [5]. When the Taliban started to take control of Kabul in September 1996, they began a reign of terror over the people, especially the women, who had their freedom severely restricted, including their access to healthcare, education, and employment. Since the Taliban decreed that male doctors could not treat female patients unless they were relatives, some female physicians and nurses were able to continue working. The workplace atmosphere was always tense with the threat of violence; female physicians and nurses were subjected to beatings by Taliban guards who enforced “morals.” Male and female doctors were ridiculed in public, women were attacked when they ventured into the streets to seek medical care for themselves or their children, and there was even a report of a pregnant woman delivering her baby in the street while her husband was being beaten for trying to take her to the hospital. To avoid reprisals, physicians cannot talk about patients they treat for injuries caused by the Taliban. The year is 2021, and doctors and patients still suffer the horror of oppression. Dr. Akbari was at her clinic in the Afghan city of Mazar-e-Sharif when she received a call from a member of the Taliban saying, “We’re entering the city. Soon we’ll come and get you.” She had given a birth control shot to a 13-year-old bride of a Taliban member. The girl was the second wife of the much older man, who required her to get pregnant. Dr. Akbari was obligated to say, “She is a child. It’s risky for any child to get pregnant. And this girl was also physically very weak.” The angry husband questioned why the doctor did such a thing and complained that now he cannot have babies. After some calls threatening the doctor, she learned he was a leader of a Taliban contingent active in the area outside the city. The contingent did not control the city itself, but as the Taliban made gains, Dr. Akbari noticed a shift in the man’s tone each time they spoke on the phone. She was constantly threatened, also, by other members of the Taliban and received pictures of dead people with promises of the same happening to her. When she received a call from the husband saying that he and his men were at the point of conquering the city, she decided, “This is it.” The woman who had an opportunity to leave her country to live in Canada with her parents but then decided to stay and get a medical degree in her country and help her people, headed to the airport without even going home to pack anything. Boarding the airplane to a country nearby with only $400, she stayed at a friend’s home, who is the only person she knows there. She was shocked to see the airplane almost filled with other women

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traveling alone, a rare sight in Afghanistan. She said, “I haven’t been able to sleep since the day I arrived. I can only sleep 2 h in a day. Overnight, everything I had has vanished” [6, 7].

References 1. Bastos ACSB. Na iminência da morte: Cuidado Paliativo e Luto Antecipatório para crianças/ adolescentes e os seus cuidadores. Universidade Federal da Bahia. 2019. https://pospsi.ufba.br/ sites/pospsi.ufba.br/files/tese_ana_clara_verso_final.pdf. 2. Shuelke T, Crawford C, Kentor R, et  al. Current grief support in pediatric palliative care. Children (Basel). 2021;8(4):278. https://doi.org/10.3390/children8040278. 3. Yeung NCY, Lu Q. Social constraints and fear of recurrence among Chinese American breast cancer survivors: an exploration of psychosocial mediators. 2021. https://onlinelibrary.wiley. com/doi/full/10.1002/pon.5784. 4. Iddrisu M, Aziato L, Ohene LA. Socioeconomic impact of breast cancer on young women in Ghana: a qualitative study. 2020. https://onlinelibrary.wiley.com/doi/full/10.1002/nop2.590. 5. Addario L.  The Taliban’s returning is catastrophic for women. The Atlantic. 2021. https://www.theatlantic.com/international/archive/2021/08/ the-­talibans-­return-­is-­awful-­for-­women-­in-­afghanistan/619765/. 6. Faiz A. Health care under the Taliban. Lancet. 1997;349(9060):1247–8. https://doi.org/10.1016/ S0140-­6736(05)62439-­7. PMID: 9130961. 7. Aizenman N. The Taliban swore to kill an Afghan doctor for giving birth control to a child bride. NPR. 2021. https://www.npr.org/sections/goatsandsoda/2021/08/19/1029000262/ the-­phone-­call-­that-­made-­an-­afghan-­woman-­doctor-­flee. 8. Austin History Center. Anonymous was a woman. https://library.austintexas.gov/ahc/ anonymous-­was-­woman.

Cancer as a Taboo: Part 2 Carola Schmidt

1 Cancer Treatment in Transgender People The cancer for me was like, I could die. I’d much rather die being happy with myself than being a person no one really knows. — Florence Montecalvo

Florence Montecalvo was diagnosed with bone cancer when she was in seventh grade. She underwent 18 rounds of chemotherapy and had three ribs removed before she realized that she was not comfortable in her own skin, at that point, of a male. Florence identified as a gay man at that time. By her junior year in high school, she started hormone therapy guided by doctors at Akron Children’s Hospital, with the support of her parents. Florence said, “I had friends in high school who got kicked out of the house. One was gay, and one was transgender. They had to take minimum wage jobs and figure out how to make it at a time they should have been children.” Florence became a patient of adolescent medicine, which provides specialized services to LGBTQ+ children, teens, and young adults. The center provides gender-­ affirming hormones, pubertal suppression, mental healthcare coordination, preventative healthcare, education, and social support for the patients and their families. Florence has a passion for housing rights that led her to major in urban planning. Young people who are transgender or gender nonconforming face a higher risk of homelessness, mental health problems, and suicide. Dr. Crystal Cole, director of the center, says that acceptance at home is vital to their health and well-being. She said, “We really want to engage the family and help the patient and family come together. Some parents are fearful and have a hard time understanding it. We can be a go-to

C. Schmidt (*) Pediatric Oncology Pharmacist & Writer, Curitiba, Paraná, Brazil e-mail: [email protected], kidscancerbooks.com © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 C. Schmidt (ed.), The Invisible Hand of Cancer, https://doi.org/10.1007/978-3-031-45774-6_5

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place for parents, where they can express their fears and concerns. We can set them up with appropriate resources” [1]. A US report indicated in 2016 that 82% of transgender individuals have considered killing themselves and 40% have attempted suicide, with suicidality highest among transgender youth. That number is about nine times greater than the general population. The first study to identify a significant association between interpersonal identity-based microaggressions and suicide attempts among transgender youth, in 2020, had findings that were consistent with research demonstrating the relationship between exposure to racial microaggressions and suicide attempts among racial minority individuals. The study interpreted its findings using the interpersonal theory of suicidality, and it concluded that higher levels of interpersonal microaggressions, such as daily negative messages targeting youth’s marginalized identity, may contribute to a sense of not belonging within a broad range of interpersonal relationships and contexts, such as social, in the community, and spiritual [2]. According to a study published in 2014 by the American Foundation for Suicide Prevention, by the Williams Institute of the University of California, suicide attempts among trans men were 46%, and 42% among trans women. Suicide attempts were higher among those who are 18–24  years old (45%), multiracial (54%), and American Indian or Alaska Native (56%), who have a high school as the highest educational background or less (48–49%) and have an annual household income of less than $10,000 (54%). Prevalence of suicide attempts is elevated among those who disclose to everyone that they are transgender or gender nonconforming (50%) and among those who report that others can recognize this always or most of the time (42–45%). Respondents who are HIV positive (51%) and respondents with disabilities (55–65%) also showed an elevated prevalence of suicide attempts. Sixty-five percent of those with a mental health condition that substantially affects a major life activity reported attempting suicide. What catches more attention in the scenario of this research is the exceptionally high prevalence of lifetime suicide attempts reported by the respondents across all demographics and experiences. The research points out that mental health factors and experiences of harassment, discrimination, violence, and rejection may interact to produce a marked vulnerability to suicidal behavior in transgender and gender-nonconforming individuals, and more research is needed [3]. In the same study published by the American Foundation for Suicide Prevention, respondents who experienced rejection by family and friends, discrimination, victimization, or violence showed an elevated prevalence of suicide attempts. For example, when the family chose not to speak/spend time with them, the prevalence of suicide attempts was 57%. The prevalence of suicide attempts was also higher among those who experienced discrimination, victimization, or violence at school, work, or when accessing healthcare. Harassment or bullying at any level of school had a prevalence of 50–54%, discrimination or harassment at work had a prevalence of 50–59%, and when a doctor or healthcare provider refused to treat them, the prevalence of suicide attempts was 60%. Moreover, respondents who suffered physical or sexual violence at work (64–65%) or at any level of school (63–78%), discrimination, victimization, or violence by law enforcement officers (57–61%) or

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physical or sexual violence by law enforcement officers (60–70%) also had elevated prevalence of suicide attempts. Additionally, experiencing homelessness was associated with a prevalence of 69% [3]. Out of the 8263 people who participated in the same study, 49 individuals committed suicide, slightly more than 4% of the participants. The study’s follow-up period ranged from 0 to 45.5 years, and the research was conducted in Amsterdam [3]. There are few studies on cancer treatment in transgender people, and more research is needed. For example, leukemia treatment in pediatrics, including teenagers, differs slightly between boys and girls, but the protocols do not mention transgender boys and girls or how to adjust the doses, time of treatment, and management. The focus on healthcare for transgender people is mainly on mental health due to the high incidence of suicide. However, more studies on cancer and other areas of healthcare are necessary. Since hormone treatments should be suppressed after a cancer diagnosis, more research is needed to guide cancer treatment and mental healthcare for transgender patients diagnosed with cancer during pubertal suppression and the use of gender-affirming hormones. Transgender people face many barriers to healthcare, which may delay cancer diagnosis and treatment and result in decreased survival rates. Among 11,776,699 people with cancer in the National Cancer Database (NCDB) in the USA, only 589 were transgender. Compared with cisgender patients, transgender patients had more diagnoses of advanced-stage lung cancer, fewer treatments for kidney and pancreas cancers, and poorer survival after diagnosis with non-Hodgkin lymphoma and prostate and bladder cancers. Similar associations were found for other cancer sites, although not statistically significant. Several reasons may contribute to the higher cancer burden among transgender individuals, such as the long-term use of gender-affirming hormones, higher rates of smoking, and excessive alcohol use due to social stigma, discrimination, economic marginalization, and unmet healthcare needs. Transgender patients also face barriers to cancer care, including lack of clinician training and transgender-specific screening guidelines, as well as discrimination in medical settings. Stigma and discrimination also lead to lower employment rates and limited access to health insurance. Delays in cancer diagnoses and treatment contribute to advanced-stage diagnosis and decreased survival. Understanding the cancer burden in the transgender community is crucial as the population ages and as best practice recommendations become more inclusive [4]. The transgender and gender-nonconforming population comprises an estimated 0.3–0.5% (25 million) of the global population, and this number has been increasing. Urologists and other healthcare providers who treat genitourinary malignancies will increasingly encounter cases of prostate cancer in transgender women (assigned male at birth). However, there is currently limited information, guidelines, and studies in the literature to summarize the challenges and opportunities faced by this unique patient population. There is insufficient information on how to best diagnose, manage, and follow transgender women diagnosed with prostate cancer. Although rare, the diagnosis of prostate cancer in transgender women is often associated with significant disease. While the treatment remains in line with standard guidelines, it is essential to consider the unique aspects of healthcare in this

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population, including their hormone usage history and gender-affirming surgical procedures. Surgical, radiation, and hormonal treatments play a role in choosing an appropriate treatment. The lack of studies and structure in general clinical trials may marginalize these patients. Transgender and gender-diverse individuals have an increased risk of mental diseases, similar to other marginalized groups, such as Black, Asian, and other minority ethnic communities. This is partly related to the phenomenon of minority stress, where chronically high levels of stress exist in marginalized groups due to prejudice and discrimination in their social environment. Continuity of care may also be an issue since many of them relocate after transitioning for a fresh start. Some individuals struggle with social or mental health issues, and others are denied access to the healthcare system [5, 6]. According to the American Cancer Society, one in eight men will be diagnosed with prostate cancer during their lifetime. About 60% of cases are diagnosed in men aged 65 or older, and it is rare in men under 40. However, the same disease in transgender women is poorly investigated. Guidelines for gender-affirming hormone therapy in transgender women recommend androgen deprivation therapy, with or without estrogen therapy when medical transition is required, with testosterone levels suppressed to