#2 How to be a better patient – recognising alarm symptoms

One of the most shocking moments during my first internship in the hospital was when I had to examine an old lady with a suspicion of having bowel cancer (also called colorectal cancer). She has had blood in her stool for the past few months. Lately she had pain during defecation and therefore went to the GP. After rectal examination, it was clear she had bowel cancer. She was referred to the department of internal medicine where I was interning. The bowel cancer grew through her bowel wall into other organs. It was clear that the cancer had been growing for a while, because of the late stage cancer and her frailty, there were no curative treatment options. It’s impossible to exactly know what her chances of survival would have been if she had sounded the alarm earlier, nevertheless it’s almost certain that her chances of curative treatment options would have been larger if the cancer was discovered earlier.

Doctors are trained to pick up alarm symptoms. In medicine these are called “red flags“. These are symptoms that indicate the patient might be having a life-threatening or life-altering disease that needs urgent medical attention. In this post I want to share the alarm symptoms for bowel cancer. According to UK statistics, 1 in 15 UK males and 1 in 18 UK females will be diagnosed with bowel cancer in their lifetime. 54% of bowel cancer cases in the UK are preventable (let’s discuss prevention tomorrow). In short, there’s a large chance you, a friend or a family member will get bowel cancer, so it’s good to be aware of the main alarm symptoms for bowel cancer:

  • Unintended weight loss: it’s hard to say exactly how much weight is worrisome. Usually a few kilograms (around 4 or more kg) weight loss becomes a bit suspicious, but it also depends on your baseline weight.
  • An inexplicable sustained change in your stool, such as regular episodes of constipation, diarrhea, or narrowing of the stool, that lasts for more than a few days
  • Having a constant sensation you need to poo despite recently having done a number two
  • Rectal bleeding: immediately alert your doctor if you have had this, even if it has just been 1 episode. There are several causes of rectal bleeding and let your doctor examine whether it’s cancer, haemorrhoids or something else.
  • Black or very (unusual) dark brown stool: this could be an indication of blood in your stool. Usually blood in the stool is even more smelly than a regular poo…
  • Unusual prolonged cramping or belly pain

Some countries provide a national bowel cancer screening programme. If you’re lucky enough for this taking place in your country, it’s important to participate. In this way you increase your chances of detecting or even preventing cancer at an early stage, increasing chances of getting curative treatments.

Let me know if I’ve missed any important alarm symptoms. I’d love to hear from you.

Credits to image creator: Anatomy vector created by brgfx – www.freepik.com

#1 How to be a better patient – an intro

Whilst being a student in medicine and science for more than a decade, I’ve experienced several remarkable situations. Whenever I see a patient, I can’t help but placing myself in their shoes: how would I behave, what would I do, what would I ask the doctor? Very often I find that patients don’t do the things I would have done. Too often I’ve seen patients confused about treatments or not standing up for their own perspective. Obviously it’s not a fair comparison, since the average patient hasn’t received medical training. Nevertheless, I believe with some basic tips and tricks, patients can be empowered and can be more in control of their experiences in medical settings. In this blog post series “How to be a better patient”, I’ll try to discuss the following things:

  • 1. How to communicate more effectively with healthcare providers
  • 2. Which medical alarm symptoms to be aware off
  • 3. How to reduce your risk of disease
  • 4. The pitfalls of modern medicine
  • And much more…

I want to give you a sneak peak into how a medical doctor thinks. If you know how a doctor thinks and how doctors approach a problem, it should become clear how to navigate the healthcare system.

Running a marathon for cancer research!

My mission is to improve care for cancer patients. Cancer research is a corner stone to making this possible. Over the years I myself have been doing research on different types of cancer, such as brain cancer, breast cancer, lung cancer and now liver cancer. However, I haven’t properly participated in raising money for charity and this needed to change. I believe in challenging yourself and voluntarily making yourself suffer, so I came up with an activity that involved something I truly detest… that is running.

The Dutch Cancer Society (called KWF) has a charity run in Rotterdam in April 2022. Of course, I had to sign up for this marathon in my hometown. Unfortunately, that means I’ll need to train in the cold and rain this winter in order to be prepared…

Over the past 2 years many charity events had to be cancelled during the COVID-19 pandemic. As a consequence, funding towards cancer research has taken a hit. That is why your donations will matter even more in the coming months and years. I hope you will be able to support patients in their fight against cancer! Please consider sponsoring me, just visit https://acties.kwf.nl/fundraisers/subramanianvenkatesan/rtm-41 and donate.  

Resistance #1: Senescence as a mechanism to resistance?

Discovery of senescence

This first blog post will be about senescence. Senescence is considered the state in which a cell has permanently stopped to divide. It is a stress response that is distinct from quiescence (= reversible cell cycle arrest), terminal differentiation and contact-inhibition. In 1961 Hayflick and Moorhead discovered that fibroblasts divide around 50 times before they stop to proliferate (1). This so-called “Hayflick limit” was later linked to shortening of telomeres with every cell cycle (2, 3). It was found that not only fibroblasts, but that non-cancerous cells in general across species and tissue origins, have a limited number of divisions after which replicative senescence is initiated (4). This was a groundbreaking discovery, because this means cells can’t divide forever!

Senescence as a barrier, preventing cancer development

Surprisingly, senescence does not only occur when the Hayflick limit is reached and replicative senescence is initiated.  In 1997 the team of Scott Lowe discovered that overactivation of growth signals provided by so-called oncogenes, such as RAS can stop cells from dividing permanently  (5). Their discovery suggested that senescence is not merely activated after a number of cell divisions, but is a protective program, triggered by abnormal levels of cellular growth signals. Around 2005 several labs found that in the stage before transforming into full-blown cancer, many cells are senescent (6, 7). This suggested that our bodies are trying to prevent cancer from developing by catching them into a non-dividing cell state, before it actually develops into full-blown cancer. Unfortunately, this isn’t always successful, and a cancer cell is still able to escape/bypass this mechanism of senescence leading to the development of cancer. Indeed, senescence is highly prevalent in the pre-stages of cancer. Once a cell has become cancerous, it is considered to have unlimited potential to divide, essentially becoming immortal.

Senescence in cancer

Even though cancer cells are considered to have an unlimited capacity for cell division, apparently, some cancers still have the capability to senesce! It appears that some cancers are better in suppressing senescence than other cancers. The question whether cancer cells can escape senescence after becoming senescent is still somewhat controversial, since there’s an ongoing debate about whether senescence is reversible. There is accumulating data that senescence is potentially reversible (8-12).

Senescence as resistance mechanism?

So how does all of this tie into resistance to therapies? It’s been shown that certain cancer treatments can damage cancer cells so much that they stop dividing and senesce, we call this therapy-induced senescence. A whole list of cancer treatments are known to induce senescence. Check out this splendid review by the Gerwitz’s lab for the long list of treatments (13). Recent evidence suggests that senescent cancer cells can make their non-senescent neighbouring cancer cells more aggressive and potentially resistant to cancer therapies (14, 15).

In short, senescence isn’t just a boring state of cells that aren’t dividing. Even the non-dividing cancer cells seem functionally relevant and can’t be ignored. It seems plausible that senescence itself can be a way to generate resistance in cancer cells. The mechanisms through which senescence can drive resistance needs more investigation.

References

(This is not a comprehensive review, simply for education and entertainment, so forgive me if I didn’t refer to your seminal discoveries)

1.         Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585-621. 2.         Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345(6274):458-60. 3.         Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279(5349):349-52. 4.         Röhme D. Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc Natl Acad Sci U S A. 1981;78(8):5009-13. 5.         Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593-602. 6.         Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-7. 7.         Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Senescence in premalignant tumours. Nature. 2005;436(7051):642-. 8.         Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 2003;424(6945):223-8. 9.         Martinez-Zamudio RI, Roux PF, de Freitas J, Robinson L, Dore G, Sun B, et al. AP-1 imprints a reversible transcriptional programme of senescent cells. Nat Cell Biol. 2020;22(7):842-55. 10.       Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003;22(16):4212-22. 11.       Yu Y, Schleich K, Yue B, Ji S, Lohneis P, Kemper K, et al. Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma. Cancer Cell. 2018;33(2):322-36 e8. 12.       Saleh T, Tyutyunyk-Massey L, Gewirtz DA. Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy. Cancer Res. 2019;79(6):1044-6. 13.       Saleh T, Bloukh S, Carpenter VJ, Alwohoush E, Bakeer J, Darwish S, et al. Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy. Cancers (Basel). 2020;12(4). 14.       Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017;7(2):165-76. 15.       Milanovic M, Fan DNY, Belenki D, Dabritz JHM, Zhao Z, Yu Y, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018;553(7686):96-100.

Fear not, plan, adapt, execute and don’t overthink

I made this figure to remind myself what to do whenever anxiety creeps up. Use fear as a cue to regroup through planning and then executing.

My first week as a medical student in the hospital

I wrote this post a long time back (February 2021), but resisted uploading it (grrr the resistance…). That said, I want to write a bit more about my journey in the hospital. Every week I end up in the craziest situations, so writing about it will be a good way to process what happened.

Witnessing a poor lady getting the diagnosis incurable pancreatic cancer, getting shouted at by a delirious patient, and performing a rectal examination were amongst the many adventures during the first week as a medical student in the hospital. As a medical student at Erasmus Medical Center in Rotterdam in The Netherlands, I’ve received 3 years of training on how the human body works. As a medical student you are taught which symptoms are linked to specific diseases, how to extract relevant information from a patient and how to perform physical examination. Nevertheless, when the time finally came to enter the hospital in my 4th year as a medical student, fear and doubt entered my mind.

I was sent to a faraway hospital in the south of The Netherlands. Since it’s a 1.5-hour drive from Rotterdam, I fortunately got allocated a room next to the hospital for 10 weeks. My first clinical rotation is in the internal medicine department. Every week I’m linked to a different doctor and tag along with them. Whenever a new patient is referred by their respective GP, I am allowed to first see them. I question them about the problem, perform the physical examination, discuss my findings with the specialist in the absence of the patient and finally the patient is called in to get the specialist’s opinion. One of the most intense consultations of the week included telling a patient in her 60s that she has got incurable pancreatic cancer (just to be clear, I simply sat beside the medical oncologist who gave the news). Seeing all the frail people in their 60s, 70s and 80s approaching the end of their lives is a strong reminder that time is limited. Even though I easily get carried away by all the minutia, this is a good moment to take some time to look back at my journey and acknowledge no one lives forever. Whether you’re 80 years old, 50 years old, 29 years old (like me) or just born, I’m sorry to say but time is running out. One-third of our lives is gone because of sleeping, what you do with the remaining two-thirds is up to you. We’ve got to spend our time consciously, because we don’t know what tomorrow will bring us. For the most us (including me), the problem isn’t that we don’t have enough, the problem is too often we don’t spend it well…

FAQs about cancer: What is it and why is it so hard to cure?

There’s currently an overload of information online and it’s difficult to figure out what’s true and what’s not. After discussing this topic with friends, family and patients, I thought it would be helpful in this blog to clarify some frequently asked questions surrounding cancer and while I’m at it, I might also debunk a few myths. To bring you up to speed, I will avoid going into too much scientific detail in this first cancer-related blog post. I have to add that as a cancer researcher I always tend to err on the side of caution and don’t like making sweeping statements or conclusions. Let me know if you think this was helpful or whether you’d rather want a different question answered.

What is cancer?

Our body is made out of billions of cells. Usually, these cells are working for us and operate on a ‘biological programme’ that makes them obey certain rules. This biological programme makes sure that cells with too many mistakes stop growing, are flagged up in the body and are cleaned up by our immune system. As we age there’s more time to accumulate mistakes. Normally this isn’t worrying since an excess of mistakes usually triggers the ‘stop growing programme’, preventing a future cancer from ever developing. However, when the perfect combination of mistakes occurs in 1 particular cell, this can damage the ‘stop growing programme’, allowing the cell to keep on growing without a brake. In other words, cancer originates from your own body and (generally) stems from a single cell gone wild that disobeys the checks and balances encoded in its biological programme.

That said, when we talk about cancer, we are actually referring to the whole collection of known cancers that can arise from the many different tissues that are present in a human body. For example, lung cancer has very different properties compared to brain cancer. You can therefore imagine that the different types of cancers arise through different ways (mechanisms) and are therefore often treated differently by medical doctors.

I have to admit this is a very crude explanation, but if it’s helpful, another post can go over this in more detail.

If we can put a man on the moon, why can we still not cure cancer?

The challenge of tackling cancer is to kill the cancer cells without killing the patient. Unfortunately, cancer cells are in many ways, highly similar to our other healthy cells in our body. An additional difficulty is that a cancer exists out of millions of cells that each can be slightly different from each other, creating groups of cancer cells with different properties and sensitivities to cancer treatments. A particular treatment might eradicate a large proportion of the cancer, but that minority of cancer cells resistant to the treatment can grow back and kill the patient. In other words, the cancer evolves according to the treatment, essentially creating a moving target.

There are many specific ways through which a cancer might defy (resist) a particular cancer therapy. Over the decades, cancer researchers have uncovered several hundreds of these different routes to resistance. I’m thinking of writing a bit more about how cancer can become resistant to therapies in several upcoming posts. Stay tuned if that might interest you!  

Note to myself: Setting goals doesn’t work, set systems instead

Setting goals does not work, it just produces frustration. Instead set systems in place in order to succeed.

Conventional wisdom states goal setting helps you stay focused, however if you don’t attain them you have failed. Scott Adams, cartoonist of the Dilbert comic strip and author of “How to fail at almost everything and still win big”, blew my mind when he proposed setting goals is futile, instead he is in favour of setting systems. With systems you aim to acquire the habit of cultivating skills rather than hunting down a specific goal. For example, people who want to become fit (or simply put want six-pack abs), shouldn’t just go to the gym and keep checking whether they are getting closer to that goal. Most people will get discouraged by not seeing a difference after 2, 3 or even 6 weeks and will ultimately give up altogether. Rather, try to cultivate the habit of working out regularly, ideally daily. The difference between systems and goals might be somewhat confusing at first. Scott Adams explains that if you’re waiting to achieve it someday in the future, it’s a goal but if you do something every day, it’s a system. He mentions that many human endeavours can be categorised into goal-oriented or system-oriented thinking. For example, losing 10kg is a goal, but working out every day is a system. Trying to get a promotion is a goal, but aiming to consistently deliver a little bit more than expected is a system.  Trying to ace a test is a goal, but devoting an extra hour in the morning before going to school on understanding the subject is a system. Trying to get a master’s degree or a PhD is a goal, but daily dedicating time on understanding and researching your topic of interest is a system.

In this way, you know what to do, just show up, do the workout and you’ve succeeded for the day. Perhaps after 6 weeks, you will not notice a difference in your body, however it is likely you will have acquired the habit of working out regularly. Eventually, you may add new exercises to the daily workout and who knows one day you’ll actually start to see a difference but remember that’s not the goal. Simply show up every day and follow the system you have set out. Just get started.

The exciting part of setting a system is that you don’t know where it may take you. Several months after diligently following the system, you might actually blow past your initial goal (that you didn’t set). And since you are following the system, you won’t look back and decide to slow down or stop because you reached your goal. The risks of setting a goal is that 1) you fail and get discouraged, 2) you hit the goal and you slow down or stop altogether and 3) you delay your happiness until you reach your goal. In contrast, pursuing your system every day, gives you the instant gratification that you are on the correct path. Let me give an example from my own experience. I believe in challenging myself and voluntarily making yourself suffer. Since I hated running, I decided to run each day, for 30 days, up to Primrose Hill and back which equates to around 5.5km. You could perceive completing a 30-day challenge as setting a goal, however I like to see it as “tricking the brain to start a system.” At the beginning I thought to myself “why am I doing this again?” and really disliked the activity. It was boring and it tired me out. However, after a few days of running I started to research literally “how to run”. I started listening to audiobooks about running and approximately midway the 30-day challenge I thought to myself “perhaps I should run a marathon?”. My initial plan was to just do this annoying 30-day challenge and then never look back on running again. Now 1 month after completing the challenge, I am still running regularly and I’m thinking to myself “why stop at a marathon, 50km sounds like a fun challenge”. I hope this illustrates, setting a goal from the get-go might limit yourself. Not in my wildest dreams, would I have set out to attempt a 50km run. I simply just started to run regularly and afterwards imagination took over. Don’t mistake me setting out to run 50k as my goal, it’s simply another step in the system I have set.

Note to myself: Break the resistance; the battle for creation

Procrastination, fear, self-doubt and much more are all different materialisations of ‘THE RESISTANCE’. Identify it, acknowledge it and defeat it every day.

Art is a battlefield, whatever you consider to be art, it’s a carnage. Bodies all around, wounded people, the hurt, the pain. Yet, here we are not giving up, picking up our weapons, charging to the frontline. Whatever your weapon is, everyone is fighting their own battle. For me it is a pipette, and medicine is my battlefield. Everyone is struggling with their own inner demon, trying to bring their gift to the world. I’ve struggled countless times pushing past doubts and many times I’ve given into it. It feels like there’s an inner fog or force field that is trying to stop me from reaching the next level, fulfilling my potential. I am guessing that if you’re reading this, you’ve felt the same.

Steven Pressfield has given this negative force a name, ‘THE RESISTANCE’. The identification/naming/revealing of this enemy, which has been elusive yet in plain sight at the same time, has been Pressfield’s greatest gift to me. In his book ‘the WAR of ART’, he details how ‘THE RESISTANCE’ keeps us from starting to work on our creation. As one of the great writers of this age, he has almost struggled decades to get his first break as a writer. The reason being is that he stopped himself from even starting. One of the first few pages in ‘the WAR of ART goes as follows: ‘There’s a secret that real writers know that wannabe writers don’t, and the secret is this: It’s not the writing part that’s hard. What’s hard is sitting down to write. What keeps us from sitting down is Resistance.’

I couldn’t agree more, my toughest battle is not to produce the work, the experiment, the article or the presentation. For me the resistance is the strongest when my alarm goes off. Doubt starts creeping in, voices that whisper it won’t make a difference, it doesn’t matter whether you start your day early. Many days ‘THE RESISTANCE’ wins, I snooze for another 30 minutes, maybe an hour. I am guessing that this blog post is an attempt to materialise my inner enemy ‘THE RESISTANCE’ in order to gain an upper hand. I’m honestly sick and tired of this doubt… Pressfield has written 3 books centred on the experience of the artist, namely: the war of art, turning pro and the artist’s journey. The war of art is the first book of this trilogy and it’s by far the most powerful. Every sentence seems to matter in this book, to the point that I want to quote every sentence, unfortunately I’m forced to highlight snippets that have impacted me most. Every time I hit that snooze button, every time I procrastinate by watching a mindless video, ‘THE RESISTANCE’ materializes. Like a devil on my shoulder, it watches my actions, and cheers me on. As Pressfield states, ‘Procrastination is the most common manifestation of Resistance.’

In the first chapter of this book, Pressfield defines our fiercest enemy ‘THE RESISTANCE’. Procrastination is just one materialization of it. ‘THE RESISTANCE’ also masquerades as fear, victimhood, unhappiness, self-doubt, criticism and rationalization of poor decisions. Fortunately, there’s a way out of the grip from ‘THE RESISTANCE’. Pressfield calls this, ‘turning pro’. He describes how the amateur gets defeated by ‘THE RESISTANCE’, whereas the pro defeats his immortal, reincarnating foe day after day. What I’ve experienced is that after I slay ‘THE RESISTANCE’ by starting my day or starting the work I’ve procrastinated, it has been defeated… for the day. Unfortunately, ‘THE RESISTANCE’ in my experience does not weaken. It’s always there lurking behind the corner waiting to pounce whenever you feel weak. I’m sorry if this is not what you wanted to hear. As Pressfield states, ‘the most important thing about art is to work. Nothing else matters except sitting down every day and trying.’ My hope is that reminding myself of the existence and powerful nature of ‘THE RESISTANCE’ allows me to focus my mind to not give in.

My hope for you is that you do the same, either by reading Steven Pressfield’s book ‘the War of Art’ or just even thinking about how ‘THE RESISTANCE’ materializes in your life. Let me finish with Pressfield’s message ‘Creative work is not a selfish act or a bid for attention on the part of the actor. It’s a gift to the world and every being in it. Don’t cheat us of your contribution. Give us what you’ve got.’ In other words don’t give in to ‘THE RESISTANCE’.

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