Nightmares

I'm on medication ... it wakes me up in the early hours and on returning to fitful sleep, I have nightmares.

Last night I dreamt that Kezia's local doctor prescribed a course of Dexamethasone. Visions of relapse and suffering ...

Happy New Year to Friends and Readers!

Dexamethasone Diary

Rob has just posted on what a week on Dexamethasone is like - I couldn't express it better.

Medical Ignorance - T-cells and the Thymus

I have not posted on ALL science for a long time as I thought I had investigated and written about as much as I needed to, that I could understand and that I could try to communicate to others.

I subscribe to the email notification service of BioMed Central for oncology papers. Most are nothing to do with leukaemia but I came across this open-access paper, Gene expression profiling of leukaemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to glucocorticoids, published in November this year.

And I was stunned by a major gap in my ignorance. However, I am also stunned at how recent the science I describe below is.

In the foetus and up to puberty white blood cell T-cell lymphocytes are produced in an organ called the thymus located in the upper chest, not in the bone marrow. In a normally functioning thymus the T-cells are filtered - good from defective, and the defective ones are killed off (apoptosis). Not until 1961 was the importance of the thymus realised - previously a thymus would be surgically removed with a resulting loss of lymphocytes and immunity!

When the T-cell precursors are in the thymus, forming an integral part of its structure, they are known as thymocytes.

The T-cells migrate to other organs (principally the spleen, lymph nodes and bone marrow) and the blood. Gradually, T-cell reproduction is, at puberty, transferred from the thymus to the bone marrow, lymph nodes and spleen and the thymus gradually becomes a redundant mass of fatty tissue.

In childhood T-cell Acute Lymphoblastic Leukaemia the thymus is pushing out loads of T-cell lymphocyte precursors (or as they are referred to in science, progenitors) known as lymphoblasts, not mature T-cell lymphocytes. This is the key to diagnosis - levels of lymphoblasts in the blood and bone marrow.

However, it is seemingly not the fault of the thymus.

The progenitors of the lymphoblasts and lymphocytes are stem cells produced in the bone marrow. Stem cells come in a variety of flavours. Our famous embryonic stem cells can differentiate into whatever part of the body they like - heart, liver, kidney, skin etc. Then they become body-part specific stem cells but some are seemingly multifuctional (interesting research was announced on Friday into using skin stem cells to cure the blood disorder Sickle Cell Anaemia).

Some become blood (hematopoietic) stem cells - those destined to become B-cell lymphocytes stay in the bone marrow, and those to be metamorphosised into T-cell lymphocytes find their way by blood to the Thymus.

Recent research into the roll of leukaemic stem cells (and when I say recent I mean this decade) has been focussed on Acute Myeloblastic Leukaemia rather than B or T-cell Lymphoblastic Leukaemia but malformed stem cells do seem to be the "culprit" in all leukaemias.

Genetically-malformed hematopoetic stem cells cannot be processed into full-blown T-cell lymphocytes but remain as T-cell lymphoblasts. It would seem that the thymus is unable to distinguish between good and bad stem cells, the progenitors, but can distinguish between good and bad product derived from good raw material. If it receives bad raw material and produces excess lymphoblasts, it won't kill off the bad cells.

At the end of the day the thymus (a factory) is pretty dumb!

The leukaemic stem cells are apparently not very receptive to chemotherapy drugs.

So I will worry.

P.S. Obviously, and as always, this is a lay-person's explanation in both its writing and its reading - if any of my science is erroneous or just slightly "fucked up", then please correct me either through the Comments or by email.

I'll try and get on to Dexamethasone and thymocytes in our next scientific post - hopefully, before I go back to the UK for Christmas.

Tantrum

Dexamethasone

Random Musings

Driving home from work today, I dwelled on the pain Kezia must go through on these bad bad bad Dexamethasone trips. Four days a month for the remaining year of treatment. Kezia and Nanda went to town today – Kezia loves going on the bus, but they didn’t get very far before Kezia said “Nanda, Kezia doesn’t feel good” and they went home … but not before buying her a (toy) mobile phone on which she apparently phoned me and roundly chastised me! For what I don’t know.

Nanda and I talked about how she is beginning to verbalise her pain which makes it a bit easier for Nanda and Jaime to respond appropriately.

I cannot bear to think about these dex trips but must. Kezia, Nanda and Jaime must live with it.

Nanda and Kezia saw Lucia and her mum at the hospital in Tuesday. It was Lucia’s first off-treatment appointment and she’s doing well (as she writes here). Nanda showed Lucia and her mum a photo of our house here. And Nanda saw a photo of YOBS with our consultant John and wants me to take a photo of Kezia with John (and I think we should include Teresa, our social-worker) as well - to show family here and for Kezia to remember.

Travel plans – I hope to spend two weeks with them from the middle of October. I am on a waiting list. The once-weekly direct flight to Europe is fully-booked for six weeks. L. at our local travel agency has assured me she has got me put at the top of the waiting list. A new passport arrived today after four months and six countries! Today I took the precaution of reserving a Xmas/New Year visit as the plane will be packed on the 22 December – L. has told me reservations are already being made.

During the last few days a wonderful perfume has surrounded the house, especially at dusk – the coffee flowered, orange and tangerine blossom …

Work is going well this week – I managed to get a computer we are donating to the local radio and running Linux connected to their broadband link. They had the cabling between two network switches fucked up.

So onto a techie post …

Small Steps

Yesterday the Macmillan nurse visited Kezia´s school (from September) to discuss her special needs with her future teacher (who just happens to be Jaime´s teacher this year – quite happy with this continuity – Gill already knows us, has met Kezia and knows of our situation). We are happy her Hickman Line is out, one less worry at school for both ourselves and Gill.

I do wonder though how Gill is meant to distinguish between and/or react to drug-induced bad moods or misbehaviour versus general childhood petulance. Kezia hits the kid next to her, steals his/her snack or goes into a corner and won´t talk and/or cries. I am sure Gill will be amazing as she deals with kids every day … but absent dad could do with some reassurance please!

On Thursday there is an “open day”, or rather hour, for September´s intake – a kind of familiarisation exercise, I guess, to help avoid tearful scenes on the first day of school. I don´t think this will be a problem with Kezia – at the moment she is impatient to start - “if Jaime can go to school, why can´t I?”. And I know Nanda is talking it up …

Kezia didn´t want to speak to me yesterday – she finished five days of Dexamethasone on Sunday and is moody. Lucia has often related how dreadful this drug is, has had to go on morphine due to the pain it caused so I can only wonder what Kezia feels especially with no means of verbalising it.

Last week´s medical blogosphere “event” seems to have been the bombing attempts in the U.K. by, at least, two NHS doctors (the other suspects, I should stress, innocent until proven guilty). NHS Blog Doctor´s very sensible post on the subject whipped up 97 comments – with particularly bigoted comments from someone called “american md”, I posted two or three of my own in reaction and whipped up Lucia´s support – the dedicated staff (Muslim or otherwise) of the Royal Manchester Children´s Hospital and the NHS must not be subjected to such abuse. I am happy to see that Dr. Crippen posted her comment in his weekly BritMeds.

However, judging by the BBC´s website (ok, it is not necessarily representative ..,), the issue seems to have dropped off the map. There was one headline (non-) piece in the Asia/Pacific section Monday about ongoing investigations in Australia, there was nothing in the U.K. section. Are the government and police not giving press statements and keeping mum or are we so used to terrorist attacks in the UK (international readers, remember what we went through with the Northern Ireland troubles) that non-successful attempts are no longer news?

And, blimey, no-one commented on my own post on the subject – the price of non-fame?

Penultimately, I will point you to two posts by bush doctor in the city about a kid in the Delta region of Nigeria with Burkitt's Lymphoma (here and here). This is what the AfrOx Project is about – don´t just throw emergency aid at healthcare in Africa or Asia but help us develop healthcare systems. Given the state of the NHS and US healthcare, perhaps you´re not so good at that …

Finally, congratulations are due to both Lucia and Fergus (Lauren and Rob´s son) for finishing chemotherapy. I don´t have a deity but will pray the other shoe doesn´t drop. In many ways this could be the most difficult stage – watching, waiting, lingering.

Please don't stop blogging - you are messages of hope for those of us behind you. Lauren and Rob - the photos of Fergus' last chemo and lumber puncture are both inspirational and useful (... and why didn't any of us think about this before?!). Thank you for sharing them.

Dexamethasone Trips

I have arrived in the middle of one.

When I arrived at Chritsmas, Kezia was at first a little shy and reticent of me - perhaps not surprising given my absence from her life. This time she has welcomed me with open arms- to the extent she walked to the shop and back with me, wanted me to accompany her in her siesta and sleep next to her in the night. She has wanted lots of cuddles and physical affection from me. Within all this she has been generally good with just a couple of sobbing, but not tantrum, episodes.

Such intellectual changes. Language coming on fast - a mixture of both languages. Jaime is teaching her alot of the English he is learning from school. But also the first signs of "thinking" - looking and considering me - I ask "Are you thinking?" she nods her head, "What are you thinking about?" she continues to consider me silently.

Growing up high on Dexamethasone.

What reality poor child are you going through? What trip is this?

P.S. Lauren reports that Fergus also gets "clingy and emotional" on Dexamethasone (see Fergus Times - link on right).

UKALL 2003 - Dexamethasone 2

I've refrained from tackling this until now as I really didn't understand even a twinkling of the science behind Dexamethasone's anti-cancer properties. After much reading I discover that not even the scientists fully understand the mechanisms.

In my last post on Dexamethasone I attempted to explain its anti-emetic (nausea, vomiting) properties. However, talking to our consultant J. over the holidays, it seems the justification for its use in the treatment of leukaemia is its anti-cancer properties – the anti-emetic effects are a beneficial side-effect.

Right, I'll try and explain what is known about its anti-cancer properties. There appear to be several mechanisms at work:

• It appears to trigger programmed cell death (apoptosis). Both good and leukaemic cells.

• They inhibit the production of interleukins which are signalling chemicals which stimulate a variety of cell behaviours. The IL-2 interleukin (there are 33 of them) is produced by T-lymphocytes. The IL-2 then binds itself to the T-lymphocyte signalling it to grow and differentiate. (This self-signalling is termed autocrine). Clearly, inhibiting the production of leukaemic T-cells (or T-cell blastogenesis) is one of our goals.

• It can also (seemingly) increase the ability other chemotherapy drugs to destroy leukaemic cells

It can also prevent white blood cells from reaching sites of infection. Hence (as with most chemotherapy drugs) there is an increased risk of infection when taking it. Strangely, as the WBCs cannot reach the infection, the white blood count may be seen to go up.

I should also add that one of the lesser known and rarer side effects of the glucocortisoids is induced diabetes - this is what H. suffered from - she got over it but insulin injections in the stomach were no fun. I guess no more dexamethasone for her!

Next in the series is Cytarabine - this is kind of cool!

Update: in the comments Lucia also reports having suffered from diabetes so they have switched her to prednisone.

UKALL 2003 - Dexamethasone 1

As previously mentioned the gluco-corticoid, (a steroid), Dexamethasone has two roles in ALL treatment. The first of these, to combat the side-effect of nausea caused by the anthracyclines. I'll discuss now, and leave its other role until a later date (when I understand it!).

Nausea and vomiting (known as emesis) are controlled in part of the brain known as ... the Vomiting Centre (not often that medical jargon is this straightforward!). The anthracyclines stimulate the production of a chemical called Serotonin (or more correctly 5-HT) in the gut. This Serotonin then binds to and stimulates the vagus nerve which in turn stimulates the spinal cord and the chemo-receptors. There are many types of these receptors sensitive to different chemical compounds and seven of them are sensitive to Serotonin. The one that stimulates the Vomit Centre is known as 5-HT₃.

So if we can successfully block, desensitise or turn off the 5-HT₃ receptor, then we can stop the nausea – and this is what Dexamethasone (as an anti-emetic) does.

Unfortunately, it has its own side-effects such as increased appetite (Kezia put on weight!), sleeplessness and mood swings.

Kezia definitely suffered from mood swings. I sometimes think it is easier for an older person to rationalise these – I'm grumpy (or as Cass of Cancergiggles calls it – Irritable Bastard Syndrome) but it's due to the medication. Kezia cannot do this and does not understand why she is upset, which must be distressing in itself.

However, there's a downside to the ability for rationalisation that comes with age. Kezia does not understand ALL, cannot imagine her own mortality or the battles still to come. She lives from day to day, oblivious to such feelings – if one day she is down, the next will be happy, not remembering yesterday. For this, we must be grateful.