Monday, April 13, 2015

Author Manuscripts - clarification of PLoS Comp Biol's policy

Just a quick post. I and some colleagues recently submitted one of our papers "Steering Evolution with Combination Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance" (which you can read a nice post on +Artem Kaznatcheev's blog here) to PLoS Computational Biology, and I was surprised that an option to submit a full 'author manuscript' wasn't present, but instead that we had to upload images separately, reformat and the like.  This surprised me, because the first time I submitted there, in a paper I wrote with +David Basanta and +Alexander Anderson I didn't remember having to do this. It might be that I just misread, but at the time I was confused.

So, I tweeted to them a quick question and it turns out they DO accept author manuscripts, but that their instructions are on the fritz right now!  

Anyways, they replied quickly with an email as well stating:

We allow a single PDF to be submitted at initial submission, although as the paper is subsequently revised, we require the manuscript to be submitted in separate parts to begin to prepare the manuscript for production. This is to avoid asking authors to do everything at once at acceptance, a process that can, in some instances, be a substantial task.
I understand that this is not clear on the author instructions and we are looking at ways of improving our instructions.

So - submit away. And, thank for the quick reply to PLoS CB... now it's just fingers crossed for our submission.

Wednesday, April 1, 2015

Healing Art of Pathology

Many apologies for the long delay in writing, residency training has been weighing heavily on my creative time - but this is coming to an end! In the realm of more good news, on July 1st I will assume the post of Clinical Instructor here at the Moffitt Cancer Center, concentrating my efforts on taking care of patients with sarcoma using radiation for one day per week. The balance of my time will be spent finishing my DPhil and pursuing the clinician-scientist track - a balance I hope to maintain for the rest of my career (life?).

Dendritic Swarm.

My relationship with the Sarcoma department here has been a very good one, and one that has transcended simply training and patient care. Immediately before I left for Oxford, my neighbor and friend +Ray Paul came to my house and asked me to feel a lump on his side...

It turned out that Ray had a myxofibrosarcoma, and a nasty one at that. Honestly, things looked pretty bleak for a while, but now, after 4 surgeries (flank, thigh, and two in the lung), two bouts of radiation therapy (flank and thigh), two clinical trials (immunotherapy and a novel tyrosine kinase inhibitor) he is NED - nearly 4 years later. Incredible, and wonderful.

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Much of Ray's story can be read on a previous post of mine on the +TEDMED  blog that discusses the healing power that Ray's own art had for him (updated here). A project he began, called My Sarcoma, during which Ray painted over the top of his OWN histology images, transformed Ray from a sick and dying patient back into a living and vibrant artist. Watching and participating was a real honor. This culminated in a beautiful opening of his art at Moffitt which received both local news attention and a national story shared with another Moffitt patient Michelle Boyd DeJong on the healing power of creativity.

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Each of the paintings that Ray has made during this journey has had more than just Ray's hands involved. Indeed, to make the paintings as you see them, a surgeon had to cut out his tumor, a pathologist had to stain and mount the tissue and a screen printer had to prepare the canvas. As an offshoot of this collaboration, our Sarcoma pathologist, Marilyn Bui, and Ray continued to talk and brainstorm, and a new project was born, a book entitled Healing Art of Pathology.

SP12-6796 x 40 - 2

Sponsored by the College of American Pathologists, this book will be a compilation of art derived from, or inspired by, pathology - the study of disease. They are seeking submissions now, with a deadline of September 1st from the art and medical world (including patients) the world over. More details can be found in the attached letter.

"Please send all submissions and/or address any questions to Caryn Tursky, CAP Press Acquisitions and  Development Editor, at by September 1, 2015. Please make the subject of the email “Healing Art Submission.”"

SP12-6796 x 20
Ray's project, My Sarcoma, featured here can be seen as well on his website

Friday, November 14, 2014

Mathematical Oncology: an introduction given at a Moffitt Cancer Center Radiation Oncology CME conference

Today at Moffitt Cancer Center I'm giving a short talk about Mathematical Oncology for a continuing medical education aimed at medical physicists and dosimetrists - though I think the talk is available to most folks with an interest in science and maths. It's a short talk (30 minutes) in which I hope to introduce the field, show some of the tools we use, and give a short example or two. I feel that this audience, in particular, is important to address because they have the skills needed to think like modellers, and work in cancer EVERY DAY.

My hope is to spread awareness of mathematical oncology, but also to lure some clever folks across the street from the clinic to the laboratory!

There are a host of great talks going on, many of which have their slides on line (I've been told) on topics as broad as #proton therapy, #StereotacticBodyRadiation, #cyberknife, #radiation toxicity, #HIV and cancer and more.

A full agenda can be seen here:

And here's my talk.

Tuesday, October 7, 2014

I see flowers & I think of metastasis: or how theoretical oncology has reshaped all of my thinking

I try to reserve weekends (or at least the hours of 8am to 8pm on the weekends) for time with my kids. I've got a little boy named Rhys, who is just now starting to learn language (he's about 18 months ago, really fun age) and a precocious little girl named Maren who is five and a half. I grew up either in a house full of books or out in the woods - my mom is a librarian and gardener and my dad is an English teacher, novelist and outdoorsman. Given this background, it is no wonder I still pay double most of my friend when I move because of the sheer weight of books my wife and I carry around, and also that I continue to love being outside.

My kids however, have a mom who was an occupational therapist and is now a photographer (gorgeous pics of our kids and other stuff on her page) and a dad who is a theoretical oncologist. So it shouldn't be surprising that my daughter doesn't mind a little gore, indeed she likes watching necropsies (thanks #thebrainscoop)

a Tweet which actually ended up in an article about Dana Scully from the #xfiles, Emilie Graslie from #thebrainscoop and the girl from the #BigBangTheory which you can read here:

and that we spend more time looking at Netter's anatomy book than almost anything else.  A few weeks ago, we busted out my microscope from medical school and I ordered a cool set of slides of amphibian and fish anatomy. She spent a few hours just fascinated and has subsequently asked to look at a ton of stuff under the scope (blue jay feathers are really fun - try it with the light from below, and then turn off the light and shine a light from above... great lesson on refraction).

That's her doing her best Ramon y Cajal impression on the left, and a tadpole stained (with H&E?) on the right. So, anyways, last weekend, we were trying to figure out what to do while her brother took a nap, and decided to see what we could see in the tanks of some of the bromeliads at the end of our street. We had watched a great David Attenborough documentary (oh yeah, they're pen pals)
in which we learned that lots of micro-animals can live in bromeliad tanks.

Neither of us could have been happier, however, than when we saw this little beauty under the scope (or, I should say \mathcal{O}(100) of them)

I turned immediate to twitter to ask my friends what it was, and was immediately told it was an #ostracod, most likely Elpidia bromeliarium. I dug a little more into it and there is actually only one species of these described in Florida, and many new species are found all the time (most recently in the Honduran cloud forest - just last year!). So, needless to say we are pretty excited about the possibility of having found a new species.

What really got me going though, was the question of how these things get around?! There is only the one stand of bromeliads in my whole neighbourhood, and these little crustaceans can't move purposefully outside of even the tank they start in! Here is an early description of them I found from a journal in the 50s:

Then, on the same day, someone tweeted about a new computational study of 'jump dispersal' vs. 'rafting' a mechanisms for animals/plants to move over large distances (from island to island, say) and I started thinking about the problem of metastatic disease. When animals or plants 'raft' from one place to another (this is often called Oceanic dispersal as well), they are often swept from river banks with a hunk of vegetation or soil, and often more than one animal (especially for sexually reproducing creatures this is very important). I remember a PNAS paper in which the researchers (using a totally medieval experimental technique where they sewed two mice together - seriously) found that many successful metastases brought their own soil with them (in this case non-cancerous cells to support the metastatic seeds).

Taken from:
There is more and more literature these days suggesting that it is clumps of circulating tumour cells that cause metastasis, not single cells (also a nice paper from my friend and collaborator, Peter Kuhn - lab page here). These clumps seem analogous to me to the rafts that other species might use, and could even be formed in the same way - in tumour associated mosaic vessels - there could certainly be a 'sweeping off' of a large clump of cells. If one disturbs the smoothness of a healthy vessel wall, there will be a disturbance in the otherwise (pretty close to) laminar flow and eddys will form and severely change the stress profile in the flowing fluid, creating a situation in which a chunk of cells could easily break free.

If true, this *sort of* obviates some of the modelling efforts that +Philip Gerlee and I (and others) have done considering the fate of single cells, but that work could certainly be reparameterised to consider the shedding rate of these clumps. My hypothesis would be that the results are quite similar, as the shedding rate would go down, but the chance of colonisation (given a clump landing somewhere) would be much higher.

Some other issues, like the Allee effect, could be overcome by this. Further, it offers some different ideas about therapeutics/preventatives. I wonder, for example, if there is any data on (non-liver) metastases in patients with Greenfield filters with colorectal cancer?

As for the little Elpidia - I found a cool study that shows, as +Benjamin Werner suggested, that they can survive in the guts of a number of creatures, so that's probably how they get around...

Anyways... ostracods, cancer, discuss.

n.b. there has been some interesting discussion on this thread already from a shorter post here:

Monday, October 6, 2014

Memantine and WBRT

After the whole brain radiation review that my collaborators and I just published came out, my friend and colleague, Jack West, put a nice post up on his website Cancer Grace about it and asked a follow up question on twitter:

He was referring to the recent Radiation Therapy Oncology Group's trial of memantine (a drug for dementia) given during whole brain radiation: RTOG0614.  So, to answer, I polled a couple of my friends who do nothing but neuro-oncology and reread the results of the trial (not out in published form yet, just as an abstract (paper #1 on this page) and the full talk from ASTRO).

As a quick summary: Whole brain radiation therapy (WBRT) is a treatment given to patients who have metastatic cancer in their brains.  There are a number of situations in which WBRT is given and it improves survival and significantly improves the life of patients.  On the downside, it has been shown to cause cognitive decline with as many as 60% of patients exhibiting measurable decline at 4 months after WBRT.  So, to combat this, a trial of memantine during and immediately after WBRT, an NMDA-receptor blocker used to treat Alzheimer's dementia was proposed and carried out.

In this trial, about 500 patients were enrolled, stratified by their RTOG brain metastasis RPA class (they only enrolled class 1 and 2 patients) and given either 20mg of memantine or placebo daily for 24 weeks.  A lot of their patients weren't able to be properly analyzed because of issues with survival (sadly, to be expected in this population), but those who were evaluable (~150) took a battery of 6 different cognitive tests.  The primary endpoint was performance on a specific test at the 24 week point, the e Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) and there was NOT a significant difference in the results of this (but it 'teetered on the edge of significance', with a p-value of 0.059).  Now, don't get me started on p-values.  Oops, too late.

The all holy p<0.05 is an arbitrary cutoff level by which we determine 'significance'.  I say again, arbitrary.  What it has become, I fear, is a gold-standard for a 'positive study'.  So in the case of this one, which technically did not meet its primary end point, many people are not swayed, because p wasn't less than or equal to 0.05.  the secondary endpoint, cognitive decline (a measure using several other of the tests) was met with p=0.01 and, crucially, there were no difference in side effects or survival. My *suspicion* is that the primary endpoint will be met if they can accrue (and analyze) another 50 patients, and this debate will end. However, until then, the jury is out.

Personally though, even though it failed to meet its primary end point, I will be recommending memantine to patients in a favorable RPA class getting WBRT, or at the very least having this discussion with my patient.

As an aside, the two Neuro specialists I polled had opposite answers, so it is fair to say that this remains in the undetermined category. But, the drug has been shown to be safe, and now *likely* efficacious. In a situation where we don't have other options, I'm sold.

Saturday, August 30, 2014

A new lymph node station in lung cancer?

Earlier this week in our morning didactics session we had an interesting discussion about advanced stage non-small cell lung cancer (NSCLC). Now, there is certainly a LOT to discuss about advanced stage NSCLC, and there is a lot of uncertainty in how to treat it with the multitude of new targetted agents coming on the market for mutations like ALK, KRAS, N-RAS, BRAF, EGFR, etc...  and the trials that have been run are often difficult to interpret because of changes in standard of care, stage migration due to novel imaging modalities (PET) and other things.

To add to all the uncertainty in treatment, the staging guidelines (AJCC in this case) can change. When I started my residency in 2009, we were on the 6th edition, and now it's the 7th. While the changes are usually small, they matter, because the trials that are now having results reported were often stratified using earlier editions of the staging guidelines, once again clouding the picture for patients needing treatment decisions today.

One thing that hasn't changed, and never will (?) however, is the location of nodal stations. Right? Maybe not! As a refresher, we care about a number of nodal stations when staging lung cancer. Here is the picture we all know and love (also available from the AJCC in poster form here):

Please direct your attention to the lymph node station labelled #7 - this is the sub-carinal station, and one that is often involved, and often biopsied because of the relative ease of access (bronchoscopically). Notice it is, by definition N2. However, it is also considered mediastinal. 

Now, this is all well and good, until you have a patient present, as we did at our cancer center several weeks ago with a Left sided T2 NSCLC with station 7 involved TO THE RIGHT OF MIDLINE. We went through the imaging carefully, it was NOT station 8R, it was station 7, creeping down and crossing midline to the RIGHT.

So, now the patient has, by one definition, T2N2 disease (there were no other contralateral nodes or other nodes to make him N3) by virtue of his involvement of station 7. HOWEVER, he could also have T2N3 disease by virtue of having contralateral mediastinal involvement! This is not a trivial difference as it is the difference between IIIA and IIIB, resectable and unresectable.

What to do? Well, he had poor performance status, so surgery was out either way, so we opted or combined, definitive chemo-radiation. However, this uncertainly raise the possibility of a need for more detail in the staging system. Sort of in jest, we proposed a change for the 8th edition - maybe we should have a station 7.5R/L dichotomy for significant involvement, or possibly a 7C/R/L trichotomy?

Saturday, August 2, 2014

Re-entry into the clinic and my first evolution paper!

Sorry for the long radio silence - I re-entered my residency after a 3 year hiatus to pursue full time research and things have been busier than anticipated. While I am on a light rotation (sarcoma), which requires only 50% of my time actually in clinic, I had forgotten what being a #resident is like, and more importantly, what having a pager is like!!!

My personal research efforts have slowed somewhat - with my efforts now divided between the clinic, being a dad and thesis writing. I've changed my focus to writing up what I have currently, rather than chasing after new results, so I haven't much to report. A student I'm working with, however, +Daniel Nichol , recently finished up a paper that he and I have been working on for some time. He is going to write a full blog post about the work, but this will take some time. In the mean time, I thought I'd at least let the community know we've finally submitted our paper to the +bioRxiv Preprints site, as well as a journal (contemporaneously), which you can find here:

In this paper, my first personal foray in theoretical #evolution we build on theory from some exciting theoretical and experimental papers from Steven Weinreich (Weinreich et al. Science) and +Jeff Gore (Tan et al. PRL) to explore the concept of 'steering' evolution as a method of preventing the emergence of resistant strains of bacteria (or cancer!).

I look forward to putting Dan's proper post up, but until then, enjoy the #preprint - we welcome comments!

We were flattered, as well, to see another blog pick up our preprint - yet another reason to use the bioRxiv or arXiv!