Archive for June, 2013
28 June 2013
Lately I’ve been reading up on circulating tumor cells: cells that are from the tumor(s) of a cancer patient that wind up in the blood. For instance: a breast cancer patient might have cells in the blood that originated from normal cells lining milk ducts in the breast, that evolved into a breast tumor, that then escaped the tumor to reach the bloodstream. These cells are the seeds of the most malicious and crippling part of the disease: metastasis.
It’s been widely estimated that 90% of cancer mortality comes from metastases, not necessarily the primary tumor (1) and it’s been known since the late 19th century that surgical interventions are much more successful at curing patients when the tumor is intact and in one place (2).
The image to right is a PET scan of a 46 year old woman with malignant melanoma. Dark regions (minus the bladder) are regions of tumor burden, and most of it are metastases. There are tumors in her lungs, skin, liver, speen, and many lymph nodes. For a moment, try to imagine being a surgeon tasked with removing as many as possible with your scalpel…
Disseminated cancer is very hard to treat; it’s a moving target in the most literal sense. HOW it spreads has been a preoccupation of mine for the better part of a decade. If it were possible to stop the advance of cancer spread in a patient, it might be possible to make cancer a chronic condition rather than a death sentence.
Circulating tumor cells (CTC’s) are the seeds of cancer in the wind: the spores of malignancy.
In one milliliter of blood (about the volume up to the first joint of a human pinky) there are roughly 9 billion (9,000,000,000) red blood cells. (source) In contrast, in advanced cancer patients there might be one CTC in that volume.
Astonishingly, there are technologies that can detect these rare cells with great accuracy. In a seminal paper in 2004, Allard et al demonstrated a re-capture rate of more than 90% when blood from healthy volunteers was spiked with known quantities of cancer cells (3). These technologies have been refined to the point that it is now possible to characterize individual CTC’s (4, 5)
The number of CTC’s gives a strong proxy for prognosis, with the field setting a threshold of 5 CTC’s per 7.5ml of blood as a negative prognostic factor for survival (4, 6, 7). In contrast, healthy volunteers seldom had cells that were captured as CTC’s, indicating a low false positive rate.
Such information could be very useful in the clinic, and number of CTC’s have been demonstrated in patients to predict cancer recurrence and drug resistance too (5). It may be possible to use CTC counts as a biomarker for tumor burden in general.
Despite their rare nature, the number of CTC’s that form tumors is extremely low. Most of the seeds do not survive and form new tumors. Even if a patient only has 5 CTC’s per 7.5ml of blood, that would reflect a moment in time where more than 3000 CTC’s were present in a patient. As would be conceptually predicted for cells not adapted to the sheer forces of the circulatory system, it was interesting to read about shards and pieces of CTC’s being detected as well in cancer patients (3).
Molecular analysis of CTC’s revealed a large heterogeneity in gene expression between individual CTC’s in the same patient (4). While this is somewhat daunting from a targeted therapy standpoint, the coming age of cheap genetic sequencing might enable us to view a macro scale of gene expression and correlation to patient survival in large populations. Such insights might make it possible to specifically target the dangerous CTC’s in the blood, and destroy the seeds in transit before they form metastases.
Based off the available information, it appears that CTC’s might be useful for tracking the disease progression of cancer patients. Genetic profiling of these cells with emerging technologies might give intimate glimpses into the basic biology of cancer spread. However, the amount of blood needed (7.5ml) and the fragile nature of blood outside the body makes me doubt its efficacy for early detection of cancer. Nonetheless, I will be following developments in this field with great interest.
1. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006 Nov 17;127(4):679-95. PubMed PMID: 17110329. Epub 2006/11/18. eng.
2. Mukherjee, S. The Emperor of all Maladies. 2010.
3. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Oct 15;10(20):6897-904. PubMed PMID: 15501967. Epub 2004/10/27. eng.
4. Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PloS one. 2012;7(5):e33788. PubMed PMID: 22586443. Pubmed Central PMCID: PMC3346739. Epub 2012/05/16. eng.
5. Marchesi V. Breast cancer: Epithelial-mesenchymal transitions in human breast cancer samples. Nature reviews Clinical oncology. 2013 Apr;10(4):184. PubMed PMID: 23419957. Epub 2013/02/20. eng.
6. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England journal of medicine. 2004 Aug 19;351(8):781-91. PubMed PMID: 15317891. Epub 2004/08/20. eng.
7. Liu MC, Shields PG, Warren RD, Cohen P, Wilkinson M, Ottaviano YL, et al. Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Nov 1;27(31):5153-9. PubMed PMID: 19752342. Epub 2009/09/16. eng.
24 June 2013
I recently came across something I rarely see in the medical literature: a review systematically dismissing a popular treatment for cancer. Actually, it’s not a cancer treatment per se, but something marketed to many cancer patients who are desperate for any form of pain relief.
Pain is a big deal. For my readers that are currently in good health, please recall the deep, jarring feeling of a broken bone, root canal, or worst headache. The type of pain that makes even the most simple tasks difficult. The type of pain eloquently portrayed by Edvard Much in his 1893 painting “The Scream”
For cancer patients, the pain can be unrelenting. It comes from various aspects of the disease, but for an example please envision a tree root slowly growing over time that cracks the solid concrete of a sidewalk. This is what metastases to the bone can do to cancer patients: literally break their bones from the inside out. Patients I’ve talked to describe it as utterly unrelenting. Although we and other groups are working to stop this process in the first place, one cannot look past the critical role played by pain medication for dramatically improving the condition of those currently battling the disease.
The late 19th and 20th century saw a revolution in pain treatment brought on by a combination of discovery, medical chemistry, and rigid application of the scientific method. Namely, clinical trials with control arms to asses, on average, how well treatments work for many people compared to those that receive no therapy, but are under the impression of receiving therapy, like a sugar pill instead of an experimental pain medication. These experiments (clinical trials) give a good proxy to predict how well a therapy will work for an individual. Through this process it’s possible to determine how well a therapy works, in what circumstances it works, and asses side effects.
In this respect, acupuncture has failed miserably. In an article “Acupuncture is Theatrical Placebo” in the journal Anesthesia and Analgesia, Dr. David Colquhoun and Dr. Steven Novella survey almost 3,000 clinical trials evaluating the efficacy of acupuncture. It’s a relatively short read and I highly recommend giving it a look if you or anyone you know has even the remotest inkling to use acupuncture to treat chronic pain.
I will use a few illustrative quotes nontheless:
“Large multicenter clinical trials conducted in Germany (references 7–10) and the United States (reference 11) consistently revealed that verum (or true) acupuncture and sham acupuncture treatments are no different in decreasing pain levels across multiple chronic pain disorders: migraine, tension headache, low back pain, and osteoarthritis of the knee.”
This point here deserves special attention. What would be a proper placebo control for acupuncture? Surely just about anyone would notice is someone pushed needles into their skin. The best controlled studies tested “proper” acupuncture, where the needles were inserted to key regions associated with traditional chinese medicine, and “sham” acupuncture, where needles were inserted to regions slightly off, or wholly off target. The patient would likely not be able to tell the difference, and would be under the impression of receiving “proper” treatment under both conditions. Under these conditions, both “sham” and “proper” acupuncture are equally consistently ineffective at combating chronic pain.
“The best controlled studies show a clear pattern, with acupuncture the outcome does not depend on needle location or even needle insertion. Since these variables are those that define acupuncture, the only sensible conclusion is that acupuncture does not work. Everything else is the expected noise of clinical trials, and this noise seems particularly high with acupuncture research. The most parsimonious conclusion is that with acupuncture there is no signal, only noise.”
Again, I was initially attracted to this article because of its no-nonsense title and tone. But even I was shocked at the magnitude of clinical trials that had been performed on acupuncture (roughly 3000) and the number of resounding “successes” (few) and the frequency of blatant internal bias and conflict of interest in the positive trials (frequent).
I recognize that the absence of disease is not health, and there is real value to improving the lives of cancer patients beyond medicine. For this reason I think that counseling, meditation, massage, and even acupuncture could have their place (if one likes the idea of having needles stuck into them. To each their own…) Even if it doesn’t help a patient live longer, there is no reason why one cannot take action to make their lives better.
That said, acupuncture is not medicine. Not for the pain of cancer. Even if we were to believe the few positive trials and discount the sea of failures, acupuncture would be the equivalent of using a garden hose to fight a house fire. Morphine and other opiates have gone through rigorous clinical trials very favorably and are currently used as first-line pain treatment. They are by no means perfect, but they are some of the best that we have at the moment. For those unfortunate souls that have pain too great for our current best pain killers, acupuncture is at best a distraction and at worst a monetary drain on already stretched families of those fighting cancer.
My last comment before signing off today is one of caution: beware of “alternative,” “hollistic,” or “complementary” medicine. These are terms used for medicine that has not, or can not be shown to work in controlled clinical trials. I.e. when subjected to actual processes of science. The authors’ tones were slightly more stern than mine:
“The argument that acupuncture is somehow more holistic, or more patient-centered, than medicine seems to us to be a red herring. All good doctors are empathetic and patient-centered. The idea that empathy is restricted to those who practice unscientific medicine seems both condescending to doctors, and it verges on an admission that empathy is all that alternative treatments have to offer.”
I will also note that “holistic medicine” or “alternative medicine” that is tested with clinical trials and shown to work repeatedly is usually referred to as “medicine.” “Medicine” that has been accepted without clinical trials (like radical masectomy or bleeding leeches) that is then subjected to clinical trials, and fails, is not considered “medicine” any longer.
5 June 2013
Within the span of one hour this morning I received news of not one, but two publications, including my first primary author paper! The publication of a primary author paper (meaning one lead the study) after peer review is a pivotal moment in the career of a scientist. Today is that day for me; I have received notice that my paper has successfully gone through rigorous peer review and has been accepted for publication.
“Src Inducible Association of CrkL with Procaspase-8 Promotes Cell Migration” has been accepted to Cell Adhesion and Migration and will be available on PubMed in a few weeks. In this study, we expand upon a mechanism by which Caspase-8 (“Procaspase-8″ indicates the immature non-activated version of the protein) can promote cellular migration, a process central to tumor metastasis, independent of its better-defined role as a cell death protein.
The book chapter: “Neuroblastoma Integrins” is currently available via open access: http://www.intechopen.com/books/neuroblastoma/neuroblastoma-integrins We reviewed and consolidated information about the role of integrins (cell adhesion molecules critical to development, cell migration, and other roles) in neuroblastoma, the most common pediatric solid cancer. We also expand upon current concepts of therapy, and suggest new avenues for investigation by clinical pediatric oncologists.
Both are now listed here in my CV: http://ryongraf.com/cv/
Graf R, Barbero S, Keller N, Chen L, Uryu S, Schlaepfer D, et al. Src-inducible association of CrkL with procaspase-8 promotes cell migration. Cell adhesion & migration. 2013 Jun 10;7(4). PubMed PMID: 23751956. Epub 2013/06/12.
Shanique A. Young, Ryon Graf and Dwayne G. Stupack (2013). Neuroblastoma Integrins, Neuroblastoma, Prof. Hiroyuki Shimada (Ed.), ISBN: 978-953-51-1128-3, InTech, DOI: 10.5772/55991. Available from: http://www.intechopen.com/books/neuroblastoma/neuroblastoma-integrins
Thanks to all my friends, family, and labmates that helped make this happen!