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Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Technology’ category

Can you imagine what it must be like to go blind? Degenerative diseases of the eye such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP) can result in loss of vision and blindness.

Retinitis pigmentosa is an inherited genetic condition for which there is no cure. It results in the progressive loss of function of the retinal photoreceptors that convert light into electrical nerve impulses that travel down the optic nerve to the brain for processing into the images we see. As you reduce the ability to process light, so you start to lose your sight and can end up totally blind.

Several companies and research groups are now working on an artificial retinal prosthesis. The term “bionic eye” is often used to describe this research, which for many may conjure up the “$6 million dollar man“. This “hype” is, however, far from the reality of where the technology currently is at.

To date, only crude images can be detected. There is no dramatic restoration of sight or vision, instead the retinal prostheses currently only offer the ability to detect light and large shapes.

However, for those who are blind, being able to detect shapes and “see” a door, could help people enormously in their activities of daily living. In the same way that we have seen tremendous increase in the megapixels for digital cameras, so it is hoped that visual acuity will improve as the technology increases the number of pixels that can be processed.

There are several research groups and companies working on different types of electrodes and different implant locations in the retina, but in essence they have a common approach.

Most of the retinal prostheses in development use an external video camera to convert light to electrical signals that are transmitted wirelessly to a retinal implant (multielectrode array) that delivers a pattern of electrical signals to the retina. This electrical stimulation of the retinal cells results in signals being passed down the optic nerve to the brain where they are processed into visual images.

The Argus II Retinal Prosthesis System (Second Sight) is the most advanced in terms of commercial approval. It has obtained CE marking and is on the market in Europe where it sells for a price of $115,000 (Source: ExtremeTech).

On September 28, 2012, the FDA ophthalmics device panel will discuss the application by Second Sight to sell the Argus II system in the United States as a humanitarian use device.

The Argus II implant consists of a coil (for receiving and transmitting wireless data) fixed on the sclera (outside of eye) and a 60 electrode array positioned on the surface of the retina.

This animation from Second Sight explains how it operates:

Argus II Clinical Trial Results

The results of a multicenter trial with 30 patients at 10 centers were published earlier this year in Ophthalmology, a journal of the American Academy of Ophthalmology (AAO). Mark S. Humayun from the Doheny Eye Institute at University of Southern California and research colleagues reported that:

“Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260.”

In addition to finding the device to be reliable over the long-term, Humayun et al concluded that:

“The data in this report suggest that, on average, prosthesis subjects have improved visual acuity from light perception to at least hand movements, with some improving to at least counting fingers.”

“These visual acuity data and other performance results to date…demonstrate the ability of this retinal implant to provide meaningful visual perception and usefulness to subjects blind as a result of end-stage outer retinal degenerations.”

Bionic Vision Australia announces first implant of Bionic Eye

Last month, Bionic Vision Australia, announced in an August 30, 2012 media release that they had “successfully performed the first implantation of an early prototype bionic eye with 24 electrodes.”

The recipient, Dianne Ashworth is quoted as saying:

 “I didn’t know what to expect, but all of a sudden, I could see a little flash…it was amazing. Every time there was stimulation there was a different shape that appeared in front of my eye,”

First Bionic Vision Australia patient with her surgeon, Dr Penny Allen.

Dianne Ashworth with her surgeon, Dr Penny Allen. Photo Credit: David Mirabella

Veronika Gouskova, Marketing and Communications Manager of Bionic Vision Australia (BVA) kindly responded by email to my questions about their news:

BSB: I saw in your Aug 30 media release that the implant was described as a “world first” by Dr Allen. Could you clarify in what way this is a “world first” when there are other retinal prosthetics on the market e.g. Argus II from Second Sight?

BVA: This is a world first implantation of a device in the suprachoroidal space at the back of the eye. Although there have been other groups working with patients around the world, this surgical position and procedure is unique to Bionic Vision Australia

BSB: How does the Australian Bionic Eye differ from the Second Sight product that is marketed in Europe?

BVA: There are a number of groups internationally working in the field of retinal implants – the fact that this research is ongoing means that the problem hasn’t yet been solved completely. Between all these groups there are a differences in technology being developed, materials used, surgical placement of the device, surgical technique and the way the electrodes or photodiodes are being stimulated (i.e. how the visual data is processed before it is sent to the implant).

At the end of the day, it’s all about ensuring the best outcome for patients. We are developing two prototypes, with different functional aims: the ‘wide-view’ device combines novel technologies with materials that have been successfully used in other clinical implants. This approach incorporates a microchip with 98 stimulating electrodes and aims to provide increased mobility for patients to help them move safely in their environment.

Our ‘high-acuity’ device incorporates a number of exciting and new technologies, such as diamond materials,  to bring together a microchip and an implant with 1024 electrodes. The device aims to provide functional central vision to assist with tasks such as face recognition and reading large print. The early prototype that we implanted with our first three patients is a stepping stone towards further development for these two devices.

Bionic Vision Australia brings together researchers from many different fields, so we have a truly multidisciplinary team. This means the clinicians and surgeons are involved in the design and development process from the start. Further, a lot of our researchers were involved in the cochlear implant, or bionic ear development – they know what it takes to bring a competitive medical implant to the market.

BSB: I saw that your device was placed between the choroid and sclera, is that significant as opposed to being on the top of the retina? Could you provide further clarification on the significance of this and the surgical technique required for implantation?

BVA: Yes, this early prototype is implanted in the suprachoroidal space, between the choroid and the sclera. This is beneath the retina. There are a number of advantages in doing this, e.g. this position greatly enhances the mechanical stability of the implant and allows for a relatively straightforward surgery. The surgical procedure involves making an incision through the sclera and sliding the implant in place.

BSB: What are the next steps, is a larger clinical trial of your device already planned/underway – when will other patients receive implants?

BVA: We have implanted this early prototype in three patients and will continue to work with these patients over the next 18 months while we further develop our full prototype devices. The next step will be of course, a larger trial with our full devices in due course.

BSB: How might your device be potentially sold/commercialized or made available – is there a commercial partner associated with Bionic Vision Australia?

BVA: Bionic Vision Australia is an unincorporated joint venture between a number of research organisations in Australia. We are funded by the Australian Research Council. A commercialisation vehicle has been set up, Bionic Vision Technologies, to commercialise the technology. This company is solely owned by the member organisations that are involved in our research.

In addition to Second Sight and Bionic Vision Australia, there are several other companies and research groups with retinal prostheses in development.

It is an area where we are seeing innovation in action as teams of multi-disciplinary researchers strive to restore sight and improve the quality of life to people who have become blind.

However, given the high cost of R&D, and the fact that much of the research is government funded, I’m not sure of the commercial opportunity. It will be interesting to see how the market for retinal prostheses develops.

Challenges that have to be overcome

A number of challenges with retinal prostheses will have to be overcome. Some of these are discussed in a 2011 editorial by James Weiland, Alice Cho and Mark Humayun on “Retinal prostheses: Current Clinical Results and Future Needs” that was published in the AAO journal, “Ophthalmology.”  I encourage anyone with an interest in this area to read this insightful review.

Some of the questions I took from this editorial were:

  • Why do some patients respond better than others with an implant?
  • Will retinal remodeling and ongoing degeneration limit the usefulness of implants?
  • What is the best surgical way to ensure optimal placement of the stimulating arrays to maximize visual acuity but avoid problems associated with fixation, and wound closure?
  • Could artificial vision be detrimental to other sensory inputs e.g. the ability of the visual cortex to process data from non-visual Braille reading?

Answers to these and other questions will come as clinical experience is gained and advances in technology improve the design and functionality. In my view this is innovation in action.

Update February 15, 2013 Argus II receives FDA approval

As expected following the positive endorsement of the Ophthalmic Devices Advisory Panel last year, the United States Food and Drug Administration (FDA) announced in a Feb 14, 2013 press release that Second Sight’s Argus II retinal prosthesis system had received approval as a humanitarian use device for the treatment of adults with advanced retinitis pigmentosa.



ResearchBlogging.orgHumayun MS, Dorn JD, da Cruz L, Dagnelie G, Sahel JA, Stanga PE, Cideciyan AV, Duncan JL, Eliott D, Filley E, Ho AC, Santos A, Safran AB, Arditi A, Del Priore LV, Greenberg RJ, & Argus II Study Group (2012). Interim results from the international trial of Second Sight’s visual prosthesis. Ophthalmology, 119 (4), 779-88 PMID: 22244176

Weiland JD, Cho AK, & Humayun MS (2011). Retinal prostheses: current clinical results and future needs. Ophthalmology, 118 (11), 2227-37 PMID: 22047893

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Regular blog readers will know I think tissue engineering is an exciting area where you can see innovation in action – advances in basic science can translate into ways to artificially create replacement organs and body parts.

Research published online 22 July 2012 in Nature Biotechnology by Janna Nawroth and colleagues at the California Institute of Technology (Caltech) and Harvard University, shows how biomedical engineers are learning from the structure and function of other animals.

In a Nature Biotechnology article titled “a tissue-engineered jellyfish with biomimetic propulsion” researchers describe how they were able to combine rat cardiac muscle cells and a synthetic elastomer membrane into a medusoid like structure that mimicked the propulsion of a jellyfish.

Credit: Caltech and Harvard University

They achieved this by forming the elastomer into a medusoid or jellyfish like shape with eight lobes around a central disc, then applying a monolayer of rat cardiac muscle tissue, which when electrically shocked, contracted in a synchronized way.

The net result was the medusoid “swam” in a similar way to a jellyfish. They effectively developed an artificial pump made out of a hybrid of living cells and silicone rubber.

The video below by Janna Nawroth, produced by Caltech and Harvard University, shows the medusoid in action, and explains how this research advances the design of muscular pumps for biomedical application:

According to the Caltech press release, this approach in reverse-engineering the function of a jellyfish “will be broadly applicable to the reverse engineering of muscular organs in humans.” 

While we are not yet able to tissue engineer a replacement human heart, it’s hard not to believe that at some point in the future we will see the development of hybrid devices that combine synthetic materials and cultured heart muscle cells.


ResearchBlogging.orgJanna C Nawroth, Hyungsuk Lee, Adam W Feinberg, Crystal M Ripplinger, Megan L McCain, Anna Grosberg, John O Dabiri, & Kevin Kit Parker (2012). A tissue-engineered jellyfish with biomimetic propulsion Nature Biotechnology, 30, 792-797 DOI: 10.1038/nbt.2269

Several retired American Football stars have ended up with chronic traumatic encephalophy (CTE), previously known as dementia pugilistica. It’s similar to Alzheimer’s disease in that the brain ends up with neurofibrillary tangles.

Science Translational Medicine Cover May 16CTE has also been seen in soldiers who have experienced blast induced traumatic brain injury (bTBI) from improvised explosive devices (IEDs). I previously wrote on this blog about how nanotechnology may revolutionize the detection of TBI using a nanomaterial that changes color.

Research published in the May 16, 2012 issue of Science Translational Magazine by Lee Goldstein and colleagues from the Molecular Aging and Development Laboratory at Boston University & other institutions, compared CTE neuropathology in blast-exposed military veterans and athletes with repetitive concussion injury.

For the first time they have shown similarities in what happens to the brains of soldiers when they are blown up and to athletes in sports that have repeated head impacts.

The reseachers looked at 8 post-mortem brains, 4 military veterans aged 22 to 45 with a history of blast exposure were compared to 4 athletes aged 17 to 27 who were either American Football players or, in one case, a wrestler. Despite the small sample size, the results showed similar brain trauma in the two groups:

“the effects of blast exposure, concussive injury, and mixed trauma (blast exposure and concussive injury) were indistinguishable.”

It is worth noting that the brain neuropathysiology seen was different from that seen with Alzheimer’s disease (AD).

The researchers went on to develop a mouse model that could be used to investigate the link between blast exposure, brain neuropathology and behavior.  I encourage you to read the STM paper for full details on this.

Some of the key findings of their mouse experiments were:

  • Blast exposure induces traumatic head acceleration in a blast neurotrauma mouse model
  • Single-blast exposure persistently impairs axonal conduction and long-term potentiation of activity-dependent synaptic transmission in the hippocampus
  • Single-blast exposure induces long-term behavioural deficits that are prevented by head immobilization during blast exposure.

The authors conclude that their results “provide compelling evidence linking blast exposure to long-lasting brain injury.”

What this research suggests to me is:

  • An ongoing need to design safer head protection for athletes and soldiers
  • The need to monitor and detect traumatic brain injury (I wrote last year about how nanomaterials were being developed to monitor blast exposure)
  • Need to identify those genetic factors (e.g. carrying the APOE e4 allele leads to a high risk of developing Alzheimer’s disease) that may lead to a heightened risk of developing dementia or CTE.

The paper by Goldstein and colleagues in STM is well worth reading if you have an interest in this area and the debate about the safety of young people in high-contact sports.


ResearchBlogging.orgGoldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716

Braingate array


Research published online first today, and in the May 17 2012 issue of Nature describes promising results of a clinical trial with tetraplegics (all four limbs paralyzed) that allowed the control of an external robotic arm (DEKA arm) using an embedded microarray in the brain, the BrainGate neural interface system.

One of the two study participants who had the array implanted 5 years ago, was able to use her mind to control a robotic arm and serve herself coffee from a bottle, 15 years after she became completely paralyzed & unable to speak.

The results from a team of researchers from the Department of Veterans Affairs, Brown University, MGH, Harvard Medical School (BrainGate Research Team) and the German Aerospace Center, Institute of Robotics and Mechatronics are promising.

The BrainGate system is the size of a small pill, and consists of a grid of 96 electrodes that are implanted in the motor cortex of the brain. By placing the grid next to the part of the brain that controls movement, neuronal activity associated with a movement can be translated into a computer command that drives an external robotic device.

The results reported by Leigh Hochberg MD, PhD & colleagues in Nature, offers hope to those paralyzed or who have limbs amputed, that in the future, innovations in neurotechnology may allow thoughts to control prosthetics or external robots.

Courtesy of Nature Video, you can watch how a paralyzed woman controls a robotic arm with her thoughts – this is an amazing video that is well worth watching:

How does it work, according to clinical trial subject T2:

I just imagined moving my own arm and the [DEKA] arm moved where I wanted it to go.

Subject S3 commented:

I think about moving my hand and wrist. I’m right handed so, it’s very comfortable and feels natural to imagine my right hand moving in the direction I want the robotic arm to move.

The challenge with this type of medical news is the danger of hype over hope, so to better put the results in perspective, I am delighted to have some expert commentary in the form of a guest blog post from D. Kacy Cullen, Ph.D, Assistant Professor at the University of Pennsylvania, Department of Neurosurgery Center for Brain Injury and Repair.

The Cullen laboratory at Penn applies Neural Engineering principles and technologies to the area of Neurotrauma, and is actively researching how to use neural tissue engineering-treatments to promote regeneration and restore function.

Commentary by D. Kacy Cullen, PhD 

This work is a natural extension/combination of the group’s previous work (1) involving human patients and computer cursor movements, and (2) non-human primates and robotic arm control.  So, this “next step” was anticipated, and in fact larger trials (involving various groups) are being initiated to investigate brain-based neural interface systems to drive the DEKA arm in subjects with limb loss (i.e. absent CNS damage/deficits).

The most compelling features to me were the decoding/training algorithm and the fact that one of the patients had her micro-electrode array implanted 5 years earlier.

Decoding/training: The use of signal filtering/thresholding in combination with open-loop (imagining and watching movement) and closed-loop (controlling the arm with visual feedback) recording/training was innovative and relatively efficient (31 min). However, in each case, the subjects had worked controlling arms previously (over years for S3 and 3 trials for T2).

A major challenge with recording ensemble neuronal activity in the motor cortex (or anywhere in the cortex) is signal attenuation and drift over time; so, each day/session typically requires re-training and re-calibration.

I would be curious to see how the subjects did in other independent trials – perhaps visual feedback can allow the user to “correct” the cortical inputs and hence reduce movement errors more rapidly in subsequent trials.  Nonetheless, it is remarkable that the subjects were able to manipulate the arm and drive it in a controlled and useful manner in a relatively short amount of time.

5 years: using an electrode array implanted 5 years earlier to control the robotic limb is very impressive.  The finding bodes well for the potential of this brain-based approach to yield useful cortical data chronically.

A major challenge is that over time the brain gradually rejects these non-organic electrodes, causing a build up of micro-scar tissue around the electrodes and a decreased neuronal density in the vicinity of the electrodes.

This process is partly due to mechanical mismatch between the electrode the brain causing inflammatory “micro-motion”.  This is likely exacerbated by subject motion/walking, which would not be an issue with the patients in this study but will be for the amputee study.

Nonetheless, this study noted “lower spike amplitudes and fewer contributing (active) channels” compared to earlier years, which is consistent with micro-scar tissue and fewer neurons close to electrodes.

Although this work is a natural next step, I do not want to trivialize the supreme competence, technical savvy, and attention to detail necessary to pull this off.  This group is highly competent and has the experience and skill to execute this very complex and multi-faceted neural engineering project to assist chronically disabled patients.


ResearchBlogging.orgHochberg, L., Bacher, D., Jarosiewicz, B., Masse, N., Simeral, J., Vogel, J., Haddadin, S., Liu, J., Cash, S., van der Smagt, P., & Donoghue, J. (2012). Reach and grasp by people with tetraplegia using a neurally controlled robotic arm Nature, 485 (7398), 372-375 DOI: 10.1038/nature11076


There was so much good science on display at the recent 2012 annual meeting of the American Association for Cancer Research (AACR) in Chicago that any blog posts are but a personal snapshot or postcard.

Bill Sellers VP Global Head Oncology Novartis Institutes for BioMedical ResearchOne enduring image I have from the plenary presentation on “The Genetic Basis for Cancer Therapy” by Bill Sellers, VP/Global Head Oncology at Novartis Institutes for BioMedical Research was the video he showed of the robots that are used for automated cell profiling.

Imagine the advertisements that show robots being used to build cars, but now the robots are undertaking automated laboratory work in pursuit of new cancer compounds. Wow!

During his presentation, Sellers described how Novartis have built a robust preclinical translational infrastructure.

He went on to say that, “many experiments we have done in the past, and even many molecules that were put in the human, really were only profiled against a limited number of preclinical models such as one cell line.”

In order to make preclinical data more reproducible, Novartis had the goal to move from testing against one cell line to testing against an encyclopedia of cell lines.

This has now become a reality with the launch of the Cancer Cell Line Encyclopedia (CCLE) in collaboration with the Broad Institute. The CCLE was recently announced by Novartis in a media release, and details were published online on March 28, 2012 in a letter to “Nature” (doi:10.1038/nature11003).

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

As described in “Nature”:The Cancer Cell Line Encyclopedia (CCLE) is a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines.

When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity.

Sellers noted in his AACR plenary presentation that the key to using the CCLE is for profiling and to:

“identify subsets of cancer cell lines that are sensitive to a given therapeutic versus those that are not. And then better yet to identify the markers of sensitivity that are differentially expressed or present in the sensitive versus insensitive cell lines.”

Novartis Institute for Biomedical Research Automated Robotic Drug DiscoveryTo do this, Sellers described how Novartis have built a robotic system that e.g. automates cell profiling.  In approx 3 months with this system we can profile 600 cell lines for about 1500 compounds, he said.

This type of preclinical automation is speeding up cancer drug discovery through the ability to more rapidly identify those compounds that are associated with and have activity against different mutations.

In my view, this will drive innovation through the effective and efficient screening of potential new cancer compounds, with the result that only those compounds with demonstrable promise progress.

AACR have made Bill Sellers plenary presentation available as a free webcast from the 2012 annual meeting (along with several others).  I encourage anyone interested in how cancer biology is driving cancer drug development to watch this.

EAU-2012-Congress-Media-Briefing-Professor-Jelle-Barentsz“The Mannogram – Yes we scan” Jelle Barentsz, Professor of Radiology at Radbound University, Nijmegen, The Netherlands told the assembled media at the recent European Association of Urology (EAU) annual Congress in Paris.

Professor Barentsz described how advances in magnetic resonance imaging (MRI), and in particular multi-parametric MRI (Mp-MRI) offer the potential for the improved detection and characterization of prostate cancer.

In the same way there is a mammogram that women use for breast cancer screening, Professor Barentsz raised the possibility that using magnetic resonance imaging, men could have a mannogram to screen and diagnose prostate cancer.

Some of the advantages of multi parametric MRI he highlighted include:

  • Prediction of tumor aggression
  • Prediction of low vs intermediate or high grade prostate cancer correctly in 95% of men in a trial as compared to 54% with TRUS (trans-rectal ultrasound guided) biopsy
  • In cases where there was a negative TRUS biopsy initially, mp-MRI and MR guided biopsy detected prostate cancer in 41% (108/265 of trial participants), with 87% of the prostate cancer detected being significant.

It is beyond the scope of this post to go into the physics of multi-parametric MRI or discuss in more detail the imaging trial data on which the above conclusions are based.  However, for those interested in this area, I have included details of some of the references Professor Barentsz kindly provided at the end of the post.

Why do we need new techniques for prostate cancer diagnosis? 

During their lifetime 1 in 6 men will be clinically diagnosed with prostate cancer.  There are 899,000 new cases and 258,000 deaths per year in Europe.

The current diagnostic tools of digital rectal examination (DRE), serum prostate specific antigen (PSA) and trans-rectal ultrasound guided (TRUS) biopsy have a number of limitations for prostate cancer detection.

This includes a lack of specificity (PSA = 36%), insensitivity (DRE = 37%) or failure to detect cancer due to sampling error with TRUS biopsy (more than 20% of cancers are not detected on first biopsy).

The result is that we end up with large numbers of men with elevated men or rising PSA, who have repeat biopsies. This comes at a high cost to health care providers, the uncertainty of diagnosis and the discomfort that comes with a TRUS biopsy (TRUS-Bx).

Many men undergo diagnostic procedures only to find they don’t have prostate cancer. One of the key issues in the prostate cancer screening debate is this unacceptable harm/benefit ratio.

Prostate biopsy to confirm cancer diagnosis is an invasive procedure as Professor Jenny Donovan, Head of the School of Social  and Community Medicine, at the University of Bristol told the EAU Congress.

In a plenary session, Prof Donovan described some of the initial findings from the PROBE (Prostate Biopsy Effects study), which looked at 1,147 men who received a TRUS-Bx.

“The majority of men tolerated biopsy reasonably well – over 60% experience minor symptoms. However, around one third experience symptoms that bothered them,” she said.

Professor Donovan went on to give examples of some of the feedback on the biopsy experience that researchers obtained:

“I found it incredibly painful and distressing – biopsy with a nail gun,” one man in the PROBE study said.

Data presented by Professor Donovan showed that after the procedure, 11% of men would not want another biopsy (this rose to 20%) seven days later.

Magnetic Resonance Imaging Guided Biopsy may offer benefits

Given the discomfort that many men experience with TRUS biopsy, and the fact a negative biopsy does not automatically mean no cancer (there’s a risk of sampling error), the use of MR guided biopsy may offer significant benefits.

One is that instead of 12 cores being sampled by the TRUS-Bx, only 2 cores are obtained using the MR guided biopsy technique that Professor Barentsz described.

Personally, I would prefer to have two precise cores samples taken from me through imaged based guidance, than have a TRUS biopsy that is like a nail gun that shoots in 12 sampling rods into the target area of the prostate.  This would be like the difference between a sniper rifle and a blunderbuss, metaphorically.

One of the practice implications of this is that radiologists may end up performing MR guided biopsies instead of urologists performing TRUS biopsies.

Urologists in private practice or those who are paid per procedure may not be happy about the practice changing implications that may result.

The MR imaging research that Professor Barentsz described at EAU is not without its limitations and one concern is the reproducibility of advanced imaging techniques outside of an expert university or academic setting.  I put this question to Professor Barentsz in the media briefing and have included an excerpt of his reply that you can listen to:

According to Professor Barentsz, the imaging techniques for MR guided prostate biopsy are readily reproducible outside the academic environment with guidelines already in place for standardized acquisition protocols and structured interpretation of results.

We are now at the point that the standardization of prostate MRI as well as the standardization of reporting with all kind of computer assistance is a fact and not fiction anymore,” said Barentsz.

The European Society of Urogenital Radiology (ESUR) recently published MR guidelines, that include a structured reporting system, called PI-RADS (prostate imaging, reporting, and data system).  This has been adopted in the United States by the American College of Radiology (ACR).

Before men with prostate cancer can expect to see these advanced imaging techniques used outside of expert centers, however, urologists and radiologists will need to agree on the benefits they offer and adapt their practice accordingly. Urologists may be reluctant to move away from TRUS biopsy, so it is likely widespread implementation will take some time and require education, and explanation of the evidence based medicine that supports the proposed change in practice.

The conclusion from Professor Barentsz’s EAU presentation is that imaging looks likely to play an increasing role in the diagnosis of prostate cancer.

It will be an exciting area to watch. The idea of a Mannogram has the potential to become a reality that would benefit the 1 in 6 men who will be diagnosed with Prostate Cancer during their lifetime.


ResearchBlogging.orgHambrock, T., Somford, D., Huisman, H., van Oort, I., Witjes, J., Hulsbergen-van de Kaa, C., Scheenen, T., & Barentsz, J. (2011). Relationship between Apparent Diffusion Coefficients at 3.0-T MR Imaging and Gleason Grade in Peripheral Zone Prostate Cancer Radiology, 259 (2), 453-461 DOI: 10.1148/radiol.11091409

Hoeks, C., Schouten, M., Bomers, J., Hoogendoorn, S., Hulsbergen-van de Kaa, C., Hambrock, T., Vergunst, H., Sedelaar, J., Fütterer, J., & Barentsz, J. (2012). Three-Tesla Magnetic Resonance–Guided Prostate Biopsy in Men With Increased Prostate-Specific Antigen and Repeated, Negative, Random, Systematic, Transrectal Ultrasound Biopsies: Detection of Clinically Significant Prostate Cancers European Urology DOI: 10.1016/j.eururo.2012.01.047

Barentsz, J., Dickinson, L., & Sciarra, A. (2011). Re: Axel Heidenreich. Consensus Criteria for the Use of Magnetic Resonance Imaging in the Diagnosis and Staging of Prostate Cancer: Not Ready for Routine Use. Eur Urol 2011;59:495–7 European Urology, 60 (1) DOI: 10.1016/j.eururo.2011.03.013

Hambrock, T., Hoeks, C., Hulsbergen-van de Kaa, C., Scheenen, T., Fütterer, J., Bouwense, S., van Oort, I., Schröder, F., Huisman, H., & Barentsz, J. (2012). Prospective Assessment of Prostate Cancer Aggressiveness Using 3-T Diffusion-Weighted Magnetic Resonance Imaging–Guided Biopsies Versus a Systematic 10-Core Transrectal Ultrasound Prostate Biopsy Cohort European Urology, 61 (1), 177-184 DOI: 10.1016/j.eururo.2011.08.042

Barentsz, J., Richenberg, J., Clements, R., Choyke, P., Verma, S., Villeirs, G., Rouviere, O., Logager, V., & Fütterer, J. (2012). ESUR prostate MR guidelines 2012 European Radiology, 22 (4), 746-757 DOI: 10.1007/s00330-011-2377-y

That was the question that I asked Walter Artibani, Professor and Chair of Urology at the University of Verona during the recent European Association of Urology (EAU) annual Congress in Paris.

Urologists have failed as scientists to generate evidence based medicine

Professor Artibani told the assembled media that urologists had failed as scientists in not generating robust clinical data to support the use of the da Vinci robotic system for the removal of the prostate gland (prostatectomy).

Something that I was not aware of until I attended the media briefing was that so called “robotic surgery” is not an automated robot performing the surgery on its own, but instead it’s actually robot assisted surgery.

The da Vinci surgical device (currently the only one on the market) is a telemanipulation system where the surgeon sits at a remote console and operates a surgical cart with three or four arms that are docked with endoscopic instruments that are inserted into the patient.

Professor Artibani in response to my question said:

“After 10 years, the urologic community missed the window to have prospective randomized clinical trial in order to have clear answers.”

What’s more he went on to say that he believed it would be unlikely we could now do a prospective trial that compared robot-assisted prostatectomy to laparascopic prostatectomy to open prostatectomy. The reason for this was that :

“Most of the patients are convinced that the new way, the novel way is the better way.”

The following is a video excerpt of Professor Artibani’s answer to my questions.  For digital accuracy, viewers should note that I added in some slides he presented earlier, and included a graphic of the paper he referenced.

Have the media sensationalized robotic surgery?

Artibani went on to say in his answer to my question that the media and journalists have not always reported the lack of robust data surrounding new surgical techniques:

“It is easy just to give the information that what is new is better and this must be demonstrated by robust data before giving the information. Unfortunately sensationalism is more important than to say and to write robust data.”

Healthcare journalists have an obligation to report on the limitations of new techniques and lack of evidence based medicine is an important one!  Gary Schwitzer’s healthcare journalist watchdog, Health News Review, attempts to hold the media to account.

We should clearly challenge surgical practice for which there is a lack of robust clinical data or evidence based medicine, and avoid sensationalism.

However, whatever the limitations of the media reporting, the reason for the lack of evidence based medicine rests firmly with the academic urology community.

Low quality of evidence for Robot-Assisted Laparoscopic Prostatectomy

In an editorial in the journal “European Urology,” Markus Graefen noted the low quality of urology research that was being published did not just apply to robot-assisted prostatectomy.  He noted that in urology,

“The number of low-quality papers is increasing; however, the body of evidence and the knowledge we have about the reported outcomes, unfortunately, is not.”


He went on to describe the need to counsel patients on the different surgical approaches available to them:

A patient with a newly diagnosed prostate cancer who is counselled for his therapeutic options today should be informed that several equal surgical approaches are available and that despite all the perfectly styled Web pages, it is not the robot that makes the difference.

He should be informed that there are indeed concerns about oncologic and functional outcomes and also evidence that in some significant papers the traditional surgical approaches look superior.

This editorial suggests that patients should ignore the marketing hype about new equipment or the notion that “new is better,” but instead focus on the experience of the surgeon with that equipment and the functional outcomes that a surgeon obtains in his/her patients.

Patients are interested in functional outcomes and low complication rates

What I heard at EAU from urologists is that patients are interested in a good functional outcome and low complication rate.

There is, however, no level 1 evidence that post-operative urinary incontinence and erectile dysfunction rates are generally better with robot-assisted radical prostatectomy.

Diana Kang and colleagues in a review of seventy-five research publications between 2005 and 2008 that reported robot-assisted laparscopic prostatectomy (RALP) data, concluded that there was a need to raise the standards of urology clinical research:

Our findings draw into question to what extent valid conclusions about the relative superiority or equivalence of RALP to other surgical approaches can be drawn and whether published outcomes can be generalised to the broader community.

There is an urgent need to raise the methodologic standards for clinical research on new urologic procedures and devices.

Men with prostate cancer who are considering surgery should be informed that there is no high-level or robust evidence to show the general superiority of robotic-assisted prostatectomy compared to other surgical techniques for radical prostatectomy.

Hopefully, the demand for evidence based urology treatment will grow, and that lessons have been learned from the way robotic-assisted surgery was introduced. Men with prostate cancer do deserve better.

ResearchBlogging.orgKang, D., Hardee, M., Fesperman, S., Stoffs, T., & Dahm, P. (2010). Low Quality of Evidence for Robot-Assisted Laparoscopic Prostatectomy: Results of a Systematic Review of the Published Literature European Urology, 57 (6), 930-937 DOI: 10.1016/j.eururo.2010.01.034

Graefen, M. (2010). Low Quality of Evidence for Robot-Assisted Laparoscopic Prostatectomy: A Problem Not Only in the Robotic Literature European Urology, 57 (6), 938-940 DOI: 10.1016/j.eururo.2010.02.004

Contrary to popular opinion, innovation is not dead in the biomedical industry, as evidenced by news of a novel drug-delivery system published as a Rapid Publication in Science Translational Medicine (STM) on February 16, 2012.

The paper from Robert Farra of MicroCHIPS, Inc. and research collaborators, describes a first-in-human testing of a wirelessly controlled drug delivery microchip.

Farra et al., report the results of a clinical trial with 8 women in whom microchips were implanted for 103 days. The data showed that the pharmacokinetic profile of microgram-quantities of the anti-osteoporosis drug, teriparatide (FORSTEO), delivered by the microchip was similar to subcutaneous injections.  However, the device did fail in one of the 8 women, so data is only reported for 7 patients, a very small patient sample.

Picture Credit: MicroCHIPS, Inc.

The drug delivery device is an array of 600-nL micro reservoirs in which the drug is stored, that is associated with a 13.0 mm x 5.4mm x 0.5mm silicon chip.

The microchip was implanted beneath the skin (subcutaneously) in the abdomen by creating a 2.5cm incision, performed during an outpatient visit.

This paper is also interesting for its use of telemedicine. A remote operator was able to establish a wireless link and send instructions directly to the implant on dosing schedule as well as receive information back on operation of the chip.

John T. Watson, Professor of Bioengineering at the University of California San Diego  commented in the accompanying editorial that:

“The microchip represents more than 10 years of engineering design and development efforts to arrive at a programmable, implantable device for subcutaneous release of a therapeutic agent in discrete doses.”

Multiple engineering design advances were made along the way.

He also noted the results from the quality-of-life surveys administered during the trial; the majority of women stating they often forgot they had the device implanted and would readily consent to a fresh implant if needed.

Innovations in drug delivery offer hope of an improved quality of life to patients with chronic disease who require daily injections.  In 2010, there were approximately 50,000 teriparatide users, not an insignificant market opportunity.  People with diabetes who require daily injection of insulin is another potential market that springs to mind.

The first-in-human results reported in Science Translational Medicine show promise and the potential of a novel implanted wireless drug delivery system.

However, many questions remain unanswered by this research including the reliability & durability of the microchip device, given that it failed in 1 out of 8 women implanted.

Further work on validating the technology, and confirming its safety, reliability and efficacy in a larger sample size will be needed before it can obtain regulatory approval.


ResearchBlogging.orgFarra, R., Sheppard, N., McCabe, L., Neer, R., Anderson, J., Santini, J., Cima, M., & Langer, R. (2012). First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip Science Translational Medicine DOI: 10.1126/scitranslmed.3003276

Watson, J. (2012). Re-Engineering Device Translation Timelines Science Translational Medicine DOI: 10.1126/scitranslmed.3003687

A survey of patients who had their prostate removed showed there was no significant difference in complication rates between open retropubic radical prostatectomy (ORRP) and robotic assisted laparoscopic surgery (RALRP).

This is an important finding because 85% of prostatectomies in the United States are undertaken using robotic-assisted techniques, yet there has been little published data to show that this technique improves functional outcomes.

At the European Association of Urology (EAU) annual congress last year in Vienna some of the challenges and opportunies with robotic surgery were raised:

  • lack of data on improved functional outcome
  • need for licensing of robotic surgeons
  • high learning curve – it takes 250 patients to become proficient

In reality, we see hospitals marketing their robotic surgery to patients in shopping malls and with advertisements on the side of buses.  You can read Gary Schwitzer’s thoughts on some of the recent marketing claims & “gizmo idolatry.”

This is why a survey comparing the results of open to robotic assisted prostate removal surgery is important evidence based medicine. Published online first in the Journal of Clinical Oncology, Barry and colleagues randomly surveyed 800 men who filed Medicare claims between August and December 2008.  685 completed surveys were returned, and information on adverse events was obtained.

The data highlights the dramatic effect on quality of life that prostate cancer surgery can have, irrespective of the surgical technique. The men rated themselves:

31.1% – moderate or big problem with continence  (95% CI 27.5 to 34.8%)

88.0% – moderate or big problem with sexual function (95% CI 85.4% to 90.6%)

Breaking this down by technique (robotic surgery versus open prostatectomy):

Continence: 27.1% of men (Open) versus 33.3% (Robotic) – not significant (P=0.113)

Sexual Function: 89.0% of men (Open) versus 87.5% (Robotic) – not significant (P=0.57)

The authors conclude in their JCO paper:

Our results do not demonstrate a lower risk of problems with incontinence or sexual function after RALRP compared with ORRP.

In fact, after adjusting for potential confounders, there was at least a strong trend toward a higher risk of patient-reported moderate or big problems with incontinence following RALRP.

The authors in their discussion do raise the interesting question as to whether patients were led to believe that they would have fewer side effects with robotic surgery, which may have impacted the survey findings.  This merits further investigation.

There is clearly a need for patients to give informed consent, and be aware of the risks and complications of prostate cancer surgery, particularly with regards fundamental quality of life issues such as continence or sexual function.

The accompanying JCO editorial by Matthew Cooperberg and colleagues from UCSF is well worth reading and raises the question as to whether men with prostate cancer should expect better outcomes than those reported in the survey?

What the survey by Barry et al did not do is look at the volume of procedures and experience level of the surgeon, both of which are associated with outcomes.

Cooperberg noted that “surgeons performing fewer than 5 prostatectomies per year account for approximately half the national volume.

A chilling statistic, and if you factor in the learning curve of more than 200 procedures to be competent at robotic surgery, it is perhaps not surprising that some men experience higher complication rates than others.

Which brings me back to the importance of the PIVOT (Prostate Cancer Intervention versus Observation Trial) data presented in the plenary session at the 2011 annual meeting of the American Urological Association (AUA) in May last year.

Why has this practice changing data not been published in a peer-reviewed journal yet?

The fact that the updated PIVOT study results presented at AUA 2011 have not been published (to the best of my knowledge) is a disservice not only to the medical and scientific community, but to men with prostate cancer whose treatment should be guided by evidence-based medicine.

The long-term results of the PIVOT trial presented by Professor Wilt showed no benefit of radical prostatectomy over watchful waiting, except for high-risk patients.  Yet, the reality is that many men end up having surgery. This may be considered overtreatment and an exposure of more men than is necessary to the complications of prostatectomy, irrespective of whether this is robotic or open surgery.

The decision to undergo radical prostatectomy should be an informed one, not only as to the risks and benefits of the surgical technique, but also whether the surgery should be performed in the first place as compared to “watchful waiting.”

I hope the paper and editorial published in the JCO this month will generate some debate. Next month I will be at the European Urology Association annual congress in Paris.


ResearchBlogging.orgBarry, M., Gallagher, P., Skinner, J., & Fowler, F. (2012). Adverse Effects of Robotic-Assisted Laparoscopic Versus Open Retropubic Radical Prostatectomy Among a Nationwide Random Sample of Medicare-Age Men Journal of Clinical Oncology DOI: 10.1200/JCO.2011.36.8621

Cooperberg, M., Odisho, A., & Carroll, P. (2012). Outcomes for Radical Prostatectomy: Is It the Singer, the Song, or Both? Journal of Clinical Oncology DOI: 10.1200/JCO.2011.38.9593

Update August 12, 2012 – Paper published in European Urology shows lower incontinence and greater rate of erection recovery with robot-assisted radical prostatectomy

A paper published online (July 20, 2012) in the journal, European Urology by Franceso Porpiglia provides some evidence that robot-assisted radical prostatectomy offers functional benefits to patients. I have not read the full paper only the freely available abstract.

The clinical trial evaluated the functional outcomes of 120 men in a randomized clinical trial where half (n=60) received radical prostatectomy (RARP) that was robot-assisted and the other half (n=60) who had the operation laparoscopically without robot assistance (LRP).

Following the surgery performed by Dr Porpiglia, the functional outcomes between the two groups were compared. Those men operated on with robot assistance showed:

  • Lower incontinence. “Continence after 3 mo was 80% in the RARP group and 61.6% in the LRP group (p = 0.044), and after 1 yr, the continence rate was 95.0% and 83.3%, respectively (p = 0.042)”
  • Better erection recovery. “Among preoperative potent patients treated with nerve-sparing techniques, the rate of erection recovery was 80.0% and 54.2%, respectively (p = 0.020).”

The challenge of this study is that although it was randomized, it reflects the results of only one surgeon with a small number of patients.

Dr Matthew Cooperberg (@cooperberg_ucsf) was quoted by Reuters saying that this was likely the best study we were going to get showing the benefits of RARP over LRP. On twitter he said the real question was now between radical prostatectomy and external radiation therapy (XRT).

Photoimmunotherapy (PIT) that uses a near-infrared (NIR) dye conjugated to monoclonal antibodies (mABs) that target epidermal growth factor receptors (EGFR) is a new type of molecular-targeted cancer therapy that appears to offer considerable promise.

Research by Makoto Mitusnaga and colleagues from the Molecular Imaging Program at the National Cancer Institute (NCI) was published recently in Nature Medicine. This paper is well worth reading if you have an interest in this area.

The NCI researchers developed a:

“mAb-based photosensitizer that is activated by NIR light for targeted PIT only when bound to the target molecule on the cancer cellular membrane.”

I think this is exciting research because unlike conventional photodynamic therapy that also damages normal tissue, photoimmunotherapy kills only antibody-bound cancer cells with no normal tissue damage:

“Further, because this agent also emits a diagnostic fluorescence, it can be used to direct the application of light to minimize exposure to nonrelevant tissues and to noninvasively monitor any therapeutic effects of excitation light.”

You can read more in the Nature Medicine paper about this exciting research that may offer an innovative new drug delivery mechanism for targeted cancer therapies.

ResearchBlogging.orgMitsunaga, M., Ogawa, M., Kosaka, N., Rosenblum, L., Choyke, P., & Kobayashi, H. (2011). Cancer cell–selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules Nature Medicine DOI: 10.1038/nm.2554

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