January 2008 Archives

Whether you were in San Jose last week or not, I hope you'll get time to read some of our daily blog posts from SPIE's Biomedical Optics Symposium (BiOS). With more than 1300 papers in the BiOS conference sessions and 150+ exhibitors plying their wares at the trade show, covering all the bases was never going to be an option. Yet if the reporting is necessarily selective, it's clear that delegates left the meeting with a number of take-home messages very much in focus.

For starters, there's the immense potential of optical radiation in cancer diagnosis and screening - not least when optical interrogation is used an adjunct to established clinical modalities like CT, MRI and PET (optics+x). A case in point is the US National Cancer Institute's Network for Translational Research in Optical Imaging (NTROI). In a session dedicated to NTROI's research, Brian Pogue, associate professor of engineering at Dartmouth College (Hanover, NH), reviewed the integration of near-infrared spectroscopy into standard MRI and CT instrumentation. While this type of hybrid imaging is still in its infancy, Pogue reckons that using it to guide therapy or to properly individualize the choice of therapy is "the next logical step".

Elsewhere, the network is also pioneering the use of functional optical imaging (specifically, diffuse optical tomography) in tandem with PET. The purpose here is not primary detection of breast cancer, rather the evaluation of a patient's response to therapy and early identification of resistance factors during treatment - information which can be used by doctors to adapt the treatment plan accordingly (see "Multimodal thinking on breast cancer").

If multimodal imaging was a defining theme at BiOS, so too was the push for combined-modality treatments. Indicative of that trend is work on laser therapies to trigger secondary host immune responses, a combination that shows real promise in controlling difficult-to-treat local tumours and metastatic disease at distant sites (see "Photoimmunotherapy: a winning combination?").

Scientists at the University of Oklahoma, for example, presented details of a laser-based treatment that, based on a Phase I clinical study, yields the highest response rate of any therapy for advanced cutaneous melanoma as well as greatly enhanced quality of survival. Called in-situ photoimmunotherapy, the technique combines local photothermal destruction of existing solid tumours with the topical administration of an immune-response modifier (a drug called imiquimod) to trigger an anti-tumour response.

Another conference thread that proved a big draw among delegates was low-light-level therapy (no doubt helped by the fact that it was singled out as an area to watch during Saturday's Hot Topics session). Notable papers reviewed the regenerative effects of laser light in the treatment of spinal-cord injury, as well as laser-induced modulations of the metabolic activities of malignant human-brain-cancer cells. It's early days, but the researchers in both instances reckon the results are further evidence that low-level light is emerging as a promising non-invasive therapy (see "A closer look at low-light therapy").

All told, if BiOS is about one thing right now, it's about technology push. As such, the meeting has a pivotal role to play in ensuring that next-generation optical modalities - both diagnostic and therapeutic - address an identifiable medical need. Beyond that, it's going to fall to photonics researchers and, ultimately, manufacturers to ensure that their optical innovations go on to deliver a price:performance edge versus incumbent clinical technologies.

My final stint at this year's BiOS meeting was a session on biophotonics and immune responses. I went along specifically to hear how laser therapies can trigger secondary host immune responses, a double-headed combination that shows real promise in controlling difficult-to-treat local tumours and metastatic disease at distant sites.

A case in point is advanced cutaneous melanoma, the sixth leading cause of cancer death in the US and one of the top three cancers worldwide in terms of recent rises in incidence. "Fundamentally, we don't have good ways to treat this," explained Mark Naylor, professor of dermatology at the University of Oklahoma (Norman, OK), citing less than 50% two-year survival for current FDA-approved chemotherapy regimes.

Naylor and his colleagues at Oklahoma are pioneering an alternative treatment for advanced melanoma called in-situ photoimmunotherapy (ISPI). The trick here is to combine local photothermal destruction of existing solid tumours (using fibre-optic delivery of 806 nm laser light) with the topical administration of an immune-response modifier (a drug called imiquimod) to trigger an anti-tumour response.

In early 2006, the Oklahoma team began enrolling patients in a phase I clinical trial of ISPI. The results so far, admittedly limited to a small study group, indicate that photoimmunotherapy is an effective treatment for stage III and some stage IV melanoma subjects.

Of the first 10 patients treated, all four stage III subjects are still alive. Of those, two are tumour-free, and two have had partial responses and are expected to achieve tumour-free status with further treatment. Of the six stage IV subjects, two are still alive and the majority survived beyond the expected median survival of 6-8 months. One stage IV subject is currently tumour-free and has survived for over three years.

Naylor's conclusion is unequivocal: the trial data show that ISPI yields the highest response rate of any therapy for advanced melanoma as well as greatly enhanced quality of survival versus traditional chemotherapy. "Over the next five to 10 years, ISPI will probably become the treatment of choice for unresectable stage III [cutaneous melanoma] disease," he added.

In a related presentation, Zheng Huang, a clinical oncologist at the University of Colorado (Denver, CO), discussed the evolving role for PDT:immunotherapy combination treatments in dermatology. Huang and his co-workers in China have been carrying out a number of early-stage clinical studies to evaluate what role PDT-induced local and systemic antitumour immune response might play in the control of malignant diseases.

Their studies to date have concentrated on the combination of ALA-PDT and topical application of imiquimod for conditions such as genital bowenoid papulosis, Bowen's disease and actinic keratosis. Initial results indicate that "improved clinical outcomes can be obtained by a combination of PDT and immunomodulation therapy", Huang told delegates.

My colleague Susan Curtis was also in San Jose this week pulling together a dedicated blog on Photonics West for her website optics.org. Susan's report from Monday's Laser and Marketplace Seminar follows.

In a year when steady single-digit growth is the norm in the optics/photonics industry, any sector expanding by more than 30% year-on-year demands close attention. According to Greg Smolka, a consultant with 20 years experience in the photonics industry behind him, the market for optical coherence tomography (OCT) systems is benefiting from new technology that is enabling more companies to enter the market.

In his talk at Monday's Lasers and Photonics Marketplace Seminar, Smolka pointed out that until 2006 the only player in the OCT market was Carl Zeiss, which introduced its first time-domain OCT system for ophthalmic imaging applications in 1996. Crucially, this first-generation technology was by covered a patent that prevented other players from launching competing products.

More recently, the introduction of Fourier-domain OCT has fundamentally altered the competitive landscape. This technology improves both the accuracy and definition of images, and also increases scan speeds by a factor of 50-100. What's more, it's not covered by the original patent.

As a result, around 19 companies have launched commercial Fourier-domain OCT products, and in so doing have extended the technique's capabilities from ophthalmology to other biomedical applications such as dentistry and cardiovascular imaging. According to Smolka, this will enable the OCT market to grow by 33.5% year-on-year, increasing from just less than $200 million in 2007 to $800 million in 2012.

What's more, Smolka says that developers of OCT systems are typically focused on end applications, and are looking for technology partners to develop and supply the specialist optical components (e.g. superluminescent diodes, lasers, CCD or CMOS image sensors, galvanometers and fibre-optic probes). One consequence, he says, will be an increase in the number of start-ups bringing new products to market, as well as significant merger and acquisition activity.

Tuesday 06.00 PT: I'm off to San Francisco International this afternoon to catch the red eye back to London, which means this is the last Main Event post from the San Jose Convention Center. I'll wrap up the show blog when I get back to the office with a review of yesterday's BiOS talks on biophotonics and immune responses, plus a report from the Laser and Marketplace Seminar at Photonics West.

Monday 18.00 PT: It's time for a change of tack here on medicalphysicsweb's BiOS blog. With all of the postings so far restricted to the conference sessions, I'm in danger of overlooking the 150+ companies who were hard at it plying their wares at the BiOS trade exhibition over the weekend.

While blockbuster launches aren't really the order of the day at BiOS, the show still featured its fair share of innovative component, subsystem and OEM products for all manner of biophotonic applications. Among the new offerings to catch my eye was the ZoroLight LED multiplexer, a product that's being pushed for applications in fluorescence studies and high-throughput screening.

Developed by Bookham (Santa Rosa, CA), an optical component/subsystem vendor traditionally associated with telecoms and industrial markets, ZoroLight can incorporate up to six LEDs in a compact module (device length typically varies from 80 to 200 mm depending on the number of LEDs).

Bookham claims that its proprietary optical-filter technology means that ZoroLight takes up less space versus traditional free-space LED multiplexing modules but with comparable efficiency. What's more, "the use of LEDs is attractive due to their 10x to 20x longer lifetime compared to bulbs and their cost saving over lasers," says Ben Standish, ZoroLight product line manager.

Custom designs are available for volume OEM applications now, while standard designs are expected to be generally available in mid-2008.

Another neat subsystem launch is a family of white-light lasers from Toptica Photonics, Germany. There are three variants - widely tunable visible lasers, visible supercontinuums and IR supercontinuums - all combining "the brilliance of lasers and the bandwidth of lamps" (at least that's what the press release says).

White light

For its part, TOPTICA is lining up applications in microscopy and expects the flexibility in wavelength to be exploited in two-colour experiments and time-resolved photon counting, for example. The broadband supercontinuums are generated in photonic-crystal fibres or highly nonlinear fibres, while individual lines can be extracted from the visible supercontinuum by using acousto-optical tunable filters.

According to the spec sheet, the total power in the infrared supercontinuum (range 1000-2100 nm) is typically 150 mW; the tunable visible laser has a bandwidth of 1 nm, a tuning range of 485-700 nm, and power between 1-10 mW; the visible supercontinuum spectrum ranges from 530-1000 nm with a total power of typically 40 mW.

At the system level, meanwhile, one of the more notable launches is the femtOgene laser microscope, billed as a "unique optical tool for nanobiotechnology, gene therapy and stem-cell research". Developed by JenLab, Germany, in collaboration with Austria's Femtolasers Produktions, the femtOgene is described as an ultracompact scanning nonlinear optical microscope with galvoscanners for beam scanning and focusing optics equipped with large-NA objectives (40x/1.3).

The instrument is based on a sub-20-femtosecond near-IR laser with high-order dispersion compensation, a technology that's said to overcome the problems of beam fluctuations observed in femtosecond laser systems based on prism technology. Specific applications for femtOgene will include optical "nanoinjection" of macromolecules; optical knock-out of cell organelles; and intracellular chromosome dissection.

That's all for today as I'm off to do some networking at the BiOS/Photonics West delegate reception this evening. More BiOS product news will be posted on the blog later this week, most likely when I get back to the office in Bristol.

Monday 14.00 PT: On Sunday, prompted by Rox Anderson's talk at the Hot Topics session (see previous post, "Looking for some hot stuff..."), I went along to listen to a couple of invited papers in a dedicated BiOS session on mechanisms for low-light-level therapy.

First up, Darayash Tata of the US Food and Drug Administration reported on an in vitro study of laser-induced modulations of the metabolic activities of malignant human-brain-cancer (glioblastoma) cells.

Tata and fellow investigator Ronald Waynant evaluated the efficacy of two light sources: a continuous-wave 633 nm wavelength helium-neon laser and a 1552 nm pulsed picosecond laser. During the study, glioblastoma cells were exposed in their growth-culture medium at several energy doses, with cellular metabolic activities measured via colorimetric assay three days after photo exposure.

Taken together, said Tata, "our findings reveal that optical or near-infrared low-level light exposures could potentially be a viable tool in reducing the metabolic activity of cancers."

In terms of a working hypothesis, the current thinking is that laser-induced changes in metabolism may result from laser-generated production of hydrogen peroxide (a natural by-product of cell respiration). More research is needed, however, to work out the exposure parameters that would optimize metabolic and cellular-growth suppression in vivo.

A second invited paper, presented by Juanita Anders, a professor in the department of anatomy, physiology and genetics at the Uniformed Services University of the Health Sciences (Bethesda, MD), highlighted the regenerative effects of laser light in the treatment of spinal-cord injury (i.e. severe central-nervous-system trauma for which there are currently no treatments).

Worldwide, it's estimated that there are 2.5 million people living with spinal-cord injury, with 130,000 new cases reported annually. All told, that equates to billions of dollars in acute and long-term care.

In recent years, Anders and her colleagues have carried out a number of light-therapy studies on rat models with spinal cord injury. The group's latest in vivo data, presented here at BiOS, demonstrate that light delivered transcutaneously promotes regeneration of axons (nerve fibres) and functional recovery.

It's early days, but Anders reckons the results are further evidence that low-level light is emerging as a "promising non-invasive therapy for acute spinal-cord injury".

Sunday 22.30 PT: Yesterday evening I joined over 500 hard-core biomedical-optics types for what's become something of a BiOS institution. I'm referring to the Hot Topics session, an annual event that's renowned as much for its beyond-the-call-of-duty timing (7 till 9.30 p.m. on conference Saturday) as for the masses of factual and quantitative information that speakers are required to cram into a 10-minute speaking slot.

Time - or rather the lack of it - precludes anything like a comprehensive write-up of all the Hot Topics. Instead I'll focus on a couple of papers that I think showcase the wide-ranging therapeutic and diagnostic potential of clinical photonics.

Rox Anderson

Rox Anderson, professor of dermatology at the Wellman Center for Photomedicine (Boston, MA), got the session started with a review of the latest advances in therapeutic lasers. He reckons that optical therapies are "poised for huge impact" and encouraged the audience to use BiOS and Photonics West to "network with MDs, heck even talk to me".

Over the years, Anderson and his colleagues have pioneered all manner of laser treatments - among them selective photothermolysis for the treatment of vascular birthmarks without scarring, as well as lasers for tattoo removal and permanent hair removal. His group is currently working on laser targeting of other skin structures, such as sebaceous glands, sweat glands and fat (see Free-electron lasers: ready to shine on medicalphysicsweb).

Anderson is particularly excited by progress in microbeam laser treatments. Here an array of invisibly small burns (or "little murders") are delivered to diseased skin tissue in such a way that it is possible to "tune" the depth of the beams. Future applications could include laser-surgery treatment for cancers of the larynx, lung, brain, bladder and breast.

Another area singled out for attention was low-level laser therapy, with Anderson citing impressive results published in the journal Stroke on the efficacy of infrared laser therapy as a new treatment strategy for ischaemic stroke (Stroke 2007 38 1843).

Subsequent Hot Topic papers, in the main, concentrated on the diagnostic capabilities of photonics. Mary-Ann Mycek, associate professor in the department of biomedical engineering at the University of Michigan (Ann Arbor, MI), provided a neat case study with a talk entitled "Probing pancreatic disease using tissue optical spectroscopy".

Pancreatic cancer is the fourth leading cause of cancer death in the US and has a five-year survival rate of only 4%. The biggest problem is late detection - due in large part to the inaccessibility of the organ, which complicates diagnosis via conventional radiological procedures (e.g. ultrasound, CT and MRI).

Subsequent treatment comprises lengthy and complex surgery, after which many patients turn out to have pancreatitis (a treatable inflammation of the organ) rather than pancreatic cancer. For any would-be optical interrogation scheme, the task is therefore to differentiate a cancerous organ from one affected by pancreatitis.

With this in mind, Mycek and her colleagues have studied fluorescence and reflectance data for normal and diseased pancreas tissue. In what's claimed to be the first limited pilot study to optically probe freshly excised human pancreatic tissue and in vivo human xenografts in mice, they observed increased reflectance from cancer cells (versus normal tissue and tissue exhibiting pancreatitis).

They've linked this behaviour to changes in optical scattering properties caused by the increased size of the cell nucleus in cancerous tissue. "Although the preliminary studies are small, optically detectable biomarkers appear to be consistent with disease progression," noted Mycek.

The other Hot Topics papers covered a diverse range of subject matter. Specifically:

• Monitoring and predicting chemotherapy using diffuse optics

• Imaging and treatment of cancer using gold nanoparticles

• Photoacoustic microscopy and computed tomography

• Real-time quantitative microscopy on the nanometre scale

• Multidimensional fluorescence imaging

• Single-molecule superresolution imaging and trapping

• Spectroscopy for diagnostic and interstitial photodynamic treatment control.

Sunday 09.00 PT: The US National Cancer Institute's Network for Translational Research in Optical Imaging is a multicentre programme tasked with realizing practical optical modalities for early cancer detection, cancer diagnosis and measurement of response to therapy. Yesterday evening I went along to a dedicated BiOS session to hear about the network's efforts in applying diffuse optical imaging for enhanced detection of breast cancer.

Brian Pogue, associate professor of engineering at Dartmouth College (Hanover, NH), kicked off the session by reviewing the integration of near-infrared spectroscopy (NIRS) into standard MRI and CT instrumentation. While this type of hybrid imaging is still in its infancy, he reckons that using it to guide therapy or to properly individualize the choice of therapy is "the next logical step".

Making light work

With this in mind, Dartmouth researchers, in collaboration with Philips Medical Systems, have developed a prototype small-animal imaging system that integrates NIRS into a 3 T MR breast biopsy coil.

"We use MR for imaging, NIR for spectroscopy," said Pogue, adding that such an approach allows quantification of molecular tracers and biophysical imaging of tissue using contrast mechanisms that are not otherwise available.

Right now, however, the optical-fibre interface (for light delivery) is too cumbersome for the clinical setting, while the cost of integration takes optical spectroscopy out of the "inexpensive category".

Soren Konecky of the University of Pennsylvania (Philadelphia, PA) provided an alternative take on the multimodal theme. His presentation reported on a small pilot study (17 patients) to evaluate the coregistration of diffuse optical tomography (DOT) and PET images of the human breast.

The purpose here is not primary detection of breast cancer, rather the evaluation of a patient's response to therapy and early identification of resistance factors during treatment - information which can be used by doctors to adapt the treatment plan accordingly.

Unlike CT, MRI and ultrasound, DOT and PET primarily measure the physiological characteristics of tissue, rather than its anatomical structure. So why use optical and PET modalities in tandem?

"The combined analysis of optically measured parameters, such as haemoglobin concentration/oxygenation and blood flow, with PET parameters, such as fluoro-deoxyglucose uptake as a measure of glucose metabolism, may provide new and important information," notes Konecky's conference abstract.

He adds that "coregistration of DOT and PET parameters affords a method for increased tumour sensitivity and specificity compared to the stand-alone modalities."

Sunday 06.00 PT: As promised, here's a brief report on the PDT sessions I attended yesterday. First up, Anna-Liisa Nieminen, associate professor of pharmaceutical and biomedical sciences at the Medical University of South Carolina (Charleston, SC), presented the latest results of a collaboration with Case Western Reserve University (Cleveland, OH). Nieminen and her colleagues are currently evaluating the relative performance of two types of cell organelles - lysosomes versus mitochondria - as binding sites for PDT photosensitizers.

"It is often found that mitochondrion-bound photosensitizers are more effective than lysosome-bound ones," Nieminen told BiOS delegates. The phthalocyanine photosensitizer Pc 4, for example, binds preferentially to mitochondria and endoplasmic reticulum and upon photoactivation induces apoptosis with high efficiency.

However, the Case-South Carolina researchers have synthesized a series of Pc 4 analogues, including a molecule called Pc 181 that appears to be taken up into human cancer cells more efficiently than Pc 4. What's intriguing about Pc 181 is that it binds preferentially to lysosomes (intracellular structures containing digestive enzymes) and is more efficient at overall cell killing than Pc 4.

Those unique properties, she added, may offer insights into the killing of cells via lysosomal photodamage and ultimately to "new photosensitizers providing much better cell kill power".

Later, the session chair Charles Gomer, professor of cancer biology, paediatrics, at the Children's Hospital Los Angeles, CA, presented a paper entitled "PDT effects on the tumour microenvironment: growing evidence for a combined-modality approach". Gomer is interested in how PDT can induce significant changes within the tumour microenvironment, changes that can lead to an angiogenic and/or a survival response.

A case in point is a molecule called survivin, an apoptosis-inhibiting protein, which is increased and activated in tumour cells and tissues following PDT. "Does PDT-mediated expression of survivin modulate treatment responsiveness?" he asked.

Gomer presented data confirming as much and concluded that a multimodality treatment approach that switches off the expression of survivin will lead to increased PDT efficacy.

Saturday 18.00 PT: Day one of BiOS has been a full-on affair - so full on, in fact, that there's barely time for me to make my excuses before I head back to the convention centre for the weekend's main event: the BiOS Hot Topics session (which runs from 7 till 9.30 tonight). For now, a headline take on Saturday is about all I can manage.

Photodynamic therapy (PDT), a technique that uses a light-activated drug to kill cancer cells, was one of the main themes in today's programme. I went along to hear a couple of invited papers on PDT effects in the tumour microenvironment, as well as catching a "bigger-picture" perspective on the impressive clinical efficacy of PDT in the treatment of early- and later-stage head-and-neck cancers.

Sign 'em up

One double espresso later (to keep the jetlag in check) and it was time to switch codes from therapeutics to diagnostics. The US National Cancer Institute's Network for Translational Research in Optical Imaging provided the content for a dedicated session reviewing progress in multimodality imaging for breast cancer, with specific emphasis on the use of diffuse optical imaging in combination with established clinical modalities like CT, MRI and PET.

I'll post more details on the above tomorrow morning, plus news and views from the Hot Topics session to follow later on Sunday.

09.00 GMT: The Main Event, medicalphysicsweb's conference blog, cranks back into action this weekend with daily reports from the Biomedical Optics Symposium (BiOS) in San Jose, California.

The BiOS meeting - part of a much larger, all-encompassing optics event called Photonics West - brings together university researchers, industry engineers and clinical scientists to discuss advances in fundamental optical science, technology development and emerging optics applications in medicine and biology. As such, BiOS has an important role to play in the transfer of photonics innovations out of the lab and into clinical practice.

Whether you're attending the meeting or not, The Main Event will endeavour to keep you in touch with the headline news from the conference sessions, as well as the pick of the products and technologies featured at the trade exhibition.

I'm off to Heathrow now. The first report on the meeting will be posted on Saturday evening PT.