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Imaging-biomarkers is Imaging-based tissue characterization

Posted in Advanced Drug Manufacturing Technology, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, International Global Work in Pharmaceutical, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacotherapy and Cell Activity, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged bio-markers, biomarkers, Cancer - General, cancer management, imaging-bio-markers, MRI, MRI sequence, research, tissue characterisation on March 10, 2013| 3 Comments »

Imaging-biomarkers is Imaging-based tissue characterization

Author – Writer: Dror Nir, PhD

• 

For everyone who is skeptical about the future role of imaging-based tissue chracterisation in the management of cancer, the following “Statement paper” ESR statement on the stepwise development of imaging biomarkers published online: 9 February 2013, by the European Society of Radiology (ESR), should provide substantial reassurance that this kind of technology will become a must! In support of this claim I quote the following information:

“The European Society of Radiology and its related European Institute for Biomedical Imaging Research (EIBIR) should have a relevant role in coordinating future developments of biomarkers and in the assessment and validation of imaging biomarkers as surrogate end points.

Acknowledgements

This paper was kindly prepared by the ESR Subcommittee on Imaging Biomarkers (Chairperson: Bernard Van Beers. Research Committee Chairperson: Luis Martí-Bonmatí. Members: Marco Essig, Thomas Helbich, Celso Matos, Wiro Niessen, Anwar Padhani, Harriet C. Thoeny, Siegfried Trattnig, Jean-Paul Vallée. Co-opted members: Peter Brader, Nicolas Grenier) on behalf of the European Society of Radiology (ESR) and with the help of Sabrina Doblas, INSERM U773, Paris, France.

It was approved by the ESR Executive Council in December 2012..”

According to ESR: “There is increasing interest in developing the quantitative imaging of biomarkers in personalised medicine”. In this perspective, “Biomarkers” are tissue properties that can be quantitatively and reproducibly measured by imaging devices. One example for a major unmet need, which I found to be most interesting is the imaging-based detection of tumor invasiveness.

Quoting from the paper: ” Biomarkers are defined as “characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathological processes, or pharmaceutical responses to a therapeutic intervention” [1]. Broadly, biomarkers fall into two categories: bio-specimen biomarkers, including molecular biomarkers and genetic biomarkers, and bio-signal biomarkers or imaging biomarkers. Bio-specimen biomarkers are obtained by removing a sample from a patient. Examples of these molecular biomarkers are genes and proteins detected from fluids or tissue samples. Bio-signal biomarkers remove no material from the patient, but rather detect and analyse an electromagnetic, photonic or acoustic signal emitted by the patient [2]. These imaging biomarkers have the advantage of being non-invasive, spatially resolved and repeatable [3]. They are of particular interest if they can overcome the limitations of the established histological “gold standards”. Indeed, invasive reference examinations, such as biopsy, can be inconclusive, are non-representative of the whole tissue (which is a tremendous limitation when assessing malignant tumours, which are known to be heterogeneous) and possess non-negligible levels of mortality and morbidity.

Genetic biomarkers indicate whether a disease may occur, but they are usually inefficient to assess the presence and stage of a disease. Similar to molecular biomarkers, imaging biomarkers can be used for early detection of diseases, staging and grading, and predicting or assessing the response to treatment [3]. Accordingly, because of their relative lower cost compared with imaging, molecular biomarkers may be more appropriate for disease screening and early detection than imaging biomarkers. With their high sensitivity, molecular biomarkers could also detect subclinical stages of disease before any morphological or functional change is detectable on imaging. In contrast, imaging biomarkers are often more useful than molecular biomarkers for disease staging, and also grading and for assessing tumour response, because localised information is crucial.”

The main messages ESR wishes to deliver in this paper are that:

• Using imaging-biomarkers to streamline drug discovery and disease progression will drive a huge advancement in healthcare.

• The clinical qualification and validation of imaging biomarkers technology pose challenges, mainly in establishing the accuracy and reproducibility of such techniques. In that respect, agreements on standards and evaluation methods (e.g. clinical studies design) is imperative.

• There should be high motivation to pursue the development of imaging-biomarkers as the “clinical value of new biomarkers is of the highest priority in terms of patient management, assessing risk factors and disease prognosis.”

The paper deals to a great extent with the requirements on accuracy, reproducibility, standardization and quality control from the process of developing imaging-biomarkers:

“Accuracy: Before being routinely used in the clinic, imaging biomarkers must be validated. Determining the accuracy implies calculating the sensitivity and specificity of the biomarker when compared with a biological process, such as tumour necrosis, which can be assessed at histopathological examination… [6–9]  [10, 11]

Reproducibility: Repeatability (measurements at short intervals on the same subjects using the same equipment in the same centres) and reproducibility (measurements at short intervals on the same subjects using different facilities in the same and different centres) studies must be conducted for image acquisition and image analysis…. Reproducibility studies are now very often included in scientific papers, as advised by the “standards for reporting of diagnostic accuracy” (STARD) criteria and should ideally include Bland-Altman plots and results of coefficients of repeatability [16, 17].

Standardisation: Standardisation relates to the establishment of norms or requirements about technical aspects. In the development of imaging biomarkers, two main aspects should be considered: Standardisation of image acquisition and Standardisation of image analysis…  [18] [19–21]  [22] [27, 28] [31–33]

Quality control: Adequate phantoms could be used to validate, on a day-to-day basis, that the biomarker stays robust and to avoid any drift in the machine, acquisition or processing protocol….  [34] [30, 35] [36] [37] [23].”

The proposed development workflow:

“Similar to new drugs, the development of biomarkers has to pass along a pipeline going from discovery, through verification in different laboratories, validation and qualification before they can be used in clinical routine. Validation includes the determination of the accuracy and the precision (reproducibility) of the biomarker and standardisation concerns both acquisition and analysis. Qualification, defined as a “graded, fit-for-purpose evidentiary process linking a biomarker with biological processes and clinical end-points”, is a validation process in large cohorts of patients involving multiple centres, similar to phase III clinical trials, to obtain regulatory approval as surrogate endpoints [4]. A more extensive path to biomarker development has been reported [5]. The first step is the proof of concept, which defines any specific change relevant to the disease that can be studied using the available imaging and computational techniques. The relationship between this change and the presence, grading and response to treatment of the disease constitutes the proof of mechanism. The images needed to extract the biomarker must be appropriate (in terms of resolution, signal and contrast behaviour). Preparation of images relates to improving the data before the analysis (such as segmentation, filtering, interpolation or registration). The analysis and modelling of the signal by computational numerical adjustment of a mathematical model allow extracting the needed information (such as structural, physical, chemical, biological and functional properties). After this voxel-by-voxel computation, the spatial distribution of the biomarker can be depicted by parametric images, defined as derived secondary images which pixels represent the distribution values of a given parameter. Multivariate parametric images obtained by statistical modelling of the relevant parameters allow the reduction of data and a clear definition of the defined disease target. The abnormal values should be defined and measured through histogram analysis. A pilot test on a small sample of subjects, with and without the disease, has to be performed to validate the process—also called proof of principle—and to evaluate the influence of potential variations related to age, sex or any other source of biases. Finally, proofs of efficacy and effectiveness on larger and well-defined series of patients will show the ability of a biomarker to measure the clinical endpoint (Fig. 1).”

Steps for the development of imaging biomarkers (adapted from [5])

The authors admit that the requirement posed on development of imaging-biomarkers represents a huge challenge and they try to offer ideas, mainly taken from the “MRI experience” to overcome certain hurdles. There is one important point on which they do not discuss: the definition of appropriate reference test. It is my own experience, based on many study protocols I developed in the past decade, that without reaching an agreement on that point, the development of imaging-biomarkers will just move in circles. Note, that today’s most “acceptable” reference test is histopathology, which everyone admits (as well mentioned in this paper); suffers many limitations. When it comes to validating imaging-biomarkers, the need to accurately match imaging products with histopathology is an additional major hurdle.

This is why, I see as a necessary step, to develop “real-time” imaging based tissue characterization combined with in-situ imaging-based histology.

 

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Alzheimer’s Disease Conundrum – Are We Near the End of the Puzzle?

Posted in Advanced Drug Manufacturing Technology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Cerebrovascular and Neurodegenerative Diseases, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Human Immune System in Health and in Disease, Innovations in Neurophysiology & Neuropsychology, International Global Work in Pharmaceutical, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Alois Alzheimer, Alzheimer, Alzheimer Disease, Alzheimers Disease, ApoE, BCHE brain imaging, Beta amyloid, biomarkers, cellular inflammatiory response, CLU, conitive loss, Decode Genetics, dementia, Icelanders, innovative applications, Kári Stefánsson, mapping, Massachusetts General Hospital, Picalm, plaque regression, Tau protein on March 9, 2013| 1 Comment »

Alzheimer’s Genomic Diagnosis and Treatment

Curator: Larry H Bernstein, MD, FCAP

 

Gene Mutation Protects Against Alzheimer’s

by Greg Miller on 11 July 2012
Brain preserver. A newly discovered gene mutation appears to protect against Alzheimer’s disease. Credit: Alzheimer’s Disease Education and Referral Center/NIA/NIH
http://news.sciencemag.org/sciencenow/2012/07/gene-mutation-protects-against-a.html

A rare mutation that alters a single letter of the genetic code protects people from the

• memory-robbing dementia of Alzheimer’s disease.

The DNA change may inhibit the buildup of β amyloid, the

• protein fragment that forms the hallmark plaques in the brains of Alzheimer’s patients.
• The mutation affects a gene called APP,
• which encodes a protein that gets broken down into pieces,
• including β amyloid.

Researchers previously identified more than 30 mutations to APP, none of them good. Several of these changes increase β amyloid formation and cause

•      a devastating inherited form of Alzheimer’s that afflicts people in their 30s and 40s—

•      much earlier than the far more common “late-onset” form of Alzheimer’s

• that typically strikes people their 70s and 80s.

The new mutation, discovered from whole-genome data from 1795 Icelanders for variations in APP that protect against Alzheimer’s, appears to do the opposite. The mutation interferes with one of the enzymes that breaks down the APP protein and causes a 40% reduction in β amyloid formation

New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F.
University of Catania, Viale Andrea Doria 6, Catania, Italy.
Br J Clin Pharmacol. 2012 Apr;73(4):504-17. doi: 10.1111/j.1365-2125.2011.04134.x.

Current approved drug treatments for Alzheimer disease (AD) include

• cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the
• NMDA receptor antagonist memantine.

These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop ‘disease modifying drugs’ hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success,

• it is crucial to have biomarkers for early detection of AD-related brain dysfunction,
  • usable before clinical onset.

Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy,

• with specific cut off values validated in clinical practice.

Disease modifying drugs developed so far include drugs to

• reduce β amyloid (Aβ) production,
• drugs to prevent Aβ aggregation,
• drugs to promote Aβ clearance,
• drugs targeting tau phosphorylation and assembly

None of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from

• methodological flaws to
• fundamental understanding of AD pathophysiology and biology.

Diagnostic criteria applicable to presymptomatic stages of AD have now been published.

These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. http://www.ncbi.nlm.nih.gov/pubmed/22035455

Gene mutation defends against Alzheimer’s disease
Rare genetic variant suggests a cause and treatment for cognitive decline.
Ewen Callaway  11 July 2012
http://www.nature.com/news/gene-mutation-defends-against-alzheimer-s-disease-1.10984

J. NIETH/CORBIS
Almost 30 million people live with Alzheimer’s disease worldwide, a staggering health-care burden that is expected to quadruple by 2050. Yet doctors can offer no effective treatment, and scientists have been unable to pin down the underlying mechanism of the disease.
Research published this week offers some hope on both counts – few people carry a genetic mutation that naturally prevents them from developing the condition – 0.5% of Icelanders have a protective gene, as are 0.2–0.5% of Finns, Swedes and Norwegians. Icelanders who carry it have a 50% better chance of reaching age 85, are more than five times more likely to reach it 85 without Alzheimer’s.   The mutation seems to put a brake on the milder mental deterioration that most elderly people experience. Carriers are about 7.5 times more likely than non-carriers to reach the age of 85 without major cognitive decline, and perform better on the cognitive tests that are administered thrice yearly to Icelanders who live in nursing homes.
The discovery not only confirms the principal suspect that is responsible for Alzheimer’s, it also suggests that the disease could be

• an extreme form of the cognitive decline seen in many older people.

The mutation — the first ever found to protect against the disease — lies in a gene that produces

• amyloid-β precursor protein (APP),
• which has an unknown role in the brain

APP was discovered 25 years ago in patients with rare,

• inherited forms of Alzheimer’s that strike in middle age.
• In the brain, APP is broken down into a smaller molecule called amyloid-β.

Visible clumps, or plaques, of amyloid-β found in the autopsied brains of patients are a hallmark of Alzheimer’s.
Scientists have long debated whether the plaques are a cause of the neuro­degenerative condition

• or a consequence of other biochemical changes associated with the disease.

The latest finding supports other genetics studies blaming amyloid-β, according to Rudolph Tanzi, a neurologist at the Massachusetts General Hospital in Boston and a member of one of the four teams that discovered APP’s role in the 1980s.
If amyloid-β plaques were confirmed as the cause of Alzheimer’s, it would bolster efforts to develop drugs that block their formation, says Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik, Iceland, who led the latest research. He and his team first discovered the mutation by comparing the complete genome sequences of 1,795 Icelanders with their medical histories. The researchers then studied the variant in nearly 400,000 more Scandinavians.
This suggests that Alzheimer’s disease and cognitive decline are two sides of the same coin, with a common cause — the build-up of amyloid-β plaques in the brain, something seen to a lesser degree in elderly people who do not develop full-blown Alzheimer’s. A drug that mimics the effects of the mutation, might slow cognitive decline as well as prevent Alzheimer’s.
Stefánsson and his team discovered that the mutation introduces a single amino-acid alteration to APP. This amino acid is close to the site where an enzyme called

• β-secretase 1 (BACE1) ordinarily snips APP into smaller amyloid-β chunks —
• and the alteration is enough to reduce the enzyme’s efficiency.

Stefánsson’s study suggests that blocking β-secretase from cleaving APP has the potential to prevent Alzheimer’s, but Philippe Amouyel, an epidemiologist at the Pasteur Institute in Lille, France, says “it is very difficult to identify the

• precise time when this amyloid toxic effect could still be modified”.

“If this effect needs to be blocked as early as possible in life to protect against Alzheimer’s disease, we will need to propose a new design for clinical trials” to identify an effective treatment.

The results demonstrate that whole-genome sequencing can uncover very rare mutations that might offer insight into common diseases.

• disease risk, may be determined by genetic variants that slightly tilt the odds of developing disease
• In this case a rare mutant may provide very key mechanistic insights into Alzheimer’s

Jonsson, T. et al. Nature     http://dx.doi.org/10.1038/nature11283 (2012).
Kang, J. et al. Nature 325, 733–736 (1987).
Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U. & Gajdusek, D. C. Science 235, 877–880 (1987).

BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss.   http://www.genengnews.com/

New Alzheimer’s Genes Found
Gigantic Scientific Effort Discovers Clues to Treatment, Diagnosis of Alzheimer’s Disease
By Daniel J. DeNoon
WebMD Health News Reviewed by Laura J. Martin, MD
http://www.webmd.com/alzheimers/news/20110403/new-alzheimers-genes-found

A massive scientific effort has found five new gene variants linked to Alzheimer’s disease. The undertaking involved analyzing the genomes of nearly 40,000 people with and without Alzheimer’s. This study was undertaken by two separate research consortiums in the U.S. and in Europe, which collaborated to confirm each other’s results.
Four genes had previously been linked to Alzheimer’s. Three of them affect only the risk of relatively rare forms of Alzheimer’s. The fourth is APOE, until now the only gene known to affect risk of the common, late-onset form of Alzheimer’s. Roughly 27% of Alzheimer’s disease can be attributed to the five new gene variants.  Even though Alzheimer’s is a very complex disease, the new findings represent a large chunk of Alzheimer’s risk, according to Margaret A. Pericak-Vance, PhD, of the U.S. consortium –

• 20% of the causal risk of Alzheimer’s disease and
• 32% of the genetic risk.

Alzheimer’s Tied to Mutation Harming Immune Response
By GINA KOLATA   Published: November 14, 2012  in NY Times
http://www.nytimes.com/2012/11/15/health/gene-mutation-that-hobbles-immune-response-is-linked-to-alzheimers.html?_r=0
Alzheimer’s researchers and drug companies have for years concentrated on one hallmark of Alzheimer’s disease: the production of toxic shards of a protein that accumulate in plaques on the brain.
Two groups of researchers working from entirely different starting points have converged on a mutated gene involved in another aspect of Alzheimer’s disease:

• the immune system’s role in protecting against the disease.

The mutation is suspected of interfering with

• the brain’s ability to prevent the buildup of plaque.

When the gene is not mutated, white blood cells in the brain spring into action,

• gobbling up and eliminating the plaque-forming toxic protein, beta amyloid.

As a result, Alzheimer’s can be staved off or averted.  People with the mutated gene have a threefold to fivefold increase in the likelihood of developing Alzheimer’s disease in old age.

Comparing Differences

Dr. Julie Williams’s, Cardiff, Wales (European team leader) report identified CLU and Picalm. A second study published in Nature Genetics, by Philippe Amouyel from Institut Pasteur de Lille in France, pinpointed CLU and CR1. The greatest inherited risk comes from the APOE gene, discovered in 1993 by a team led by Allen Roses, now director of the Deane Drug Discovery Institute at Duke UMC, in Durham, North Carolina.
The findings “are beginning to give us insight into the biology, but I don’t think you can expect treatments overnight,” Dr. Michael Owen (Cardiff, Wales) said. Instead, the genes will show a mosaic of risk, and “the key issue is what hand of cards you’re dealt,” he said.

Promise for Early Diagnosis
BHCE genetic data combined with brain imaging using agent florbetapir connects the BHCE gene to AD plaque buildup. BHCE is an enzyme that breaks down acetylcholine in the brain, which is depleted early in the disease and results in memory loss.

Dr. Bernstein’s comments:

1. There has been a long history of failure of drugs to slow down the progression of Alzheimer’s.  Regression of the plaques has not corresponded with retention of cognitive ability, which has been behind the arguments over beta amyloid or tau.
2. We now have two particularly interesting mutations –
   1. ApoE gene mutation that increases risk
   2. APP mutation that quite dramatically affects retention of cognition

Related articles

• Alzheimer’s Disease: Green Tea Extract Found To Interfere With The Formation Of Amyloid Plaques (medicalnewstoday.com)
• Aging Brain – The Specific Gene That Causes It (belmarrahealth.com)
• The Pathogenic Aβ43 Is Enriched in Familial and Sporadic Alzheimer Disease (plosone.org)
• Damaged blood vessels loaded with amyloid worsen cognitive impairment in Alzheimer’s disease (eurekalert.org)
• Major step toward an Alzheimer’s vaccine (nextbigfuture.com)
• Damaged blood vessels loaded with amyloid worsen cognitive impairment in Alzheimer’s disease (medicalxpress.com)
• Top Signs You are at Risk for Alzheimer’s (belmarrahealth.com)
• A Reliable Way to Detect Endogenous Murine β-Amyloid (plosone.org)

β-amyloid fibrils. (Photo credit: Wikipedia)

English: PET scan of a human brain with Alzheimer’s disease (Photo credit: Wikipedia)

Depiction of amyloid precursor protein processing, created by I. Peltan Ipeltan (Photo credit: Wikipedia)

English: Diagram of how microtubules desintegrate with Alzheimer’s disease Français : La protéine Tau dans un neurone sain et dans un neurone malade Español: Esquema que muestra cómo se desintegran los microtúbulos en la enfermedad de Alzheimer (Photo credit: Wikipedia)

English: Histopathogic image of senile plaques seen in the cerebral cortex in a patient with presenile onset of Alzheimer disease. Bowdian stain. The same case as shown in a file “Alzheimer_dementia_(1)_presenile_onset.jpg”. (Photo credit: Wikipedia)

 

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Virtual Biopsy – is it possible?

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Ecosystems & Industrial Concentration in the Medical Device Sector, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, biopsy, Cancer - General, coherence tomography, health, medicine, OCT, optical coherence, optical coherence tomography, research, resolution reconstruction, virtual biopsy on March 3, 2013| 7 Comments »

Virtual Biopsy – is it possible?

Author and Curator: Dror Nir, PhD

• 

In a remark made to my last post: New envelopment in measuring mechanical properties of tissue, Dr. Aviva Lev-Ari, PhD, RN, Director and Founder of our Open Access Online Scientific Journal:  Leaders of Pharmaceutical Business Intelligence, asked whether OCT can be used for the purpose of performing biopsy. My answer to her question was “YES”. I thought that it will be worthwhile explaining why I am so “optimistic” about this:

A conventional biopsy is a process where a tissue sample is being cut out of the body and after being subjected to all kind of chemical processes a thin-film of tissue is trimmed and read under the microscope by a trained pathologist. Can imaging provide histological assessment of “thin-film” of tissue without cutting it out of the body? The answer would be positive if the imaging will result with high resolution reconstruction of a tissue sample identical in quality to a “live-sample” that is put under the microscope.

I was happy to find support to my optimism regarding the feasibility of constructing such device in the following article: Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma published on February 20^th 2013 in Ann Rheum Dis doi:10.1136/annrheumdis-2012-202682

 This article reports an original, first study to perform histological comparison and explore Optical coherence tomography (“OCT”) as a potential imaging technique for the clinical assessment of patients presenting with systemic sclerosis (“SSc”). In their study the investigators used a device emitting low-intensity infrared laser beam, capable of producing high-contrast images of skin up to 2 mm deep with resolutions of 4–10 μm.

[START ORIGINAL PAPER]

ABSTRACT

Background

Skin involvement is of major prognostic value in systemic sclerosis (SSc) and often the primary outcome in clinical trials. Nevertheless, an objective, validated biomarker of skin fibrosis is lacking. Optical coherence tomography (OCT) is an imaging technology providing high-contrast images with 4 μm resolution, comparable with microscopy (‘virtual biopsy’). The present study evaluated OCT to detect and quantify skin fibrosis in SSc.

Methods

We performed 458 OCT scans of hands and forearms on 21 SSc patients and 22 healthy controls. We compared the findings with histology from three skin biopsies and by correlation with clinical assessment of the skin. We calculated the optical density (OD) of the OCT images employing Matlab software and performed statistical analysis of the results, including intraobserver/ interobserver reliability, employing SPSS software.

 Results

Comparison of OCT images with skin histology indicated a progressive loss of visualisation of the dermal–epidermal junction associated with dermal fibrosis. Furthermore, SSc affected skin showed a consistent decrease of OD in the papillary dermis, progressively worse in patients with worse modified Rodnan skin score (p<0.0001). Additionally, clinically unaffected skin was also distinguishable from healthy skin for its specific pattern of OD decrease in the reticular dermis (p<0.001). The technique showed an excellent intraobserver and interobserver reliability (intraclass correlation coefficient >0.8).

Conclusions

OCT of the skin could offer a feasible and reliable quantitative outcome measure in SSc. Studies determining OCT sensitivity to change over time and its role in defining skin vasculopathy may pave the way to defining OCT as a valuable imaging biomarker in SSc.

Virtual skin biopsy by OCT

The OCT images acquisition allowed the reconstruction of a virtual skin biopsy measuring 4×0.4×2 mm. The main structure of the healthy skin was easily recognisable by OCT (figure 1).

Virtual biopsy of forearm skin by optical coherence tomography. Representative 3D reconstruction from the tomography of healthy and systemic sclerosis (SSc) (site modified Rodnan skin score=3) skin scans. The keratin of the skin appears as a white line on the surface (k). The epidermis (ED) is quite visible in the healthy skin by the contrast with the increased optical density of the papillary dermis (PD). The dermal– epidermal junction (DEJ) is quite visible in the healthy skin between the ED and PD. On the contrary, neither clear distinction of ED and PD or DEJ is appreciable in the SSc skin. The vessels (*) are numerous and very well recognisable in healthy skin, whereas they appear less numerous and less distinct in the OCT image of SSc skin. Total depth of 3D reconstruction=1.2 mm. Scale bars are calculated by ImageJ.

Some quantitative results  – in images:

Validation of optical coherence tomography (OCT) images by histology. (A and B) H&E staining (A) and corresponding OCT scan (B) from a healthy control (HC). The green line is the mean A-scan of the entire OCT image (100 scans) overlaid by matching the scale bars of OCT and histology. The green arrow indicates the nadir of the valley in the mean A-scan, which corresponds to the dermal–epidermal junction clearly visible on both images. The green arrowhead indicates the second peak of the mean OCT A-Scan which corresponds by the overlay to the most superficial region of the papillary dermis. (C and D) H&E staining (C) and corresponding OCT scan (D) from a systemic sclerosis (SSc) patient (site modified Rodnan skin score =3). The red line is the mean A-scan of the OCT image, overlaid by matching the scale bars in the two panels. The red arrow indicates the nadir in the valley of the mean A-scan, which in this case does not correspond to the dermal–epidermal junction. The red arrowhead corresponds to the second peak in mean A-Scan. (E) Overlay of HC and SSc. Scale bar=240 μm.

Optical coherence tomography (OCT) of affected and not affected skin in plaque morphea. (A) OCT of not affected skin. Vertical scale represents depth in micrometre from the surface. The dermal–epidermal junction (DEJ) level is indicated by the white dotted line. Mean A-scan curve is overlaid and displayed in green. (B) OCT of affected skin in morphea patient. Mean A-scan curve is overlaid and displayed in red. Note the poorly visible DEJ and the valley of the curve below the DEJ (arrowhead). (C) Overlay of mean A-scan curves from the analysis of affected and unaffected skin in a morphea patient. Note that in the curves overlay graph both the difference depth of the first valley is clearly appreciable (arrowheads). Similarly the second mean A-scan peak (arrow) is subtle in the affected skin, similar to scleroderma affected skin.

DISCUSSION

The current gold standard for semiquantitative assessment of skin fibrosis, the mRSS, suffers from several shortcomings ranging from the subjectivity of skin palpation assessments and the high level of skill required from the clinical investigator. Even more importantly, a meta-analysis of three independent studies determined an overall within patient interobserver SD of five units independently of the mean skin score,[6 21] which represents an SE ranging from 20% to 26%. A primary outcome measure with 25% of SE entails the recruitment of a large number of patients to attain statistical validity in minimally significant changes, a task often difficult to accomplish given the comparatively low incidence of SSc.

A robust imaging biomarker for the assessment of skin fibrosis in SSc has not previously been reported. Herein we report the first study aimed to validate OCT for the quantitative assessment of skin involvement in SSc.

To date, the limited data on surrogate outcome measures for skin involvement are largely composed of histopathological or molecular changes in affected skin.[22 23] Despite conceptually very valuable, these studies, involving skin biopsies, are invasive and limited because of a site bias, referring to only one precise body area. Moreover, they are difficult to repeat in longitudinal manner and showed no sensitivity to change over time.[24] In this study, we evaluated OCT skin scanning as a reliable and quanti­tative tool that could be used as a surrogate marker of skin fibrosis. The technique requires minimal operator training, less than 10s per site examined, and offers the great advantage of saving image files for further or centralised operator independ­ent analysis. This latter is a particularly useful tool limiting the ‘hands on’ time in the clinic office and allowing a centralised, blinded assessment of results in clinical trials.

We observed an excellent correlation of OCT mean A-Scan curves and mRSS score at the site of analysis. More importantly, the corroboration of our OCT findings with pathological changes at the DEJ provides a robust construct validity for the technique. Of interest, we found that the changes of the OD of the dermis in SSc are similar to the ones observed in a case of plaque morphea, corroborating even further the potential value of OCT in measuring skin fibrosis.

Additional Comment

HFUS (High Frequensy Ultrasound) has been recently suggested to offer a quantitative assessment of skin thickness in SSc by several studies.8–10 In contrast with ultrasound, OCT does not require any use of gels, is able to give a higher resolution images and the analysis algo­rithm is automatic, not involving any operator interpretation. Nevertheless, since the penetration of OCT is limited to the first millimetre of skin, OCT and HFUS may be explored as comple­mentary imaging biomarkers in SSc.

REFERENCES

1     Jimenez SA, Derk CT. Following the molecular pathways toward an understanding
of the pathogenesis of systemic sclerosis. Ann Intern Med 2004;140:37–50.

2     Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder.
J Clin Invest 2007;117:557–67.

3     Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med
2009;360:1989–2003.

4     Clements PJ, Hurwitz EL, Wong WK, et al. Skin thickness score as a predictor and
correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine trial. Arthritis Rheum 2000;43:2445–54.

5     Steen VD, Medsger TA Jr. Improvement in skin thickening in systemic sclerosis
associated with improved survival. Arthritis Rheum 2001;44:2828–35.

6     Pope JE, Baron M, Bellamy N, et al. Variability of skin scores and clinical
measurements in scleroderma. J Rheumatol 1995;22:1271–6.

Clements PJ, Lachenbruch PA, Seibold JR, et al. Skin thickness score in systemic

sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20:1892–6.

   8     Akesson A, Hesselstrand R, Scheja A, et al. Longitudinal development of skin
involvement and reliability of high frequency ultrasound in systemic sclerosis. Ann Rheum Dis 2004;63:791–6.

   9     Moore TL, Lunt M, McManus B, et al. L. Seventeen-point dermal ultrasound scoring
system—a reliable measure of skin thickness in patients with systemic sclerosis. Rheumatology (Oxford) 2003;42:1559–63.

10     Kaloudi O, Bandinelli F, Filippucci E, et al. High frequency ultrasound

measurement of digital dermal thickness in systemic sclerosis. Ann Rheum Dis 2010;69:1140–3.

11     Aden N, Shiwen X, Aden D, et al. Proteomic analysis of scleroderma lesional skin
reveals activated wound healing phenotype of epidermal cell layer. Rheumatology (Oxford) 2008;47:1754–60.

12     Aden N, Nuttall A, Shiwen X, et al. Epithelial Cells Promote Fibroblast Activation via
IL-1alpha in Systemic Sclerosis. J Invest Dermatol 2010;130:2191–200.

13     Gambichler T, Jaedicke V, Terras S. Optical coherence tomography in dermatology:
technical and clinical aspects. Arch Dermatol Res 2011;303:457–73.

14     Marschall S, Sander B, Mogensen M, et al. Optical coherence tomography-current
technology and applications in clinical and biomedical research. Anal Bioanal Chem 2011;400:2699–720.

15     Coleman AJ, Richardson TJ, Orchard G, et al. Histological correlates of optical
coherence tomography in non-melanoma skin cancer. Skin Res Technol 2013;19: e10–9.

16     Preliminary criteria for the classification of systemic sclerosis (scleroderma).
Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581–90.

17     Collins TJ. ImageJ for microscopy. Biotechniques 2007;43:25–30.

18     Clendenon JL, Phillips CL, Sandoval RM, et al. Voxx: a PC-based, near real-time

volume rendering system for biological microscopy. Am J Physiol Cell Physiol 2002;282:C213–18.

19     Bland JM, Altman DG. Statistical methods for assessing agreement between two
methods of clinical measurement. Lancet 1986;1:307–10.

20     LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis):
classification, subsets and pathogenesis. J Rheumatol 1988;15:202–5.

21     Merkel PA, Silliman NP, Clements PJ, et al. Patterns and predictors of change in
outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2012;64:3420–9.

22     Farina G, Lafyatis D, Lemaire R, et al. A four-gene biomarker predicts skin disease
in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2010;62:580–8.

23     Milano A, Pendergrass SA, Sargent JL, et al. Molecular subsets in the gene
expression signatures of scleroderma skin. PLoS One 2008;3:e2696.

  24   Pendergrass SA, Lemaire R, Francis IP, et al. Intrinsic gene expression subsets of

diffuse cutaneou

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New development in measuring mechanical properties of tissue

Posted in Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Cancer - General, Clinical trial, elastography, health, Magnetic resonance imaging, magnetic resonance imaging mri, OCT, research, science, tissue, tissue differentiation on February 22, 2013| Leave a Comment »

New development in measuring mechanical properties of tissue

Author – Writer: Dror Nir, PhD

• 

Measuring the effects induced onto imaging by the mechanical properties of tissue is a common approach to differentiate tissue abnormalities. In previous posts I discussed the applicability of imaging applications that visualize variations in tissue stiffness; e.g. ultrasound-elastography and MRI-elastography as aid in the diagnosis workflow of cancer. Today, I would like to report on a recent publication made in SPIE Newsroom describing an optical-imaging system to measure tissue stiffness at high resolution. I think that such emerging technologies should be followed up as they bear promise to bridge deficiencies of the traditional modalities currently in use.

Reporting on: Optical elastography probes mechanical properties of tissue at high resolution

By: David Sampson, Kelsey Kennedy, Robert McLaughlin and Brendan Kennedy

Information published at: SPIE Newsroom – Biomedical Optics & Medical Imaging

Probing the micro-mechanical properties of tissue using optical imaging might offer new surgical tools that enable improved differentiation of tissue pathologies, such as cancer or atherosclerosis.

11 January 2013, SPIE Newsroom. DOI: 10.1117/2.1201212.004605

Elastography is an emerging branch of medical imaging that uses mechanical contrast to better characterize tissue pathology than can be achieved with structural imaging alone. It achieves this by imaging a tissue’s response to mechanical loading. Although commercial products based on ultrasonography and magnetic resonance imaging (MRI) have been available for several years, these new modalities offer superior tissue differentiation deep in the human body. However, elastography is limited by its low resolution compared with the length scales relevant to many diseases. Increasing the resolution with optical techniques might offer new opportunities for elastography in medical imaging and surgical guidance.

An elastography system requires a means of loading the tissue to cause deformation and an imaging system with sufficient sensitivity and range to capture this deformation. Implicit in these requirements is access to the tissue of interest. Optical elastography has previously been largely based on schemes that suit small tissue samples rather than intact tissue in living humans. Additionally, such schemes have not had the sensitivity or range to produce high-fidelity images of mechanical properties. We have addressed both these issues in our recent work, developing the means to access tissues in vivo and improve the sensitivity and range of optical elastography using phase-sensitive optical coherence tomography as the underlying modality. The use of optical coherence tomography to perform elastography has come to be referred to as optical coherence elastography.¹

To make optical coherence elastography on human subjects feasible, we designed an annular piezoelectric loading transducer (see Figure 1), through which we could simultaneously image, enabling the first in vivo dynamic optical coherence elastography on human subjects.² We were subsequently able to extend this to three dimensions (see Figure 2), in collaboration with Stephen Boppart’s group at the University of Illinois at Urbana-Champaign.³ This extension took advantage of the high speed of spectral-domain optical coherence tomography, and the maturity of phase-sensitive detection techniques originally developed for Doppler flowmetry and microangiography.

 

Figure 1. Schematic (left) and photograph (right) of the annular load transducer and imaging optics for in vivo optical coherence elastography.

 

Figure 2. 2D images of in vivo human skin selected from 3D stacks. (a) Optical coherence tomography image and (b) the same image overlaid by the 2D dynamic elastogram recorded at 125Hz load frequency, highlighting the greater strain in the epidermis. Reprinted in modified form with permission.³

For general access to tissues in the body, optical coherence elastography faces two basic limitations. The free-space probe requires miniaturization for versatile access to tissue in confined or convoluted geometries. We addressed this in studies of the elastic properties of human airways using catheter-based anatomical optical coherence tomography.⁴

 

Figure 3. (a) Schematic diagram of needle optical coherence elastography. The phase difference Δφ=φ₁– φ₂ determines the displacement, d, when scaled by the wavelength, λ, and refractive index, n. (b) Needle and pig trachea. (c) Local displacement versus distance, with tissue boundaries indicated by red stars. (d) Representative histology. Reprinted in modified form with permission.⁶

More fundamentally, optical coherence tomography can only penetrate, at best, 1–2mm into most tissues, limiting it to superficial applications. To address this issue, we combined optical coherence elastography with needle probes, an active research area in our group (see Figure 3).⁵ We conveniently use the needle probe itself to deform the tissue during insertion.⁶ The deformation ahead of the needle tip depends on the mechanical properties of the tissue encountered, as well as on the nearby tissue environment, particularly on any interfaces ahead of it. We measure the local sub-micrometer displacement of the tissue between two positions of the moving needle probe. We plot this displacement versus distance ahead of the probe: see Figure 3(c). The slope of the displacement at location z is a measure of the local strain. A change in slope signifies a change in tissue stiffness; the steeper the slope, the softer the tissue (other things being equal). Figure 3 highlights this effect in a layered sample of pig trachea. The positions of the changes in slope correlate well with the tissue interfaces shown in the accompanying histology: see Figure 3(d).

The other key area of improvement we have focused on is lowering the optical coherence elastography noise floor by increasing the detection sensitivity, which is vital to make clinical imaging practical. We firstly showed that Gaussian-smoothed, weighted-least squares strain estimation improved the sensitivity of estimates by up to 12dB over conventional finite-difference methods.⁷ Next, we showed that performance could be further improved at low optical coherence tomo- graphy signal-to-noise ratios (and, therefore, at greater depths in tissue) by employing a 2D Fourier transform technique.⁸Combined with other system refinements, these improvements have enabled us to reach a displacement sensitivity of 300pm for typical optical coherence tomography signal-to-noise ratios in tissue, with room for improvement.

The Young’s modulus of soft tissue varies from kPa to tens of MPa, whereas the scattering coefficient of such tissues—which is largely responsible for determining the contrast of optical coherence tomography—is typically in the range 2–20mm⁻¹. This apparent native advantage in mechanical over optical contrast (see the example in Figure 4), combined with the maturation of optical coherence elastography methods, bodes well for the future. In our group, we are pursuing tumor-margin identification using elastography; others have begun to consider corneal elastography,^{9, 10} and still others are examining shear wave schemes with the aim of probing Young’s modulus much deeper in tissues.^11,12

 

Figure 4. Optical coherence tomography (a) and optical coherence elastography (b) images of the same phantom with two inclusions visible, showing enhanced mechanical over scattering contrast.

Optical elastography currently sits at a similar stage of development as ultrasound elastography did in 1999. Based on a similar trajectory, this field will rapidly expand over the next decade. Our recent results point to the first convincing applications of optical elastography being just around the corner.

We acknowledge funding for this work from Perpetual Trustees, the Raine Medical Research Foundation, the Cancer Council of Western Australia, the Australian Research Council, the National Health and Medical Research Council (Australia), and the National Breast Cancer Foundation (Australia).

---

David Sampson

Optical+Biomedical Engineering Laboratory
School of Electrical, Electronic and Computer Engineering

and
Centre for Microscopy, Characterisation and Analysis
The University of Western Australia

 

Perth, Australia

Kelsey Kennedy, Robert McLaughlin, Brendan Kennedy

Optical+Biomedical Engineering Laboratory
School of Electrical, Electronic and Computer Engineering
The University of Western Australia

Perth, Australia

---

References:

1. J. Schmitt, OCT elastography: imaging microscopic deformation and strain of tissue, Opt. Express 3(6), p. 199-211, 1998.doi:10.1364/OE.3.000199

2. B. F. Kennedy, T. R. Hillman, R. A. McLaughlin, B. C. Quirk, D. D. Sampson, In vivo dynamic optical coherence elastography using a ring actuator, Opt. Express 17(24), p. 21762-21772, 2009.doi:10.1364/OE.17.021762

3. B. F. Kennedy, X. Liang, S. G. Adie, D. K. Gerstmann, B. C. Quirk, S. A. Boppart, D. D. Sampson, In vivo three-dimensional optical coherence elastography, Opt. Express 19(7), p. 6623-6634, 2011.doi:10.1364/OE.19.006623

4. J. P. Williamson, R. A. McLaughlin, W. J. Noffsingerl, A. L. James, V. A. Baker, A. Curatolo, J. J. Armstrong, Elastic properties of the central airways in obstructive lung diseases measured using anatomical optical coherence tomography, Am. J. Resp. Crit. Care 183(5), p. 612-619, 2011.doi:10.1164/rccm.201002-0178OC

5. R. A. McLaughlin, B. C. Quirk, A. Curatolo, R. W. Kirk, L. Scolaro, D. Lorenser, P. D. Robbins, B. A. Wood, C. M. Saunders, D. D. Sampson, Imaging of breast cancer with optical coherence tomography needle probes: Feasibility and initial results, IEEE J. Sel. Topics Quantum Electron. 18(3), p. 1184-1191, 2012. doi:10.1109/JSTQE.2011.2166757

6. K. M. Kennedy, B. F. Kennedy, R. A. McLaughlin, D. D. Sampson, Needle optical coherence elastography for tissue boundary detection, Opt. Lett. 37(12), p. 2310-2312, 2012. doi:10.1364/OL.37.002310

7. B. F. Kennedy, S. H. Koh, R. A. McLaughlin, K. M. Kennedy, P. R. T. Munro, D. D. Sampson, Strain estimation in phase-sensitive optical coherence elastography, Biomed. Opt. Express 3(8), p. 1865-1879, 2012.doi:10.1364/BOE.3.001865

8. B. F. Kennedy, M. Wojtkowski, M. Szkulmowski, K. M. Kennedy, K. Karnowski, D. D. Sampson, Improved measurement of vibration amplitude in dynamic optical coherence elastography, Biomed. Opt. Express 3(12), p. 3138-3152, 2012. doi:10.1364/BOE.3.003138

9. R. K. Manapuram, S. R. Aglyamov, F. M. Monediado, M. Mashiatulla, J. Li, S. Y. Emelianov, K. V. Larin, In vivo estimation of elastic wave parameters using phase-stabilized swept source optical coherence elastography, J. Biomed. Opt. 17(10), p. 100501, 2012.doi:10.1117/1.JBO.17.10.100501

10. W. Qi, R. Chen, L. Chou, G. Liu, J. Zhang, Q. Zhou, Z. Chen, Phase-resolved acoustic radiation force optical coherence elastography, J. Biomed. Opt. 17(11), p. 110505, 2012. doi:10.1117/1.JBO.17.11.110505

11. C. Li, G. Guan, S. Li, Z. Huang, R. K. Wang, Evaluating elastic properties of heterogeneous soft tissue by surface acoustic waves detected by phase-sensitive optical coherence tomography, J. Biomed. Opt. 17(5), p. 057002, 2012. doi:10.1117/1.JBO.17.5.057002

12. M. Razani, A. Mariampillai, C. Sun, T. W. H. Luk, V. X. D. Yang, M. C. Kolios, Feasibility of optical coherence elastography measurements of shear wave propagation in homogeneous tissue equivalent phantoms,Biomed. Opt. Express 3(5), p. 972-980, 2012. doi:10.1364/BOE.3.00097

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On the road to improve prostate biopsy

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, tagged Cancer - General, characterization technology, gleason score, health, histoscanning, medicine, Prostate biopsy, Prostate cancer, prostate guided biopsies, Prostate-specific antigen, psa level, psa screening, systematic prostate biopsies, tissue characterization on February 15, 2013| 3 Comments »

On the road to improve prostate biopsy

Author and Curator: Dror Nir, PhD

• 

Urologists are in constant search for a method that will improve the outcome of prostate biopsy, particularly when it comes to ruling-in and ruling-out clinically significant prostate cancer. As stated in my recent post – State of the art in oncologic imaging of Prostate; “The disease’s staging and related prognosis are determined during diagnosis based on PSA level and the Gleason score of biopsy’s samples. Although prostate-specific antigen (PSA) screening resulted in the diagnosis of prostate cancer at earlier stages and with lower Gleason scores, it has also contributed to concerns about over-diagnosis, overtreatment of clinically insignificant disease, associated treatment-related toxicity, and escalating costs”. I already reported in the past on research conduc ted in this area; New clinical results supports Imaging-guidance for targeted prostate biopsy and Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention? Today I report on recent publication presenting the advantage of using targeted trans-perineal biopsy following HistoScanning imaging instead of systematic TRUS biopsies: Computer-aided (HistoScanning) Biopsies Versus Conventional Transrectal Ultrasound-guided Prostate Biopsies: Do Targeted Biopsy Schemes Improve the Cancer Detection Rate? (Moritz F. Hamann, Claudius Hamann, Eckhard Schenk, Amr Al-Najar, Carsten M. Naumann, and Klaus-Peter Jünemann, Urology, Volume 81, Issue 2, February 2013, Pages 370-375

I have mentioned HistoScanning (ultrasound-based tissue characterization technology which I have invented and developed to a medical device) in many of my previous posts. HistoScanning for prostate is a specific HistoScanning application that is applied to the ultrasound’s raw signal (not the image) following a comprehensive scan of the prostate capturing its entire volume. The whole process takes about ten minutes and the output is a digital 3D map of the prostate gland where locations suspicious of presenting with prostate cancer are indicated.

HistoScanning report with 2, bilateral, basal lesions.

 

The urologist translates such map into a “prostate regional biopsy scheme” when planning his biopsies and direct the needle, under ultrasound guidance, to these predefined suspicious locations.

The systematic biopsy patterns targeted 7 sectors bilaterally: transition zone, apex, center, and base, each medially and laterally.

In that sense, the workflow is similar to using MRI for tumor detection and creating a tumor map for targeting the biopsy.

As reasoning for conducting the study the investigators argue that: “Exact staging of prostate cancer before treatment is essential for relevant therapeutic decision making. Current procedures, such as nerve-sparing prostatectomy and brachytherapy, as well as active surveillance and future focal treatment options, depend on the reliable identification of cancerous lesions within the prostate. Systematic prostate biopsies with at least 10 to 12 cores are the current standard method to detect and locate significant prostate cancer, as scientific evidence during the last decades has shown. Nevertheless, there are no homogeneous data concerning the required number of cores and the technical approach of prostate biopsy procedures. The unstable histologic results on active surveillance and the well-known discrepancy between transrectal diagnostics and radical prostatectomy specimens underline the neces­sity to develop reliable diagnostic tools for precise detection and localization of prostate cancer. Recent data on HistoScanning computer-aided ultra-sonography have shown favorable results. To generate a greater diagnostic yield than systematic needle biopsies, we integrated HistoScanning-guided targeted biopsies in our general prostate biopsy regimen. We report the cancer detection rate in a prospective series of 80 patients.”

The study’s objective was: “To define potential improvement in prostate cancer detection by application of a computer-aided, targeted, biopsy regimen using HistoScanning.”

Materials and Methods: “The data were collected prospectively from 80 men who consecutively underwent a systematic 14-core prostate biopsy supplemented by targeted transrectal and perineal ultrasound-guided biopsies. All biopsies were performed between March 2011 and September 2011. Indications for prostate biopsy were suspicious findings at the digital rectal examination (DRE), or serum prostate-specific antigen (PSA) level >10 ng/mL, or both. In case of elevated serum PSA levels >4 ng/mL a PSA-velocity of >0.75 ng/mL p.a. and free-to-total PSA ratio <15% were seen as the indication for prostate biopsies. Thirty-six patients had undergone a previous transrectal prostate biopsy. All patients were informed of the mode of the extended prostate biopsy scheme and its potential complications. All patients provided written informed consent for the procedure.After indication and before starting the biopsy procedure, all patients underwent a standardized 3-dimensional (3D) transrectal ultrasound (TRUS) with an end-fire array of a BK 8818 probe. Computer-aided analysis of the raw (radio-frequency) back-scatter data was performed by using the Conformite Europeene-marked and commercially available HistoScanning device, admitted for medical use in the Euro­pean Union (software version 2.1, Advanced Medical Diag­nostics, Belgium).”

“Each patient was diagnosed preoperatively by HistoScanning, defining a maximum of 3 suspicious areas. These areas were biopsied, both transrectally and via the perineum, with a maximum of 3 cores per location.”

Results: “We detected prostatitis in 30 patients (37.5%), premalignant lesions in 10 (12.5%), and prostate cancer in 28 (35%). The transrectal technique was used to detect 78.6% of all cancers using 14 cores by systematic biopsy. With a maximum of 9 targeted cores, 82.1% of all cancers were detected with the targeted perineal approach and 53.6% were detected with the targeted transrectal approach. Although our data did not show significant difference in the performance of targeted transperineal compared with systematic transrectal biopsies, the detection rate of targeted transrectal biopsies was significantly lower.”

 

Conclusion: “The presented targeted biopsy scheme achieved an overall detection rate of 85% of prostate-specific antigen–relevant pathologic lesions within the prostate. Thus, the presented procedure shows an improved detection rate compared with standard systematic prostate biopsies, and the number of cores required is reduced. Furthermore, the perineal HistoScanning-aided approach seems to be superior to the transrectal approach with respect to the prostate cancer detection rate. The presented procedure might be a step toward reliable ultrasound-based tissue characterization and toward fulfilling the requirements of novel therapeutic strategies.”

 

The authors’ included an elaborated discussion on the background to their study and its results. This discussion is important for understanding the limitation of the study results and for putting the authors conclusion into balanced context: “When other solid-organ cancer guidelines are compared with prostate cancer guidelines, the common methods of prostate cancer detection are unmasked as an outmoded concept because cancer detection is based on chance as a result of a blinded, subjective examination. A systematic biopsy with at least 10 to 12 cores is considered the standard procedure in prostate cancer diagnostics to date. 1,2 The continuous increase in the number of biopsy cores taken over the last years has predictably improved the detection rate, but several studies report detection rates of only 30% to 40% even in repeated biopsies. 5,9 It is noteworthy that the recommendations must be seen as a compromise bbetween the cancer detection rate and the invasiveness of the surgical procedure. Modern diagnostic procedures, including magnetic resonance imaging, elastography, computerized analysis of TRUS/artificial neuronal network analysis, and HistoScanning, try to overcome this principle of approach.7,10,11 The current therapeutic concepts and further currently evolving therapy strategies depend on sophisticated prostate cancer diagnostics. It is more important than ever to look for ways to detect and locate the cancer before subjecting patients to more or less invasive procedures as the indication for surgical treatment or prostate-preserving (focal) tumor therapy. The results of magnetic resonance imaging for prostate cancer detection are very promising so far and show a sensitivity of up to 80%. Elastography has also shown promising capabilities for cancer detection, with a recent review article reporting that several studies show 74% to 75% sensitivity.11 HistoScanning has shown 93% sensitivity in detecting and locating prostate cancer. 12 As a matter of principle, our study is unable to report on the accuracy or sensitivity of prostate cancer detection because the exact number of cancer lesions in our patients collective remains incomputable. Integration of HistoScanning for guided, targeted biopsies helped us achieve a prostate cancer detection rate of 35%. These data are lower than results from current publications on initial prostate biopsies but higher than those of repeated biopsy protocols.4,5,13 Given that tumors looked for during initial biopsies are usually large and easy to detect, we believe that this finding is caused by the smaller overall risk of cancer in a repeated biopsy setting, as was the case in 37.5% of our patients (0.61 biopsies per patient). Overall, HistoScanning seems to improve selective targeting of suspicious prostate lesions. Taking into account all malignant, premalignant, and atypical histologic findings, including prostate cancer, atypical small acinar proliferations, and high-grade prostatic intraepithelial  eoplasia, the detection rate of relevant prostatic lesions by specimens from perineal-targeted biopsies rises to 47.5% and 85%, including prostatitis, respectively. Apart from the high quality of the HistoScanning tissue analysis, we believe in a significant effect of the technical approach used to perform the biopsy. As our data show, prostate cancer detection rates from specimens obtained from perineal-targeted biopsies differed significantly from the transrectal-targeted biopsy regimen, a difference that occurred independently from previous tissue analysis because both targeted approaches are aligned to the same scanning process. Compared with the transrectal approach, the perineal biopsy technique might reduce variables that can influence the needle placement. Furthermore, longitudinal biopsy punches following the axis of the prostate seem to allow more accurate sampling of the anterior part. Theoretically, because previous studies reported inhomogeneous results comparing transrectal and transperineal prostate biopsies.3,4,13 The use of a 14-gauge needle in perineal biopsies might be responsible for a systematic bias because it possibly yields more tissue than transrectal cores. Despite this potential advantage, systematic transrectal biopsies do not reflect a significant difference in the detection rate. Nevertheless, due to the individual setting, our study is unable to report standardized results on the accuracy of comparing transrectal and transperineal needle placement. Template-guided mapping biopsies have recently attracted attention because of the high rate of cancer detection as initial (75%) and even repeat biopsy procedures (46%). 14 It notably increases the ability to locate and differentiate cancer foci within the prostatic gland, implicating mapping biopsies for active surveillance or focal treatment purposes regardless of the considerable surgical trauma generated by the use of extended biopsy protocols. A reduction of tissue trauma by generating a greater diagnostic yield would be a favorable methodologic aspect as initiated by our study. Regarding cancer detection, the presented data show no significant differences between the perineal-targeted and transrectal-targeted systematic biopsy regimen, but even though considerably fewer tissue samples (14 vs 9 cores; -35%) were taken from selected prostate areas, we detected no significant limitations by the perineal approach. These data are even more encouraging when bearing in mind that the number of samples represents a crucial factor in prostate cancer detection rates, as recently reported. A critical issue in the present study is in the implementation of the modified biopsy procedures. Although the surgeons at our center are experienced in using TRUS, our data show a learning curve during the first 80 procedures. In addition, the overlaying of the HistoScanning image analysis to the B-mode grey-scale live ultrasound picture is done by the surgeon performing the biopsy. This process implies a bias in individual interpretation of the TRUS picture and manual needle guidance. The online fusion of HistoScanning with the ultrasound image presumably would increase the handling accuracy. Further methodologic limitations lie in the heterogeneous and small collective of patients that were included in the study. With regard to the reasonably high number of previous negative biopsy specimens, patient selection can affect the hit rate of positive biopsy specimens. This circumstance might make the cancer detection frequency with HistoScanning look relatively small in this particular study compared with other diagnostic methods in patients undergoing an initial biopsy, but this is due to the daily routine in an academic referral center.

For completeness of this reporting and before stating my own conclusion I bring here below two comments that were made, one by Dr. Stephen Jones of Glickman Urological and Kidney Institute, Cleveland, Ohio and the reply by the first author:

COMMENT

The promise of image-guided diagnosis and management of prostate cancer has been frustratingly elusive. Early pioneers of prostate ultrasound imaging reported that hyperechoic lesionswere indicative of malignancy, but it rapidly became clear that the opposite was actually more realistic. Even so, these hypoechoic lesions were soon shown to be poor indicators of prostate cancer. Thus, the value of visual abnormalities on grey-scale prostate ultrasound imaging remains essentially negligible with current technology. As a result, a number of alternative imaging modalities have been developed and introduced with great excitement. Typically, images in the publications showcase an apparently obvious cancer standing out in contrast to adjacent benign tissues. Unfortunately, the data still reveal minimal value from most of these technologies, and those reported in this article are similarly disappointing. HistoScanning demonstrated interesting color images, but coupled with a transperineal-targeted biopsy found exactly one more case of prostate cancer than did the current standard of care—the 14-core extended transrectal biopsy. This “difference” is actually statistically identical (P >.99). Exactly the same number of patients (n¼ 4) was found exclusively by both transperineal HistoScan-targeted biopsy as with standard transrectal biopsy, and when targeted using the transrectal approach, the technology actually missed almost half of the cancers that were identified overall. Furthermore, these data do not support the suggestion that 9 cores are less morbid or traumatic than 14 cores, and the literature is replete with reports demonstrating this is simply not true. This is especially misleading when those 9 cores come at the cost, morbidity, time, and complexity of an operation such as this performed under general anesthesia. So the real question remains whether HistoScanning or any emerging technology to image the prostate—improves visualization of prostate cancer. Although magnetic resonance imaging is beginning to show notable promise, the clinical value of most other modalities remains mostly anecdotal. As one whose desire for a solution remains frustratingly unfulfilled, I hope that some imaging technique will demonstrate clinical value during my career. J. Stephen Jones, M.D., Department of Regional Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, Ohio

REPLY

In accordance with your comprehensive notes, we have to search for diagnostic improvement and underline the need further investigations in the field of prostate cancer diagnostics and staging. Minimally invasive techniques, focal and targeted therapy modalities, and low-risk cancer surveillance probably are future treatment modalities for prostate malignancies that progressively challenge common diagnostic pathways. Sophisticated therapy strategies will require reliable staging results. The constant increase of cores taken during systematic prostate biopsy apparently will not overcome the well-known diagnostic uncertainties. Consequently, imaging techniques and methods of biopsy targeting will gain in importance. Clearly, the presented data do not show significant improvement in the overall detection rate of prostate cancer in our patient cohort. Further, the maximum number of 9 biopsy cores must be attributed to the initial study design and will undergo further investigation; however, the results rather support the study approach than reduce its validity. Considering the indeterminate number of cancers, the proof of superiority remains incomputable. Compared with the current standard of care of 12 to 14 cores, we detected no significant limitations, although perineal-targeted biopsies took significantly fewer cores (3-9 cores [35%]). Maintaining the detection rate unchanged and focusing on 1 to 3 preselected suspicious index lesions display a proof of principle rather than disappointing results. In line with future treatment options mentioned above, any less invasive, focused diagnostic procedure represents an encouraging advance compared with the common and recommended practice of a nonselective, systematic biopsy of the prostate to harbor cancerous tissue. Moritz F. Hamann, M.D., Department of Urology and Pediatric Urology, University of SchleswigeHolstein, Campus Kiel, Kiel, Germany

As mentioned by the authors, further improvement of the outcome of HistoScanning-based targeted biopsies of prostate is expected when an implementation of image-fusion application between the “off-line” generated 3D tumor map and the real-time ultrasound guiding the needle will be available; similar to the results presented already when using ultrasound-MRI image fusion applications for prostate biopsy. Of course, the ultimate biopsy workflow (which I am currently engaged in developing) that urologist are asking for is the one comprised of real-time ultrasound-based tissue characterization and real-time ultrasound guidance of the needle to the lesion.

References

1. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61-71.

2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Available at http://www.nccn.org 2011 Accessed May 2011.

3. Abdollah F, Novara G, Briganti A, et al. Trans-rectal versus transperineal saturation re-biopsy of the prostate: is there a difference in cancer detection rate? Urology. 2011;77:921-925.

4. Hara R, Yoshimasa J, Tomohiro F, et al. Optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. Urology. 2008;71:191-195.

5. Patel AR, Jones JS. Optimal biopsy strategies for the diagnosis and staging of prostate cancer. Curr Opin Urol. 2009;19:232-237.

6. Al Otaibi M, Ross P, Fahmy N, et al. Role of repeated biopsy of the prostate in predicting disease progression in patients with prostate cancer on active surveillance. Cancer. 2008;113:286-292.

7. Braeckman J, Autier P, Garbar C, et al. Computer-aided ultrasonography (HistoScanning): a novel technology for locating and characterizing prostate cancer. BJU Int. 2008;101:293-298.

8. Braeckman J, Autier P, Soviany C, et al. The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers. BJU Int. 2008;102:1560-1565.

9. Presti JC Jr, O’Dowd G, Miller C, et al. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a community multi-practice study. J Urol. 2003;169:125-129.

10. Turkbey B, Mani H, Shah V, et al. Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds. J Urol. 2011;186: 1818-1824.

11. Trabulsi EJ, Sackett D, Gomella L, et al. Enhanced transrectal ultrasound modalities in the diagnosis of prostate cancer. Urology. 2010;76:1025-1033.

12. Simmons LA, Autier P, Zat_ura F, et al. Detection, localisation and characterisation of prostate cancer by Prostate HistoScanning. BJU Int. 2012;110:28-35.

13. Emiliozzi P, Corsetti A, Tassi B, et al. Best approach for prostate cancer detection: a prospective study on transperineal versus transrectal six-core prostate biopsy. Urology. 2003;61:961-966.

14. Taira AV, Merrick GS, Galbreath RW, et al. Performance of transperineal template-guided mapping biopsy in detecting prostate cancer in the initial and repeat biopsy setting. Prostate Cancer Prostatic Dis. 2010;13:71-77.

 

Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

 

Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Prostate Cancer and Nanotecnology

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Imaging agent to detect Prostate cancer-now a reality

Scientists use natural agents for prostate cancer bone metastasis treatment

Today’s fundamental challenge in Prostate cancer screening

ROLE OF VIRAL INFECTION IN PROSTATE CANCER

Men With Prostate Cancer More Likely to Die from Other Causes

New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

New clinical results supports Imaging-guidance for targeted prostate biopsy

 

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State of the art in oncologic imaging of Colorectal cancers.

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Liver & Digestive Diseases Research, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Personalized and Precision Medicine & Genomic Research, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, tagged American Cancer Society, Cancer - General, Clinical trial, colorectal cancers, health, liver metastasis, medicine, Personalized medicine, research, science on February 2, 2013| 2 Comments »

State of the art in oncologic imaging of Colorectal cancers.

Author-Writer: Dror Nir, PhD

Word Cloud By Danielle Smolyar

This is the fourth post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging^†‡ that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on colorectal cancer imaging. It reviews current and developing radiologic practices in CRC with respect to screening, preoperative evaluation, surveillance, and post-treatment re-staging.

Colorectal cancer (CRC) is an example to successful imaging-based screening evident by noticeable reduction in mortality rates. The 5-year survival rate of CRC patients diagnosed at an early stage is 90%.1 121 According to this review; “(CRC) is the third most common cancer worldwide and the second most frequent cause of cancer death in the United States. The American Cancer Society estimates that 143,460 new cases of CRC will be diagnosed and 51,690 deaths from CRC will occur in the United States in 2012.120 Because of screening and removal of premalignant polyps, incidence rates have declined over the last 3 decades.”

The authors found out that the increased use of CT in CRC screening has the potential of reducing its costs and associated tisks 122 In addition, use of DW-MRI enabled better outcomes of CRC liver metastasis treatment as it enables tailored localized treatment of such lesions.123 124 Finally, the authors found that: “MRI for staging of rectal cancer has become standard practice and, in some instances, is performed in lieu of surgeon-performed endorectal US (ERUS), providing the radiologist with an even greater role in the management of patients with CRC.125 “

 Screening

“CRC is a largely preventable disease, as the progression of the adenoma-carcinoma sequence of mutations is slow and leaves ample time to intervene. Nonetheless, approximately 41% of the population (in the USA) eligible for screening remains unscreened. 126 Most screening is performed using non-imaging tests”

Any of these screening strategies will reduce mortality from CRC.126, 127 

Among imaging tests used for screening, barium enema has seen a continual decline in usage, at least in part due to the landmark study showing that this test detected only 39% of polyps identified at colonoscopy, including only 48% of those > 1 cm in size.131 The recent (and largest, with > 2500 patients) multicenter CT colonography (CTC, also known as virtual colonoscopy) screening study, performed by the American College of Radiology Imaging Network, found that CTC had sensitivity of 90% and similar specificity for polyps > 9 mm, and the number of centers using CTC has increased.122 Widespread deployment of CTC remains hindered, in part, by the 2009 decision of the Center for Medicare and Medicaid Service (CMS) to deny reimbursement based on 1) potential radiation risk, 2) impact of detection of extracolonic findings, and 3) efficacy in the 65 years and older age group of concern to CMS. Data from studies reported after this decision put CTC in a good position to be reconsidered for reimbursement. The median estimated effective dose is currently 5 to 6 mSv, a dose far less than that received from a standard CT exam and even comparable to or lower than that received from a barium enema examination. In fact, the radiation dose from CTC is equivalent to that received from cosmic radiation in a 1-year period.132 Extra-colonic findings occur in 7% to 11% of cases and lead to extra examinations in about 6% with a relevant new diagnosis made in 2.5%, according to the experience of the largest screening center in the United States.133 Furthermore, when detection of extracolonic cancers and aortoiliac aneurysms is included along with CRC screening, CT colonography (CTC) has been shown to be more clinically effective and more cost-effective than optical colonoscopy.134 In an observational study, CTC accuracy was maintained in patients aged 65 to 79 years, who were compared to the overall general population sample. In the older patients, CTC remained a safe and effective modality and program outcome measures, such as colonoscopy referral and extracolonic work-up rates, remained similar to those in other screened groups.135“

 Detection and Characterization

“Diagnosis and clinical staging of primary colonic adenocarcinoma is most often accomplished by combining colonoscopy with biopsy and performing cross-sectional imaging to detect metastatic disease.

Although CT and MRI are widely used for preoperative whole-body staging, they are not recommended first-line methods for detection of primary lesions. In contradistinction, CTC has matured into an excellent diagnostic method for detection of CRC. Data drawn largely from screening studies tell us that its sensitivity for polyps > 10 mm is 90% or greater, and that it will detect nearly every cancer. In fact, a recent meta-analysis of more than 11,000 patients indicated that CTC had sensitivity of 96.1% (398 of 414) for CRC, and when cathartic cleansing and fecal tagging were used, no cancers were missed (Fig. 16).137 Detection of flat cancers remains a challenge with CTC as compared with endoscopic methods in which mucosal surface details are better appreciated. CTC not only detects CRC, but with its cross-sectional depiction also allows characterization of tumors using the TNM staging system138 with reasonable T- and N-stage accuracies of 83% and 80%, respectively.139 CTC is an operator-dependent technique that has shown great variability between radiologists with different degrees of training. Computer-aided detection (CAD) was developed for this reason and because 10,000 to 15,000 images must be scrutinized for each large adenoma detected. In a screening cohort of 3077 consecutive asymptomatic adults, stand-alone CAD had sensitivities of 97% and 100% for advanced neoplasia and cancer, respectively.140

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

With magnetic resonance colonography (MRC), detection of masses is limited because techniques employing air cause susceptibility artifacts, and those employing dark-lumen techniques with water-filling and intravenous gadolinium are under scrutiny because of concerns about the potential risk of nephrogenic systemic fibrosis. In addition, in the largest screening study, the sensitivity of MRC was only 70% in patients with colorectal lesions more than 10 mm in size.141

Imaging plays a critical role in detecting liver metastases in order to properly stage and treat the patient with colorectal cancer. NCCN guidelines recommend contrast-enhanced CT or MRI.142 “

MRI is the most promising imaging modality for management of rectal cancer.

Staging of this cancer is primarily accomplished with US, typically performed by surgeons. MRI using phased-array coils provides complete visualization of the pelvic anatomy and, especially, the circumferential resection margin, an important landmark for the standard total mesorectal excision.

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

 

 The MERCURY study125established the near equivalence of MRI to histopathology for identification of this margin, an important advantage of MRI over ERUS, with which the margin is not routinely visualized.147 T- and N- stage accuracies of MRI (87% and 74%, respectively) were similar to those of ERUS (82% and 74%, respectively).148 Accurate lymph node identification remains a problem for MRI. Toward this end, a new albumin-bound gadolinium agent has shown some promise, and further results are awaited.149”

 Role of Imaging in Assessing Treatment Response

“Imaging plays a critical role in 1) determining response to systemic and loco-regional treatment of liver metastases, 2) assessing response to local treatment and restaging rectal cancer primary lesions, and 3) detecting and assessing the treatment response of extra-hepatic metastatic disease. Systemic treatment (and in some centers, hepatic artery infusion) of non-resectable liver metastases with chemotherapy aims at reduction of the metastatic burden, which, occasionally may allow attempts at curative liver resection.

Due to the limitations of CT with regard to soft tissue contrast and fatty liver. MRI has greater sensitivity for remaining (or new) lesions < 1.0 cm due to its superior soft tissue contrast. In a recent meta-analysis of 25 eligible studies, MRI showed higher sensitivity than CT on a per-patient basis (P = .05) and on a per-lesion basis as well (P = .0001). With its 81.1% sensitivity and 97.2% specificity, MRI is thus the preferred modality.151 Nonetheless, under the current NCCN guidelines, CT remains the preferred modality.142 

Loco-regional (“liver-directed”) therapies include radiofrequency, microwave ablation, transarterial chemo- or particle embolization and irreversible electroporation. With these treatments, responding lesions can actually increase in size, and simple size criteria are no longer sufficient to determine response. The European Association for the Study of the Liver has issued new criteria to assess viability of remaining tumor based on enhancing residual volume by multiphase CT or MRI.152 However, the field is rapidly changing and there is no consensus on the optimal imaging strategy following loco-regional therapy.

Recent meta-analyses of randomized controlled trials comparing low-intensity and high-intensity surveillance programs have shown advantages for more intense follow-up in Stages I-III disease;170-173 however, controversies remain regarding the optimal surveillance strategy. “

Lymphoma Imaging

To be followed…

Other research papers related to the management of Colorectal cancer were published on this Scientific Web site:

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

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Direct Flow Medical Wins European Clearance for Catheter Delivered Aortic Valve

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Valves & Tools, tagged Aortic valve, Catheter, CE mark, Direct Flow Medical, Inflatable on January 29, 2013| 6 Comments »

Direct Flow Medical Wins European Clearance for Catheter Delivered Aortic Valve

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 7/15/2018

Direct Flow Medical, which markets a CE-marked transcatheter aortic valve implantation (TAVI) device, has closed after funding from a Chinese pharmaceutical company did not come through. According to newspaper The Press Democrat, all 250 company’s employees have been made redundant and it officially ceased trading on 30 November.

The paper reports that Direct Flow’s former president and chief executive officer Dan Lemaitre, in a phone interview, told them the company had expected an influx of funding from a Chinese pharmaceutical company on 18 November but the deal collapsed two days before the money was scheduled to arrive. Lemaitre said this was because “the terms of which were changed dramatically in a very unacceptable fashion.”

The Press Democrat claims that the 12-year-old company had no other options and its lender—PDL BioPharma Inc—refused to extend the US$65 million funding arrangement it had with Direct Flow for the past three years and foreclosed upon the business.

SOURCE

https://cardiovascularnews.com/tavi-company-direct-flow-medical-closes-after-failing-to-secure-funding/

 

TAVI company Direct Flow Medical closes after failing to secure funding

16th January 2017

 

Catheter Delivered Aortic Valve from Direct Flow Medical Wins European Clearance (w/video)

by GENE OSTROVSKY on Jan 28, 2013 • 1:32 pm

Having unveiled attractive results of a study on its transcatheter aortic valve, Direct Flow Medical (Santa Rosa, CA) has just announced CE Mark approval for the device. The polymer frame prosthesis sits on top of the diseased natural valve with its inflatable rings guaranteeing contact along the perimeter.

Since the new valve only uses physical pressure from the inflatable rings to hold on, it can be repositioned at any time or removed completely if necessary.

Here’s more about the valve from its product page:

The bovine pericardial leaflets are attached to an inflatable polyester fabric cuff which conforms to the native aortic valve annulus and left ventricular outflow tract to form a seal to minimize the potential of paravalvular leak. The Bioprosthesis is designed with independently inflatable ventricular and aortic rings, which encircle and capture the native valve annulus to provide positive axial anchoring of the device. Inflation of the cuff with a saline and contrast solution renders the valve immediately functional and permits fluoroscopic visualization. Before final deployment, the saline and contrast mixture is exchanged under pressure, maintaining cuff shape and position, with a solidifying Polymer that hardens to form the permanent support structure.

 

WATCH VIDEO 

Direct Flow Medical: Transcatheter Aortic Valve

 

Flashback: Direct Flow Medical Transcatheter Aortic Valve Does Well in Clinical Study

Product page: Direct Flow Medical Transcatheter Aortic Valve System…

SOURCE:

http://www.medgadget.com/2013/01/catheter-delivered-aortic-valve-from-direct-flow-medical-wins-european-clearance-wvideo.html?

http://www.medgadget.com/2013/01/catheter-delivered-aortic-valve-from-direct-flow-medical-wins-european-clearance-wvideo.html?goback=%2Egde_4346921_member_205701983%2Egmr_675087%2Eanp_675087_1359500095698_1%2Egmr_675087%2Egde_675087_member_208816811%2Egmr_675087

Other articles related to this topics were published on this Open Access Online Scientific Journal, include the following:

August 7, 2012 – Transcatheter Aortic Valve Implantation (TAVI): risk for stroke and suitability for surgery

http://pharmaceuticalintelligence.com/2012/08/07/transcatheter-aortic-valve-implantation-tavi-risky-and-costly-2/

August 2, 2012 – Transcatheter Aortic Valve Implantation (TAVI): Risky and Costly

http://pharmaceuticalintelligence.com/2012/08/02/transcatheter-aortic-valve-implantation-tavi-risky-and-costly/

June 4, 2012 – Investigational Devices: Edwards Sapien Transcatheter Aortic Valve Transapical Deployment http://pharmaceuticalintelligence.com/2012/06/04/investigational-devices-edwards-sapien-transcatheter-heart-valve/

June 10, 2012 — Investigational Devices: Edwards Sapien Transcatheter Aortic Heart Valve Replacement Transfemoral Deployment http://pharmaceuticalintelligence.com/2012/06/10/investigational-devices-edwards-sapien-transcatheter-aortic-heart-valve-replacement-transfemoral-deployment/

 June 19, 2012 — The Centers for Medicare & Medicaid Services (CMS) covers transcatheter aortic valve replacement (TAVR) under Coverage with Evidence Development (CED) http://pharmaceuticalintelligence.com/2012/06/19/the-centers-for-medicare-medicaid-services-cms-covers-transcatheter-aortic-valve-replacement-tavr-under-coverage-with-evidence-development-ced/

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• Recent Posts

  • FDA Moves Forward With Its Guidance Framework for Rare Disease Trials: 2026 August 3, 2026
  • Artificial Intelligence TRANSFORMS Medicine, Biotech and Healthcare, How? August 3, 2026
  • In Memoriam: Nobel Laureate J. Michael Bishop for discovery of Retroviral Oncogenes July 31, 2026
  • Companies Actively Engaging Artificial Intellegence for Drug Design: 2026 July 31, 2026
  • AI-Native Drug Discovery Landscape 2026 – How LPBI Group Differentiates in the New Era of Foundation Models July 19, 2026
  • In Memoriam: In Remembrance of Cancer Researchers who passed in 2026 July 13, 2026
  • Urgent Request for Action on Proposed Rule Affecting Federal Funding Grant Review July 7, 2026
  • 2026 Tang Prize in Biopharmaceutical Science Awarded to Three Pioneers of Cellular Immunotherapy Revolutionizing Treatments for Blood Cancers and Solid Tumors July 5, 2026
  • Protected: KOL on Competitive Dynamics: LPBI Group’s Founder’s Radar Screens on AI-in-Health, Life Sciences & BioPharma June 15, 2026
  • Tumor Infiltrating Lymphocytes (TIL) as a first of kind FDA approved immunotherapy for cancer June 12, 2026

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