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Posts Tagged ‘health’

Breast Cancer and Mitochondrial Mutations

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Nutrigenomics, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged breast cancer, Cancer - General, Conditions and Diseases, Energy development, health, NADH dehydrogenase, Nicotinamide adenine dinucleotide, Scripps Research Institute on March 4, 2013| 1 Comment »

Breast Cancer and Mitochondrial Mutations

Author: Larry H Bernstein, MD, FCAP

Screen Shot 2021-07-19 at 7.22.43 PM

Word Cloud By Danielle Smolyar

How Aggressive Breast Tumors and Mitochondrial Mutations Are Linked

Feb 18, 2013 Brunhilde H. Felding, Ph.D., Scripps Research Institute (TSRI)
Mitochondrial complex I critically determines the energy output of cellular respiration. The Felding team discovered that the balance of key metabolic cofactors processed by complex I—specifically,

nicotinamide adenine dinucleotide (NAD+) and NADH,

the form it takes after accepting a key electron in the energy production cycle—

was disturbed in aggressive breast cancer cells.

The team altered genes tied to NAD+ production. The resulting shift again showed that

higher NADH levels meant more aggressive tumors,
while increased NAD+ had the opposite effect.

The scientists found that enhancing the NAD+/NADH balance through the nicotinamide treatment inhibited metastasis, and the mice lived longer.

http://www.geneng.com/gennewsHighlights/How_Aggressive_Breast_Tumors_and_Mitochondrial_Mutations_Are_Linked/

http://www.JCl.org/Mitochondrial_Complex1_activity_and_NAD+_NADH_balance_regulate_breast_cancer_progression

Reduction and oxidation of the NAD. Created using ACD/ChemSketch 10.0 and . (Photo credit: Wikipedia)

Comparison of the absorbance spectra of NAD+ and NADH (Photo credit: Wikipedia)

English: By Richard Wheeler (Zephyris) 2006. The structure of the peripheral domain of an NADH dehydrogenase (mitochondrial complex I) related protein; bacterial FMN dehygrogenase PDB 2FUG. (Photo credit: Wikipedia)

http://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/

http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/

http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

http://pharmaceuticalintelligence.com/2012/09/10/%CE%B2-integrin-emerges-as-an-important-player-in-mitochondrial-dysfunction-associated-gastric-cancer/

http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/

http://pharmaceuticalintelligence.com/2013/01/26/remembering-a-great-scientist-among-mentors/

http://pharmaceuticalintelligence.com/2013/01/26/portrait-of-a-great-scientist-and-mentor-nathan-oram-kaplan/

http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

Promising New Approach To Preventing Progression Of Breast Cancer (medicalnewstoday.com)
misshapen chemo drug particles may be better at targeting breast cancer (fiercebiotechresearch.com)
Key Enzyme Missing From Triple-Negative Breast Cancer (medicalnewstoday.com)

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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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Attitudes of Patients about Personalized Medicine

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, Cancer - General, Conditions and Diseases, health, Larry H. Bernstein, medicine, Ohio State University Medical Center, ovarian cancer, Personalized medicine on March 2, 2013| 4 Comments »

Attitudes of Patients about Personalized Medicine

Curator: Larry H Bernstein, MD, FCAP

Attitudes of Patients With Cancer About Personalized Medicine

SW Gray, K Hicks-Courant, et al.

jop.ascopubs.org/content/8/6/329.full.pdf

http://ovariancancerandus.blogspot.com/…/jop-attitudes-of-patients-With-Cancer-About-Personalized-Medicine-and-Somatic-Genetic-Testing/

Personalized Medicine (Photo credit: Wikipedia)

Personalized medicine gearing up to tackle cancer (pharmaceuticalintelligence.com)
http://pharmaceuticalintelligence.com/wp-admin/Understanding_the_Role_of_Personalized_Medicine
Nanotechnology, personalized medicine and DNA sequencing (pharmaceuticalintelligence.com)
Institute for Personalized Medicine established by UPMC (triblive.com)
Personalized medicine: the future of medicine! (gtms1314.wordpress.com)
http://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/
http://pharmaceuticalintelligence.com/2013/02/27/genomics-ethics-dna-fragments-are-products-of-nature-or-patentable-genes/

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Understanding the Role of Personalized Medicine

Posted in Health Economics and Outcomes Research, Health Law & Patient Safety, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Cancer - General, Conditions and Diseases, genetics, health, Larry H. Bernstein, medicine, Personalized medicine on March 2, 2013| 3 Comments »

Understanding the Role of Personalized Medicine

Reporter: Larry H. Bernstein, MD, FCAP

Do Patients Understand the Role of Cancer Genetic Testing?

Maurie Markman, MD

www.medscape.com/viewarticle/777814
http:www.medscape.com/do_patients_understand_the_ role_of_cancer_genetic_testing?/Markman/

Personalized Medicine (Photo credit: Wikipedia)

Personalized medicine gearing up to tackle cancer (pharmaceuticalintelligence.com)
Directions for genomics in personalized medicine (pharmaceuticalintelligence.com)
Nanotechnology, personalized medicine and DNA sequencing (pharmaceuticalintelligence.com)
Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com (pharmaceuticalintelligence.com)
Personalized medicine: the future of medicine! (gtms1314.wordpress.com)
Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School (pharmaceuticalintelligence.com)
Institute for Personalized Medicine established by UPMC (goerie.com)
Global Epigenetics Technology Market – Analysis and Forecasts 2012 – 2017 (prweb.com)

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Cardiac Ca2+ Signaling: Transcriptional Control

Posted in Biological Networks, Cardiovascular Pharmacogenomics, Cell Biology, Disease Biology, Gene Regulation and Evolution, Genetics & Pharmaceutical, Genome Biology, Molecular Genetics & Pharmaceutical, Nutrition and Phytochemistry, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged Ca2+/calmodulin-dependent protein kinase, Calcium in biology, Green fluorescent protein, health, heart, Open source intelligence, Protocols, Second messenger system, Signal transduction, Transcription (genetics) on March 2, 2013| 2 Comments »

Cardiac Ca2+ Signaling: Transcriptional Control

Reporter: Larry H Bernstein, MD, FCAP

The other side of cardiac Ca2+ signaling: transcriptional control

A Domínguez-Rodríguez, G Ruiz-Hurtado, Jean-Pierre Benitah and AM Gómez

Ca2+ is not only a key element in excitation-contraction coupling (EC coupling), but
it is also a pivotal second messenger in cardiac signal transduction,
being able to control processes such as
- excitability,
- metabolism, and
- transcriptional regulation.

Front. Physio. 2012; 3:452. http://dx.doi.org/fphys.2012.00452/
http://www.fphys.com/The other side of cardiac Ca2+ signaling: transcriptional control

calcium release calmodulin

English: A rendition of the CaMKII holoenzyme in the (A) Closed and the (B) Open conformation (Photo credit: Wikipedia)

Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity and Sinoatrial Nodal Pacemaker Cell Energetics (plosone.org)
The L-type Ca2+ Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells (plosone.org)
Calreticulin Induces Dilated Cardiomyopathy (plosone.org)
Phosphorylation and Feedback Regulation of Metabotropic Glutamate Receptor 1 by Calcium/Calmodulin-Dependent Protein Kinase II (jneurosci.org)
Watching Neurons in action (greenfluorescentblog.wordpress.com)

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Mobilizing Scientific Societies: Editorial by Science Editor-in-Chief Dr. Bruce Alberts

Posted in Health Economics and Outcomes Research, HealthCare IT, Interviews with Scientific Leaders, Scientist: Career considerations, tagged AAAS, Aviva Lev-Ari, Bruce Alberts, Chronicle of Higher Education, Educational Resources, health, medicine, National Science Foundation, science, Science education, STEM, United States on February 24, 2013| Leave a Comment »

Mobilizing Scientific Societies: Editorial by Science Editor-in-Chief Dr. Bruce Alberts

Reporter: Stephen J. Williams, Ph.D

This image has an empty alt attribute; its file name is ArticleID-28.png

WordCloud Image Produced by Adam Tubman

In a weekly editorial, Dr. Bruce Alberts, Editor-in –Chief of the journal Science discussed issues pertaining to science education in the United States[1]. He suggests the US science education system may need to be more flexible in its approach to science education in grade and high school. He considers the one major problem is the “broad coverage of each subject, which kills student interest and makes genuine comprehension impossible. Dr. Alberts suggest that state-based textbooks and the inability of the scientific community to understand teacher’s needs is driving this inadvertent problem. The current textbooks used for scientific education focus more on memorization of a multitude of scientific terms than on concept development, experimentation and inquisition, and conclusion. Materials are desperately needed for teachers to guide students to confront the overall concept, and working in teams, design potential methods to further explore these concepts. He suggest this style of teaching would require close partnerships between top-notch teachers , educational experts and scientific societies in order to research the effect of current curriculum materials but also develop new Web-based curriculum.

In a recent interview in the March 2013 issue of Wired magazine with Clayton Christensen, Ph.D. the author of the famed book The innovator’s Dilemma, Dr. Christensen forwqarns the impending changes in higher education due to increased availability of online learning. As he states, universities are on the precipice of a collapse in the future and those which survive will evolve hybrid models of education, part online and part classroom but will provide more specialized offerings to fit current needs. Indeed, as listed below these changes and suggestions in science education may well be underway. Below is a brief listing of scientific societies who have undertaken these challenges and formed extensive programs in STEM education.

FASEB (Federation of American Societies for Experimental Biology) programs such as:

Resources for Faculty and K-12 Teachers

APS Frontiers in Physiology Program – Provides professional development for middle and high school teachers by providing them with tools and resources and connecting them with researchers on-line and through workshops.

APS Physiology Understanding Week – Fosters relationships among teachers, students, and physiologists. PhUn Week encourages member physiologists across the nation to volunteer and work with teachers in their local community to visit a classroom during the first week in November.

Leap to the Top in Science Classes from AAAS found at:

http://news.aaas.org/2013_annual_meeting/0214leap-to-the-top-in-science-classes.shtml

A progress report from the 2013 AAAS meeting follows:

Often, in the daily grind of slogging through a difficult science class, students see fully formed scientists and their discoveries as a distant blur. Remote men and women somehow make advanced science happen.

New efforts aim to bring students face to face with creative, imaginative scientists right in their classroom.

With a lifetime of scientific contributions at their back, many retired scientists, engineers, and physicians are returning to school, not as pupils or as instructors, but as classroom volunteers in public elementary, middle, and high schools.

This week over 400 teachers and scientists gathered in Boston for the first International Teacher-Scientist Partnership Conference, organized by AAAS Education and Human Resources and the University of California, San Francisco Science & Health Education Partnership, sponsored by the National Science Foundation. Presenters are scheduled to share a range of partnership models over three days, from scientists generating digital education tools, to teachers participating in research.

Throughout the first day of the conference, the conversation turned to the idea of bringing scientists into the classroom to work directly with the students.

Virginia Shepherd from Vanderbilt University shared a comprehensive analysis of the university’s nearly 20-year-old Graduate STEM Fellows in K-12 Education program. Presentation attendees duly applauded the success of the program but said that they had trouble establishing similar programs in their state for lack of funding.

A handful of organizations represented at the conference have found that an affordable way to bring scientists into the classroom is to recruit retired scientists.

Volunteers at Northeastern University’s Retirees Enhancing Science Education through Experiments and Demonstrations program, or RE-SEED, spend at least one day a week in an elementary, middle, or high school classroom in Massachusetts helping students conduct experiments as part of the existing curriculum.

“Retired scientists and engineers have a lot of experience from a lifetime of working in laboratories. They can make what the students are learning relevant,” said Christos Zahopoulos, a professor of education and engineering at Northeastern University.

Since founding RE-SEED in 1991, Zahopoulos has helped to start similar programs in 15 states, conducting on-site trainings for volunteers. While such programs start out strong, many of them have since faded, with only a handful remaining, he said.

Even though retirees are offering a free service to the schools, getting them trained and placed takes a certain amount of funding, Zahopoulos says. He has been fortunate to fund RE-SEED with private donations. Many programs were not so lucky.

AAAS’ Senior Scientists and Engineers (SSE), a service-oriented organization for retired scientists and engineers, has managed to sustain a similar program for seven years. In 2005, Zahopoulos helped SSE establish its own volunteer program.

Donald Rea, a former research chemist for NASA’s Jet Propulsion Laboratory and SSE volunteer coordinator for Virginia, hopes that helping to reinforce science education will enhance the public understanding of science in years to come.

“If you want to have an influence on science literacy, you want to get [kids] while they are young. So we work in classrooms as young as second grade,” Rea said.

This kind of investment takes many years to fully mature. So, how do Rea and Zahopoulos measure success? They look to their teachers, volunteers, and students.

Rea said he measures success by the eagerness of schools and teachers to participate year after year.

For Zahopoulos, hints of success sometimes come in the mail. He says one student wrote in to RE-SEED upon graduating from high school, several years after any contact with a RE-SEED volunteer, to say that she had decided to major in biology and had enrolled in a pre-medicine program.

Both Rea and Zahopoulos said they have been amazed at the dedication and eagerness of volunteers.

“When we first started, we asked volunteers to commit to one day a week for one year. Now we have volunteers who have been with us for 18 years and some volunteer as many as 4 times per week,” Zahopoulos said.

Ron McKnight, a former Department of Energy physicists and SSE volunteer has recently taken on the task of coordinating volunteers living in Montgomery County, Md. He still volunteers in middle school science classrooms and is considering taking on another assignment.

When asked what he loves about volunteering, he replied, “Whenever a kid I’m working with asks a really good question, that’s when I have a really good day.”

National Science Foundation (NSF) Research on Learning in Formal and Informal Settings (DRL)

Information can be found at http://www.nsf.gov/div/index.jsp?div=DRL

DRL invests in projects to improve the effectiveness of STEM learning for people of all ages. Its mission includes promoting innovative research, development, and evaluation of learning and teaching across all STEM disciplines by advancing cutting-edge knowledge and practices in both formal and informal learning settings. DRL also promotes the broadening and deepening of capacity and impact in the educational sciences by encouraging the participation of scientists, engineers, and educators from the range of disciplines represented at NSF. Therefore, DRL’s role in the larger context of Federal support for education research and evaluation is to be a catalyst for change—advancing theory, method, measurement, development, and application in STEM education. The Division seeks to advance both early, promising innovations as well as larger-scale adoptions of proven educational innovations. In doing so, it challenges the field to create the ideas, resources, and human capacity to bring about the needed transformation of STEM education for the 21st century.

Society of Toxicology K-12 Educational Outreach for Scientists

http://www.toxicology.org/ai/k12o/k-12scientists.asp

This sites contains multiple .pdf files on volunteering and mentoring topics including

Scientist Mentor Ideas
Links to Other Mentoring Sites
Resources for toxicologists to use in K-12 Outreach
Regional Chapter K-12 Outreach

References:

1. Alberts B: Mobilizing scientific societies. Science 2012, 338(6113):1396.

for high school teachers please see https://www.teachercertificationdegrees.com/top-blogs/science-teacher/

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

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Drug Delivery Platform Technology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged Cancer - General, Cancer cell, Conditions and Diseases, European Molecular Biology Laboratory, Genitourinary, health, Prostate cancer on February 14, 2013| 7 Comments »

Curator: Aviva Lev-Ari, PhD, RN

Screen Shot 2021-07-19 at 7.16.18 PM

Word Cloud By Danielle Smolyar

A new etiology for Prostate Cancer based on Integrative Genomic Analyses reveals difference in Pathomechanism between Early onset and and Non-Early onset was reported this week in Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013

Early Onset: Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG

Non Early onset:

Around 65 years of age at onset: elderly-onset PCAs displayed primarily non-androgen-associated structural rearrangement (SR) formations.

Treatment Comparison for Clinically Localized Primary Prostate Cancer Therapies

Treatment	Description	Selected Risks	Recovery	Selected Outcomes
HIFU – (high intensity focused ultrasound)	Minimally invasive use of focused ultrasound waves to ablate diseased tissue	Incontinence: 0-10% ^1-3 Impotence: 8-50%^4,5 Rectal Injury: <3% ^4-6	Catheter worn for approximately 2-3 weeks; can return to normal activities within a few days	55-95% biochemical disease-free survival rate at 5 years; 55-98% negative biopsy^1-9
Cryotherapy	Minimally invasive procedure using controlled freeze and thaw cycles to destroy the prostate	Incontinence: 3-10% ¹⁰ Impotence: 40-100% ¹⁰ Rectal Injury: 0-3% ¹⁰	2-3 hour procedure with possible overnight stay; return to normal activities within a few days	50-92% biochemical disease-free survival at 5 years; 87-98% negative biopsy ^11,12
Radical Prostatectomy	Surgery to remove prostate, open or laparoscopic	Incontinence: 9-20% ¹³ Impotence: 4-85%¹³ Rectal Injury:0-5%¹⁴	2-3 day hospital stay, catheter for 2-3 weeks for open surgery; shorter hospitalization and fewer postoperative complications for laparoscopic procedure	68–98% biochemical disease-free survival^15,16
External Beam Radiation	6-8 week treatment; external machine concentrating radiation beams to the prostate	Incontinence: 4-15% ¹⁷ Impotence: 41-62% ¹⁷ Rectal Injury: 15%¹⁷	Five treatments per week for 6-8 weeks, up to 2 months fatigue after full course of treatment	55–86% biochemical disease-free survival^18-19
Brachytherapy	Minimally invasive implants of radiation seeds in the prostate	Incontinence: 3-18% ²⁰ Impotence: 14-82% ²⁰ Rectal Injury: 3%²¹	1-2 hour procedure with possible overnight stay	78–89% biochemical disease-free survival²²

Data presented are for clinically localized, low-high risk primary prostate cancer. The information provided in the chart is therapy and not device specific and may not include all potential risks, recovery and outcome information. For further information please see references.

The Sonablate^® 500 is approved for investigational use within the U.S. and is being studied for the treatment of prostate cancer in clinical trials in the U.S. The FDA has made no decision as to the safety or efficacy of the Sonablate^® 500 for the treatment of prostate cancer. Currently, the device is available for the treatment of prostate cancer outside the U.S. in more than 30 countries.

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxByzdV

Prostate Cancer and Nanotecnology

Dr. T. Barlyia summaried:

Early detection of prostate cancer increased dramatically the five-year survival of patients. “This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated”. The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/

BIND-014 is a programmable nanomedicine that combines a targeting ligandand a therapeutic nanoparticle. BIND-014 contains docetaxel, a proven cancer drug which is approved in major cancer indications including breast, prostate and lung, encapsulated in FDA-approved biocompatible and biodegradable polymers. BIND-014 is targeted to prostate specific membrane antigen (PSMA), a cell surface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumors. In preclinical cancer models, BIND-014 was shown to deliver up to ten-fold more docetaxel to tumors than an equivalent dose of conventional docetaxel. The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumor activity and tolerability. BIND-014 is currently in Phase 1 human clinical testing in cancer patients with advanced or metastatic solid tumor cancers (NCT01300533). The early development of BIND-014 was funded in part by the National Cancer Institute and the U.S. National Institutes of Standards and Technology (NIST) under its Advanced Technology Program (ATP).

http://www.bindbio.com/content/pages/news/news_detail.jsp/q/news-id/70

State of the art in oncologic imaging of Prostate

Dr. D. Nir summarizes:

In regards to treatment choice: “active surveillance, focal therapy, radical prostatectomy, and radiation therapy represent a range of treatments with varying degrees of invasiveness for men with different disease grades and stages. Active surveillance and focal therapy, which are relatively new options, are promising but are complicated by uncertainties in risk stratification that affect treatment decision-making, as well as by uncertainties regarding the definition of appropriate outcome measures. Biopsy, which leaves the possibility of under sampling, is not sufficient to resolve these uncertainties. Novel biomarkers and modern imaging are expected to play increasingly important roles in facilitating broader acceptance of both active surveillance and focal therapy. Further research, particularly involving prospective validation, is needed to facilitate standardization and establish the roles of advanced imaging tools in routine prostate cancer management.”

My summary: Prostate cancer is a disease managed by urologists, not radiologists. This disease’s multi-choice of pathways is “craving” for tissue characterization. Nothing could fit the urologist’s work-flow better than ultrasound-based tissue characterization!

http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

Age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms.

Early Onset:

Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG,

Non Early onset:

Around 65 years of age at onset: elderly-onset PCAs displayed primarily non-androgen-associated SRs.

Integrative Genomic Analyses Reveal an Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

Joachim Weischenfeldt,Ronald Simon,Lars Feuerbach,Karin Schlangen,Dieter Weichenhan,Sarah Minner,Daniela Wuttig,Hans-Jörg Warnatz,Henning Stehr,Tobias Rausch,Natalie Jäger,Lei Gu,Olga Bogatyrova,Adrian M. Stütz,Rainer Claus,Jürgen Eils,Roland Eils,Clarissa Gerhäuser,Po-Hsien Huang,Barbara Hutter,Rolf Kabbe,Christian Lawerenz,Sylwester Radomski,Cynthia C. Bartholomae,Maria Fälth,Stephan Gade,Manfred Schmidt,Nina Amschler,Thomas Haß,Rami Galal,Jovisa Gjoni,Ruprecht Kuner,Constance Baer,Sawinee Masser,Christof von Kalle,Thomas Zichner,Vladimir Benes,Benjamin Raeder,Malte Mader,Vyacheslav Amstislavskiy,Meryem Avci,Hans Lehrach,Dmitri Parkhomchuk,Marc Sultan,Lia Burkhardt,Markus Graefen,Hartwig Huland,Martina Kluth,Antje Krohn,Hüseyin Sirma,Laura Stumm,Stefan Steurer,Katharina Grupp,Holger Sültmann,Guido Sauter,Christoph Plass,Benedikt Brors,Marie-Laure Yaspo,Jan O. Korbel send email

,Thorsten Schlomm See Affiliations

Genome sequencing revealed age-related genetic alterations in PCA
Early-onset PCAs display a specific abundance of androgen-driven rearrangements
These age-linked alterations coincide with activity levels of the androgen receptor
This is an observation of age-specific DNA alterations in a common cancer

Summary

Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with “classical” (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions includingTMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic “androgen-type” pathomechanism in EO-PCA.

Early onset prostate cancer tumors tend to have a propensity for containing balanced structural rearrangements, particularly involving genes regulated by the androgen hormone, according to a study in Cancer Cell. As part of the International Cancer Genome Project’s Early-Onset Prostate Cancer project, researchers from Germany and the UK performed whole-genome sequencing on tumor and matched normal samples from 11 individuals who were surgically treated for prostate cancer at a median age of 47 years old. The tumors were also subjected to transcriptome and methylome sequencing.

When they compared sequences from these tumors with sequences from a previously described set of samples taken from seven individuals diagnosed with prostate cancer at around 65 years of age, investigators saw a rise in gene fusion-producing structural changes in the early onset samples.

Those fusions often affected ETS family genes and other genes prone to androgen-related regulation, researchers reported. In contrast, tumors from individuals whose prostate cancer appeared later in life were more apt to contain structural rearrangements affecting genes without any androgen ties.

Follow-up tests using samples from more than 10,000 other patients seemed to support this link between age at prostate cancer diagnosis and androgen receptor rearrangement, study authors said, pointing to a distinct, androgen-driven “pathomechanism” in early-onset forms of the disease.

SOURCE:

http://www.genomeweb.com//node/1191311?hq_e=el&hq_m=1498692&hq_l=5&hq_v=5f2bf80408

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB

REFERENCES

Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU international 2006;97:56-61.
Uchida T, Ohkusa H, Yamashita H, et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2006;13:228-33.
Muto S, Yoshii T, Saito K, Kamiyama Y, Ide H, Horie S. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Japanese journal of clinical oncology 2008;38:192-9.
Ahmed HU, Zacharakis E, Dudderidge T, et al. High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series. British journal of cancer 2009;101:19-26.
Inoue Y, Goto K, Hayashi T, Hayashi M. Transrectal high-intensity focused ultrasound for treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2011;18:358-62.
Uchida T, Shoji S, Nakano M, et al. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. International journal of urology : official journal of the Japanese Urological Association 2009;16:881-6.
Sumitomo M, Hayashi M, Watanabe T, et al. Efficacy of short-term androgen deprivation with high-intensity focused ultrasound in the treatment of prostate cancer in Japan. Urology 2008;72:1335-40.
Sumitomo M, Asakuma J, Yoshii H, et al. Anterior perirectal fat tissue thickness is a strong predictor of recurrence after high-intensity focused ultrasound for prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2010;17:776-82.
Dudderidge T, Ahmed H, Emberton M. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU international 2009;104:1170-1; author reply 1.
Shelley M, Wilt TJ, Coles B, Mason MD. Cryotherapy for localised prostate cancer. Cochrane Database Syst Rev 2007:CD005010.
Cheetham P, Truesdale M, Chaudhury S, Wenske S, Hruby GW, Katz A. Long-term cancer-specific and overall survival for men followed more than 10 years after primary and salvage cryoablation of the prostate. Journal of endourology / Endourological Society 2010;24:1123-9.
Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL, Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. The Journal of urology 2008;180:554-8.
Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA : the journal of the American Medical Association 2009;302:1557-64.
Williams SB, Prasad SM, Weinberg AC, et al. Trends in the care of radical prostatectomy in the United States from 2003 to 2006. BJU international 2011;108:49-55.
Mullins JK, Feng Z, Trock BJ, Epstein JI, Walsh PC, Loeb S. The impact of anatomical radical retropubic prostatectomy on cancer control: the 30-year anniversary. The Journal of urology 2012;188:2219-24.
Loeb S, Zhu X, Schroder FH, Roobol MJ. Long-term radical prostatectomy outcomes among participants from the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam. BJU international 2012.
Budaus L, Bolla M, Bossi A, et al. Functional outcomes and complications following radiation therapy for prostate cancer: a critical analysis of the literature. European urology 2012;61:112-27.
Grimm P, Billiet I, Bostwick D, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU international 2012;109 Suppl 1:22-9.
Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Annals of internal medicine 2008;148:435-48.
Buckstein M, Kerns S, Forysthe K, Stone NN, Stock RG. Temporal patterns of selected late toxicities in patients treated with brachytherapy or brachytherapy plus external beam radiation for prostate adenocarcinoma. BJU international 2012.
Orio PF, 3rd, Merrick GS, Galbreath RW, Butler WM, Lief J, Wallner KE. Patient-reported long-term rectal function after permanent interstitial brachytherapy for clinically localized prostate cancer. Brachytherapy 2012;11:341-7.
Critz FA, Benton JB, Shrake P, Merlin ML. 25 year disease free survival rate after irradiation of prostate cancer calculated with the prostate specific antigen definition of recurrence used for radical prostatectomy. The Journal of urology 2012.

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB

Other research papers related to the management of Prostate cancer were published on this One Access Online Scientific Journal

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

Prostate Cancer and Nanotecnology

http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/

State of the art in oncologic imaging of Prostate

http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute
http://pharmaceuticalintelligence.com/2013/02/06/genomically-guided-treatment-after-clia-approval-to-be-offered-by-weill-cornell-precision-medicine-institute/

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Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Statistical Methods for Research Evaluation, tagged Aviva Lev-Ari, Biology, breast cancer, Cancer - General, chromosomal abberation, Conditions and Diseases, Dana–Farber Cancer Institute, DNA, DNA Sequencing, driver mutations, gene, genetics, genome, health, Journal of the National Cancer Institute, medicine, Melanoma, mutation, mutations, National Institutes of Health, passenger mutations, Personalized medicine, Proceedings of the National Academy of Sciences of the United States of America, research, science, Telomerase reverse transcriptase on February 10, 2013| Leave a Comment »

Rewriting the Mathematics of Tumor Growth[1]; Teams Use Math Models to Sort Drivers from Passengers[2]: Two JNCI Reviews by Mike Martin Regarding Genomics, Cancer, and Mutation

Curator: Stephen J. Williams, Ph.D.

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Recently, there has been extensive interest in the cancer research and oncology community on detecting those mutations responsible for the initiation and propagation of a neoplastic cell (driver mutations) versus those mutations that are randomly (or by selective pressures) acquired due to the genetic instability of the transformed cell. The impact of either type of mutation has been a topic for debate, with a recent article showing that some passenger mutations may actually be responsible for tumor survival. In addition many articles, highlighted on this site (and referenced below) in recent years have described the importance of classifying driver and passenger mutations for the purposes of more effective personalized medicine strategies directed against tumors. Two review articles by Mike Martin in the Journal of the National Cancer Institute (JCNI) shed light on the current efforts and successes to discriminate between these passenger and driver mutations and determine impact of each type of mutation to tumor growth. However, as described in the associated article, the picture is not as clear cut as previously thought and highlights some revolutionary findings. In Rewriting the Mathematics of Tumor Growth, researchers discovered that driver mutations may confer such a small growth advantage that, multiple mutations, including the so called passenger mutations are necessary in order to sustain tumor growth. In fact, much experimental evidence has suggested at least six defined genetic events may be necessary for the in-vitro transformation of human cells. The following table shows some of the genetic events required for in-vitro transformation in cell culture systems.

Genetic events required for transformation

Species	Cell type	# of genes required for tumor formation*	Genes used	Reference	Events required for priming
Human	FibroblastsEmbryonic kidney	3	hTERTH-rasLarge T	(a)Hahn(Weinberg)	2LT+hTERT
	Mammary epithelialMyoblastsEmbryonic kidney	6	hTERTH-rasP53^DDc-myccyclin D1CDK4	(b)Kendall(Counter)	Hras required for tumorigenesis so probably 5 events needed
	Fibroblasts	4	Large TSmall TH-rashTERT	(c)Sun(Hornsby)	2Large T + H-ras
	Fibroblasts	4	Large TSmall ThTERTRas	(d)Rangarajan(Weinberg)	3hTERT, Ras and either small or largeT
	Keratinocytes	4	CyclinD1dnp53EGFR c-myc	(e)Goessel(Opitz)	3 for anchorage independence (cyclin D1, dnp53, EGFR),Cyclin D1+dnp53 for immortalization
	HOSE	6	CDK4, cyclin D, hTERT plus combination of either P53^DD, myrAkt, and H-ras or P53^DD, H-ras, c-myc Bcl2	(f)Sasaki(Kiyono)	5
	HOSE	3	hTERTSV40 earlyH-ras orK-ras	(g)Liu(Bast)	2hTERT+ SV40 early
	HOSE	3	Large ThTERTH-ras orc-erB-2	(h)Kusakari(Fujii)	2hTERT+large T
Rat	Fibroblasts	2	Large TH-ras	(i)Hirakawa	Did not analyze
	Fibroblasts	2	Large TH-ras	(d)Rangarajan(Weinberg)	Large T
Mouse	MOSEIn p53^-/- background	3	c-mycK-rasAkt	(j)Orsulic

Pig	Fibroblasts	6	p53^DDhTERTCDK4H-ras c-myccyclin D1	(k)Adam(Counter)	5 need all butp53^DD

Note: priming means events required to immortalize but not fully transform. * Note that both ability to form colonies in soft agarose and subsequently tested for tumor formation in immunocompromised mice.

a. Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., and Weinberg, R. A. (1999) Creation of human tumour cells with defined genetic elements, Nature 400, 464-468.

b. Kendall, S. D., Linardic, C. M., Adam, S. J., and Counter, C. M. (2005) A network of genetic events sufficient to convert normal human cells to a tumorigenic state, Cancer Res 65, 9824-9828.

c. Sun, B., Chen, M., Hawks, C. L., Pereira-Smith, O. M., and Hornsby, P. J. (2005) The minimal set of genetic alterations required for conversion of primary human fibroblasts to cancer cells in the subrenal capsule assay, Neoplasia 7, 585-593.

d. Rangarajan, A., Hong, S. J., Gifford, A., and Weinberg, R. A. (2004) Species- and cell type-specific requirements for cellular transformation, Cancer Cell 6, 171-183.

e. Goessel, G., Quante, M., Hahn, W. C., Harada, H., Heeg, S., Suliman, Y., Doebele, M., von Werder, A., Fulda, C., Nakagawa, H., Rustgi, A. K., Blum, H. E., and Opitz, O. G. (2005) Creating oral squamous cancer cells: a cellular model of oral-esophageal carcinogenesis, Proc Natl Acad Sci U S A 102, 15599-15604.

f. Sasaki, R., Narisawa-Saito, M., Yugawa, T., Fujita, M., Tashiro, H., Katabuchi, H., and Kiyono, T. (2009) Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes, Carcinogenesis 30, 423-431.

g. Liu, J., Yang, G., Thompson-Lanza, J. A., Glassman, A., Hayes, K., Patterson, A., Marquez, R. T., Auersperg, N., Yu, Y., Hahn, W. C., Mills, G. B., and Bast, R. C., Jr. (2004) A genetically defined model for human ovarian cancer, Cancer Res 64, 1655-1663.

h. Kusakari, T., Kariya, M., Mandai, M., Tsuruta, Y., Hamid, A. A., Fukuhara, K., Nanbu, K., Takakura, K., and Fujii, S. (2003) C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro, Br J Cancer 89, 2293-2298.

i. Hirakawa, T., and Ruley, H. E. (1988) Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene, Proc Natl Acad Sci U S A 85, 1519-1523.

j. Orsulic, S., Li, Y., Soslow, R. A., Vitale-Cross, L. A., Gutkind, J. S., and Varmus, H. E. (2002) Induction of ovarian cancer by defined multiple genetic changes in a mouse model system, Cancer Cell 1, 53-62.

k. Adam, S. J., Rund, L. A., Kuzmuk, K. N., Zachary, J. F., Schook, L. B., and Counter, C. M. (2007) Genetic induction of tumorigenesis in swine, Oncogene 26, 1038-1045.

However it may be argued that the aforementioned experimental examples were produced in cell lines with a more stable genome than that which is seen in most tumors and had used traditional assays of transformation, such as growth in soft agarose and tumorigenicity in immunocompromised mice, as endpoints of transformation, and not representative of the tumor growth seen in the clinical setting.

Therefore Bert Vogelstein, M.D., along with collaborators around the world developed a model they termed the “sequential driver mutation theory”, in which they describe that driver mutations multiply over time with each mutation “slightly increasing the tumor growth rate through a process that depends on three factors”:

Driver mutation rate
The 0.4% selective growth advantage
Cell division time

This model was based on a combination of experimental data and computer simulations of gliobastoma multiforme and pancreatic adenocarcinoma. Most tumor models follow a Gompertz kinetics, which show how tumor growth is exponential but eventually levels off over time.

This new theory shows though that a tumor cell with only one driver mutation can only grow so much, until a second driver mutation is required. Using data for the COSMIC database (Catalog of Somatic Mutations in Cancer) together with analysis software CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations) the researchers analyzed 713 mutations sequenced from 14 glioma patients and 562 mutations in nine pancreatic adenocarcinomas, revealing at least 100 tumor suppressor genes and 100 oncogenes altered. Therefore, the authors suggested these may be possible driver mutations, or at least mutations required for the sustained growth of these tumors. Applying this new model to data obtained from Dr. Giardiello’s publication concerning familial adenopolypsis in New England Journal of medicine in 19993 and 2000, the sequential driver mutation model predicted age distribution of FAP patients, number and size of polyps, and polyp growth rate than previous models. This surprising number of required driver mutations for full transformation was also verified in a study led by University of Texas Southwestern Medical Center biologist Jerry Shay, Ph.D., who noted “this team’s surprise nearly 45% of all colorectal candidate oncogenes (65 mutations) drove malignant proliferation”[3].

However, some investigators do not believe the model is complex enough to account for other factors involved in oncogenesis, such as epigenetic factors like methylation and acetylation. In addition the review also discusses host and tissue factors which may complicate the models, such as location where a tumor develops. However, most of the investigators interviewed for this review agreed that focusing on this long-term progression of the disease may give us clues to other potential druggable targets.

Teams Use Math Models to Sort Drivers From Passengers

A related review from Mike Martin in JNCI [2] describes a statistical method, published in 2009 Cancer Informatics[4], which distinguishes chromosomal abnormalities that can drive oncogenesis from passenger abnormalities. Chromosomal abnormalities, such as deletions, additions, and translocations are common in cancer. For instance, the well-known Philadelphia chromosome, a translocation between chromosome 9 and 22 which results in the BCR-ABL tyrosine kinase fusion protein is the molecular basis of chronic myelogenous leukemia.

In the report, Eytan Domany, Ph.D., from Weizmann Institute and several colleagues from University of Lausanne, University of Haifa and the Broad Institute were analyzing chromosomal aberrations in a subset of medulloblastoma, which had more gain and losses in chromosomes than had been attributed to the disease. Using a statistical method they termed a “volumetric sieve”, the investigators were able to identify driver versus passenger aberrations based on three filters:

Fraction of patients with the abnormality
Length of DNA involved in the aberrant chromosome
Abnormality’s copy number

Another method to sort the most “important” chromosomal aberrations from less relevant alterations is termed GISTIC[5], as the website describes is: a tool to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth (at the Broad Institute website http://www.broadinstitute.org/software/cprg/?q=node/31). The method allows for comparison across multiple tumors so noise is eliminated and improves consistency of analysis. This method had been successfully used to determine driver aberrations is mesotheliomas, leukemias, and identify new oncogenes in adenocarcinomas of the lung and squamous cell carcinoma of the esophagus.

Main references for the two Mike Martin articles are as follows:

1. Martin M: Rewriting the mathematics of tumor growth. Journal of the National Cancer Institute 2011, 103(21):1564-1565.

2. Martin M: Aberrant chromosomes: teams use math models to sort drivers from passengers. Journal of the National Cancer Institute 2010, 102(6):369-371.

3. Eskiocak U, Kim SB, Ly P, Roig AI, Biglione S, Komurov K, Cornelius C, Wright WE, White MA, Shay JW: Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth. Cancer research 2011, 71(13):4359-4365.

4. Shay T, Lambiv WL, Reiner-Benaim A, Hegi ME, Domany E: Combining chromosomal arm status and significantly aberrant genomic locations reveals new cancer subtypes. Cancer informatics 2009, 7:91-104.

5. Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S et al: Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proceedings of the National Academy of Sciences of the United States of America 2007, 104(50):20007-20012.