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Posts Tagged ‘Medical imaging’


The Role of Medical Imaging in Personalized Medicine

Writer & reporter: Dror Nir, PhD

The future of personalized medicine comprise quantifiable diagnosis and tailored treatments; i.e. delivering the right treatment at the right time. To achieve standardized definition of what “right” means, the designated treatment location and lesion size are important factors. This is unrelated to whether the treatment is focused to a location or general. The role of medical imaging is and will continue to be vital in that respect: Patients’ stratification based on imaging biomarkers can help identify individuals suited for preventive intervention and can improve disease staging. In vivo visualization of loco-regional physiological, biochemical and biological processes using molecular imaging can detect diseases in pre-symptomatic phases or facilitate individualized drug delivery. Furthermore, as mentioned in most of my previous posts, imaging is essential to patient-tailored therapy planning, therapy monitoring, quantification of response-to-treatment and follow-up disease progression. Especially with the rise of companion diagnostics/theranostics (therapeutics & diagnostics), imaging and treatment will have to be synchronized in real-time to achieve the best control/guidance of the treatment.

It is worthwhile noting that the new RECIST 1.1 criteria (used in oncological therapy monitoring) have been expanded to include the use of PET (in addition to lymph-node evaluation).

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In previous posts I already discussed many examples concerning the use of medical imaging in personalized medicine: e.g. patients’ stratification; Imaging-biomarkers is Imaging-based tissue characterization, the future of imaging-biomarkers in diagnostic; Ultrasound-based Screening for Ovarian Cancer, imaging-based guided therapies; Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma, treatment follow-up; the importance of spatially-localized and quantified image interpretation in cancer management, and imaging-based assessment of response to treatment; Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging

Browsing through our collaborative open-source initiative one can find many more articles and discussions on that matter; e.g. Tumor Imaging and Targeting: Predicting Tumor Response to Treatment: Where we stand?, In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

In this post I would like to highlight the potential contribution of medical imaging to development of companion diagnostics. I do that through the story on co-development of Vintafolide (EC145) and etarfolatide (Endocyte/Merck). Etarfolatide is a folate-targeted molecular radiodiagnostic imaging agent that identifies tumors that overexpress the folate receptor. The folate receptor, a glycosylphosphatidylinositol anchored cell surface receptor, is overexpressed on the vast majority of cancer tissues, while its expression is limited in healthy tissues and organs. Folate receptors are highly expressed in epithelial, ovarian, cervical, breast, lung, kidney, colorectal, and brain tumors. When expressed in normal tissue, folate receptors are restricted to the lungs, kidneys, placenta, and choroid plexus. In these tissues, the receptors are limited to the apical surface of polarized epithelia. Folate, also known as pteroylglutamate, is a non-immunogenic water-soluble B vitamin that is critical to DNA synthesis, methylation, and repair (folate is used to synthesize thymine).

Vintafolide (EC145) delivers a very potent vinca chemotherapy directly to cancer cells by targeting the folate receptor expressed on cancer cells. Approximately 80-90 percent of ovarian and lung cancers express the receptor, as do many other types of cancer. Clinical data have shown that patients with metastases that are all positive for the folate receptor, identified by etarfolatide, benefited the most from the treatment with vintafolide, the corresponding folate-targeted small molecule drug conjugate.

Having both drug and imaging agent rely on folate receptors within the patients body Endocyte’s strategy was to develop the imaging agent and to use it to accelerate R&D and regulation. Endocyte and Merck entered into a partnership for vintafolide in April 2012. Under this partnership Merck was granted an exclusive license to develop, manufacture and commercialize vintafolide. Endocyte is responsible for conducting the PROCEED Phase 3 clinical study in women with platinum resistant ovarian cancer and the Phase 2b second line NSCLC (non-small cell lung cancer) study named TARGET. Merck is responsible for further clinical studies in additional indications. This Co-development of a diagnostic and therapeutic agent, was conducted according to the FDA guidance on personalized medicine and resulted with vintafolide gaining, already in 2012, status of orphan drug in EMA.

 

 The following is an extract from a post by Phillip H. Kuo, MD, PhD, associate professor of medical imaging, medicine, and biomedical engineering; section chief of nuclear medicine; and director of PET/CT at the University of Arizona Cancer Center.

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Figure 1 — Targeted Radioimaging Diagnostic and Small Molecule Drug Conjugate

Etarfolatide is comprised of the targeting ligand folic acid (yellow), which has a high folate receptor binding affinity, and a Technetium-99m–based radioimaging agent (turquoise). Etarfolatide identifies metastases that express the folate receptor protein in real time (A). The folic acid-targeting ligand is identical to that found on vintafolide, the corresponding therapeutic small molecule drug conjugate, which also contains a linker system (blue) and a potent chemotherapeutic drug (red) (B).

 

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Figure 2 — Whole-Body Scan With 111In-DTPA-Folate 

Diagnostic images of whole-body scans obtained following administration of the targeted radioimaging agent 111In-DTPA-folate, which is constructed with the same folic acid ligand as that engineered in etarfolatide. The healthy patient image on the left shows no folate receptor-positive abdominal tumor. Instead, only healthy kidneys (involved in excretion) are revealed. The patient on the right shows folate receptor-positive tumors in the abdomen and pelvis. Patients with metastases, identified with the companion imaging diagnostic etarfolatide as folate receptor-positive are most likely to respond to treatment with the corresponding small molecular drug conjugate vintafolide. Note: Vintafolide currently is being evaluated in a phase 3 clinical trial for platinum-resistant ovarian cancer and a phase 2 trial for non–small-cell lung cancer. Both studies also are using etarfolatide.

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Figure 3 — Vintafolide’s Mechanism of Action

Folate is required for cell division, and rapidly dividing cancer cells often express folate receptors to capture enough folate to support rapid cell growth. Elevated expression of the folate receptor occurs in many human malignancies, especially when associated with aggressively growing cancers. The folate-targeted small molecule drug conjugate vintafolide binds to the folate receptor (A) and subsequently is internalized by a natural endocytosis process (B). Once inside the cell, vintafolide’s serum-stable linker selectively releases a potent vinca alkaloid compound (C) to arrest cell division and induce cell death.

Epilog

I think that those of you who reached this point in my post deserve a special bonus! So here it is: A medical-imaging initiative that is as ambitious and complex as the initiative to send humans into deep-space.

This is the The European Population Imaging Infrastructure initiative of the Dutch Federation of University Medical Centres (NFU) and the Erasmus University Medical Centre Rotterdam, Department of Radiology, chaired by Professor Gabriel P. Krestin. The NFU has made available initial funding for the development of this initiative.

The European Population Imaging Infrastructure closely cooperates with the European Biomedical Imaging Infrastructure Project EURO-BioImaging which is currently being developed.

The ultimate aim of the infrastructure is to help the development and implementation of strategies to prevent or effectively treat disease. It supports imaging in large, prospective epidemiological studies on the population level. Image specific markers of pre-symptomatic diseases can be used to investigate causes of pathological alterations and for the early identification of people at risk.

More information on this infrastructure and on the role of the European Population Imaging Infrastructure in this can be found in the Netherlands Roadmap for Large-Scale Research Facilities, the applicaton for funding of the Roadmap Large Scale Research Facilities Application form of the Roadmap EuroBioImaging, and on the Euro-BioImaging website.

Certainly, while making progress with this initiative, many lessons will be learned. I recommend to explore this site and Enjoy!

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Following (or not) the guidelines for use of imaging in management of prostate cancer.

Writer and curator: Dror Nir, PhD

Over diagnosis and over treatment is a trend of the last two decades. It leads to increase in health-care costs and human-misery.

The following headline on Medscape; Swedes Show That We Can Improve Imaging in Prostate Cancer elicited my curiosity.

I was expecting “good news” – well, not this time!

In spite the “general language” the study that the above mentioned headline refers to is not addressing the global use of imaging in prostate cancer patients’ pathway but is specific to use of radionuclide bone-scans as part of patients’ staging.  The “bad-news” are that realization that the Swedish government had to invest many man-years to achieve “success” in reducing unnecessary use of such imaging in low risk patients. Moreover, the paper reveals under-use of such imaging technology for staging high risk prostate cancer patients.

Based on this paper, one could come to the conclusion that in reality, we are facing long lasting non-conformity with established guidelines related to the use of “full-body” imaging as part of the prostate cancer patients’ pathway in Europe and USA.

Here is a link to the original paper:

Prostate Cancer Imaging Trends After a Nationwide Effort to Discourage Inappropriate Prostate Cancer Imaging, Danil V. MakarovStacy LoebDavid UlmertLinda DrevinMats Lambe and Pär Stattin Correspondence to: Pär Stattin, MD, PhD, Department of Surgery and Perioperative Sciences, Urology and Andrology, Umeå University, SE- 901 87 Umeå, Sweden (e-mail:par.stattin@urologi.umu.se).

JNCI J Natl Cancer Inst (2013)doi: 10.1093/jnci/djt175

 

For convenience, here are the highlights:

  • Reducing inappropriate use of imaging to stage incident prostate cancer is a challenging problem highlighted recently as a Physician Quality Reporting System quality measure and by the American Society of Clinical Oncology and the American Urological Association in the Choosing Wisely campaign.

 

  • Since 2000, the National Prostate Cancer Register (NPCR) of Sweden has led an effort to decrease national rates of inappropriate prostate cancer imaging by disseminating utilization data along with the latest imaging guidelines to urologists in Sweden.

  • Results Thirty-six percent of men underwent imaging within 6 months of prostate cancer diagnosis. Overall, imaging use decreased over time, particularly in the low-risk category, among whom the imaging rate decreased from 45% to 3% (P < .001), but also in the high-risk category, among whom the rate decreased from 63% to 47% (P < .001). Despite substantial regional variation, all regions experienced clinically and statistically (P < .001) significant decreases in prostate cancer imaging.

 

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  • These results may inform current efforts to promote guideline-concordant imaging in the United States and internationally.

  • In 1998, the baseline low-risk prostate cancer imaging rate in Sweden was 45%. Per the NCCN guidelines (7), none of these men should have received bone imaging unless they presented with symptoms suggestive of bone pain (8,24). In the United States, the imaging rate among men with low-risk prostate cancer has been reported to be 19% to 74% in a community cohort and 10% to 48% in a Surveillance Epidemiology and End Results (SEER)–Medicare cohort (10–13,16). It is challenging to compare these rates directly across the two countries because the NPCR aggregates all staging imaging into one variable. However, our sampling revealed that 88% of those undergoing imaging had at least a bone scan, whereas only 11% had any CTs and 10% had any MRI. This suggests that baseline rates of bone scan among low-risk men in Sweden were similar to those among their low-risk counterparts in the United States, whereas rates of axial imaging were likely much lower. During the study period, rates of prostate cancer imaging among low-risk men in Sweden decreased to 3%, substantially lower than those reported in the United States at any time.

  • Miller et al. describe a decline in imaging associated with a small-scale intervention administered in three urology practices located in the United States participating in a quality-improvement consortium. Our study’s contribution is to demonstrate that a similar strategy can be applied effectively at a national scale with an associated decline in inappropriate imaging rates, a finding of great interest for policy makers in the United States seeking to improve health-care quality.

  • In 1998, the baseline high-risk prostate cancer imaging rates in Sweden were 63%, and decreased by 43% in 2008 (rising slightly to 47% in 2009). Based on our risk category definitions and the guidelines advocated in Sweden, all of these men should have undergone an imaging evaluation (8,24). Swedish rates of prostate cancer imaging among men with high-risk disease are considerably lower than those reported from the SEER–Medicare cohort, where 70% to 75% underwent bone scan and 57% to 58% underwent CT (13,16). These already low rates of imaging among men with high-risk prostate cancer only decreased further during the NPCR’s effort to promote guideline-concordant imaging. Clearly in both countries, imaging for high-risk prostate cancer remains underused despite the general overuse of imaging and numerous guidelines encouraging its appropriate use (3–9).

Similar items I have covered on this this Open Access Online Scientific Journal:

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

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Follow-up on Tomosynthesis

Writer & Curator: Dror Nir, PhD

Tomosynthesis, is a method for performing high-resolution limited-angle (i.e. not full 3600 rotation but more like ~500) tomography. The use of such systems in breast-cancer screening is steadily increasing following the clearance of such system by the FDA on 2011; see my posts – Improving Mammography-based imaging for better treatment planning and State of the art in oncologic imaging of breast.

Many radiologists expects that Tomosynthesis will eventually replace conventional mammography due to the fact that it increases the sensitivity of breast cancer detection. This claim is supported by new peer-reviewed publications. In addition, the patient’s experience during Tomosynthesis is less painful due to a lesser pressure that is applied to the breast and while presented with higher in-plane resolution and less imaging artifacts the mean glandular dose of digital breast Tomosynthesis is comparable to that of full field digital mammography. Because it is relatively new, Tomosynthesis is not available at every hospital. As well, the procedure is recognized for reimbursement by public-health schemes.

A good summary of radiologist opinion on Tomosynthesis can be found in the following video:

Recent studies’ results with digital Tomosynthesis are promising. In addition to increase in sensitivity for detection of small cancer lesions researchers claim that this new breast imaging technique will make breast cancers easier to see in dense breast tissue.  Here is a paper published on-line by the Lancet just a couple of months ago:

Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study

Stefano Ciatto†, Nehmat Houssami, Daniela Bernardi, Francesca Caumo, Marco Pellegrini, Silvia Brunelli, Paola Tuttobene, Paola Bricolo, Carmine Fantò, Marvi Valentini, Stefania Montemezzi, Petra Macaskill , Lancet Oncol. 2013 Jun;14(7):583-9. doi: 10.1016/S1470-2045(13)70134-7. Epub 2013 Apr 25.

Background Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening.

Methods Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases—2D only and integrated 2D and 3D mammography—yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar’s test.

Findings 7292 women were screened (median age 58 years [IQR 54–63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p<0.0001). Cancer detection rates were 5·3 cancers per 1000 screens (95% CI 3.8–7.3) for 2D only, and 8.1 cancers per 1000 screens (6.2–10.4) for integrated 2D and 3D screening. The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2.7 cancers per 1000 screens (1.7–4.2). 395 screens (5.5%; 95% CI 5.0–6.0) resulted in false positive recalls: 181 at both screen reads, and 141 with 2D only versus 73 with integrated 2D and 3D screening (p<0·0001). We estimated that conditional recall (positive integrated 2D and 3D mammography as a condition to recall) could have reduced false positive recalls by 17.2% (95% CI 13.6–21.3) without missing any of the cancers detected in the study population.

Interpretation Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening.

Funding National Breast Cancer Foundation, Australia; National Health and Medical Research Council, Australia; Hologic, USA; Technologic, Italy.

Introduction

Although controversial, mammography screening is the only population-level early detection strategy that has been shown to reduce breast-cancer mortality in randomised trials.1,2 Irrespective of which side of the mammography screening debate one supports,1–3 efforts should be made to investigate methods that enhance the quality of (and hence potential benefit from) mam­mography screening. A limitation of standard 2D mammography is the superimposition of breast tissue or parenchymal density, which can obscure cancers or make normal structures appear suspicious. This short coming reduces the sensitivity of mammography and increases false-positive screening. Digital breast tomosynthesis with 3D images might help to overcome these limitations. Several reviews4,5 have described the development of breast tomosynthesis technology, in which several low-dose radiographs are used to reconstruct a pseudo-3D image of the breast.4–6

Initial clinical studies of 3D mammography, 6–10 though based on small or selected series, suggest that addition of 3D to 2D mammography could improve cancer detection and reduce the number of false positives. However, previous assessments of breast tomosynthesis might have been constrained by selection biases that distorted the potential effect of 3D mammography; thus, screening trials of integrated 2D and 3D mammography are needed.6

We report the results of a large prospective study (Screening with Tomosynthesis OR standard Mammog­raphy [STORM]) of 3D digital mammography. We investi­gated the effect of screen-reading using both standard 2D and 3D imaging with tomosynthesis compared with screening with standard 2D digital mammography only for population breast-cancer screening.

  

Methods

Study design and participants

STORM is a prospective population-screening study that compares mammography screen-reading in two sequential phases (figure)—2D only versus integrated 2D and 3D mammography with tomosynthesis—yielding paired results for each screening examination. Women aged 48 years or older who attended population-based screening through the Trento and Verona screening services, Italy, from August, 2011, to June, 2012, were invited to be screened with integrated 2D and 3D mammography. Participants in routine screening mammography (once every 2 years) were asymptomatic women at standard (population) risk for breast cancer. The study was granted institutional ethics approval at each centre, and participants gave written informed consent. Women who opted not to participate in the study received standard 2D mammography. Digital mammography has been used in the Trento breast-screening programme since 2005, and in the Verona programme since 2007; each service monitors outcomes and quality indicators as dictated by European standards, and both have published data for screening performance.11,12

 

study design

Procedures

All participants had digital mammography using a Selenia Dimensions Unit with integrated 2D and 3D mammography done in the COMBO mode (Hologic, Bedford, MA, USA): this setting takes 2D and 3D images at the same screening examination with a single breast position and compression. Each 2D and 3D image consisted of a bilateral two-view (mediolateral oblique and craniocaudal) mammogram. Screening mammo­grams were interpreted sequentially by radiologists, first on the basis of standard 2D mammography alone, and then by the same radiologist (on the same day) on the basis of integrated 2D and 3D mammography (figure). Thus, integrated 2D and 3D mammography screening refers to non-independent screen reading based on joint interpretation of 2D and 3D images, and does not refer to analytical combinations. Radiologists had to record whether or not to recall the participant at each screen-reading phase before progressing to the next phase of the sequence. For each screen, data were also collected for breast density (at the 2D screen-read), and the side and quadrant for any recalled abnormality (at each screen-read). All eight radiologists were breast radiologists with a mean of 8 years (range 3–13 years) experience in mammography screening, and had received basic training in integrated 2D and 3D mammography. Several of the radiologists had also used 2D and 3D mammography for patients recalled after positive conventional mammography screening as part of previous studies of tomosynthesis.8,13

Mammograms were interpreted in two independent screen-reads done in parallel, as practiced in most population breast-screening programs in Europe. A screen was considered positive and the woman recalled for further investigations if either screen-reader recorded a positive result at either 2D or integrated 2D and 3D screening (figure). When previous screening mammograms were available, these were shown to the radiologist at the time of screen-reading, as is standard practice. For assessment of breast density, we used Breast Imaging Reporting and Data System (BI-RADS)14 classification, with participants allocated to one of two groups (1–2 [low density] or 3–4 [high density]). Disagreement between readers about breast density was resolved by assessment by a third reader.

Our primary outcomes were the number of cancers detected, the number of cancers detected per 1000 screens, the number and percentage of false posi­tive recalls, and the incremental cancer detection rate attributable to integrated 2D and 3D mammography screening. We compared the number of cancers that were detected only at 2D mammography screen-reading and those that were detected only at 2D and 3D mammography screen-reading; we also did this analysis for false positive recalls. To explore the potential effect of integrated 2D and 3D screening on false-positive recalls, we also estimated how many false-positive recalls would have resulted from using a hypothetical conditional false-positive recall approach; – i.e. positive integrated 2D and 3D mammography as a condition of recall (screening recalled at 2D mammography only would not be recalled). Pre-planned secondary analyses were comparison of outcome measures by age group and breast density.

Outcomes were assessed by excision histology for participants who had surgery, or the complete assessment outcome (including investigative imaging with or without histology from core needle biopsy) for all recalled participants. Because our study focuses on the difference in detection by the two screening methods, some cancers might have been missed by both 2D and integrated 2D and 3D mammography; this possibility could be assessed at future follow-up to identify interval cancers. However, this outcome is not assessed in the present study and does not affect estimates of our primary outcomes – i.e. comparative true or false positive detection for 2D-only versus integrated 2D and 3D mammography.

 

Statistical analysis

The sample size was chosen to provide 80% power to detect a difference of 20% in cancer detection, assuming a detection probability of 80% for integrated 2D and 3D screening mammography and 60% for 2D only screening, with a two-sided significance threshold of 5%. Based on the method of Lachenbruch15 for estimating sample size for studies that use McNemar’s test for paired binary data, a minimum of 40 cancers were needed. Because most screens in the participating centres were incident (repeat) screening (75%–80%), we used an underlying breast-cancer prevalence of 0·5% to estimate that roughly 7500–8000 screens would be needed to identify 40 cancers in the study population.

We calculated the Wilson CI for the false-positive recall ratio for integrated 2D and 3D screening with conditional recall compared with 2D only screening.16 All of the other analyses were done with SAS/STAT (version 9.2), using exact methods to compute 95 CIs and p-values.

Role of the funding source

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author (NH) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

7292 participants with a median age of 58 years (IQR 54–63, range 48–71) were screened between Aug 12, 2011, and June 29, 2012. Roughly 5% of invited women declined integrated 2D and 3D screening and received standard 2D mammography. We present data for 7294 screens because two participants had bilateral cancer (detected with different screen-reading techniques for one participant). We detected 59 breast cancers in 57 participants (52 invasive cancers and seven ductal carcinoma in-situ). Of the invasive cancers, most were invasive ductal (n=37); others were invasive special types (n=7), invasive lobular (n=4), and mixed invasive types (n=4).

Table 1 shows the characteristics of the cancers. Mean tumour size (for the invasive cancers with known exact size) was 13.7 mm (SD 5.8) for cancers detected with both 2D alone and integrated 2D and 3D screening (n=29), and 13.5 mm (SD 6.7) for cancers detected only with integrated 2D and 3D screening (n=13).

 

Table 1

Of the 59 cancers, 39 were detected at both 2D and integrated 2D and 3D screening (table 2). 20 cancers were detected with only integrated 2D and 3D screening compared with none detected with only 2D screening (p<0.0001; table 2). 395 screens were false positive (5.5%, 95% CI 5.0–6.0); 181 occurred at both screen-readings, and 141 occurred at 2D screening only compared with 73 at integrated 2D and 3D screening (p<0.0001; table 2). These differences were still significant in sensitivity analyses that excluded the two participants with bilateral cancer (data not shown).


Table 2

5.3 cancers per 1000 screens (95% CI 3.8–7.3; table 3) were detected with 2D mammography only versus 8.1 cancers per 1000 screens (95% CI 6.2–10.4) with integrated 2D and 3D mammography (p<0.0001). The incremental cancer detection rate attributable to inte­grated 2D and 3D screening was 2.7 cancers per 1000 screens (95% CI 1.7–4.2), which is 33.9% (95% CI 22.1–47.4) of the cancers detected in the study popu­lation. In a sensitivity analysis that excluded the two participants with bilateral cancer the estimated incre­mental cancer detection rate attributable to integrated 2D and 3D screening was 2.6 cancers per 1000 screens (95% CI 1.4–3.8). The stratified results show that integrated 2D and 3D mammography was associated with an incrementally increased cancer detection rate in both age-groups and density categories (tables 3–5). A minority (16.7%) of breasts were of high density (category 3–4) reducing the power of statistical comparisons in this subgroup (table 5). The incremental cancer detection rate was much the same in low density versus high density groups (2.8 per 1000 vs 2.5 per 1000; p=0.84; table 3).


Table 3

Table 4-5

Overall recall—any recall resulting in true or false positive screens—was 6.2% (95% CI 5.7–6.8), and the false-positive rate for the 7235 screens of participants who did not have breast cancer was 5.5% (5.0–6.0). Table 6 shows the contribution to false-positive recalls from 2D mammography only, integrated 2D and 3D mammography only, and both, and the estimated number of false positives if positive integrated 2D and 3D mammography was a condition for recall (positive 2D only not recalled). Overall, more of the false-positive rate was driven by 2D mammography only than by integrated 2D and 3D, although almost half of the false-positive rate was a result of false positives recalled at both screen-reading phases (table 6). The findings were much the same when stratified by age and breast density (table 6). Had a conditional recall rule been applied, we estimate that the false-positive rate would have been 3.5% (95% CI 3.1–4.0%; table 6) and could have potentially prevented 68 of the 395 false positives (a reduction of 17.2%; 95% CI 13.6–21.3). The ratio between the number of false positives with integrated 2D and 3D screening with conditional recall (n=254) versus 2D only screening (n=322) was 0.79 (95% CI 0.71–0.87).

Discussion

Our study showed that integrated 2D and 3D mam­mography screening significantly increases detection of breast cancer compared with conventional mammog­raphy screening. There was consistent evidence of an incremental improvement in detection from integrated 2D and 3D mammography across age-group and breast density strata, although the analysis by breast density was limited by low number of women with breasts of high density.

One should note that we investigated comparative cancer detection, and not absolute screening sensitivity. By integrating 2D and 3D mammography using the study screen-reading protocol, 1% of false-positive recalls resulted from 2D and 3D screen-reading only (table 6). However, significantly more false positives resulted from 2D only mammography compared with integrated 2D and 3D mammography, both overall and in the stratified analyses. Application of a conditional recall rule would have resulted in a false-positive rate of 3.5% instead of the actual false-positive rate of 5.5%. The estimated false positive recall ratio of 0.79 for integrated 2D and 3D screening with conditional recall compared with 2D only screening suggests that integrated 2D and 3D screening could reduce false recalls by roughly a fifth. Had such a condition been adopted, none of the cancers detected in the study would have been missed because no cancers were detected by 2D mammography only, although this result might be because our design allowed an independent read for 2D only mammography whereas the integrated 2D and 3D read was an interpretation of a combination of 2D and 3D imaging. We do not recommend that such a conditional recall rule be used in breast-cancer screening until our findings are replicated in other mammography screening studies—STORM involved double-reading by experienced breast radiologists, and our results might not apply to other screening settings. Using a test set of 130 mammograms, Wallis and colleagues7 report that adding tomosynthesis to 2D mammography increased the accuracy of inexperienced readers (but not of experienced readers), therefore having experienced radiologists in STORM could have underestimated the effect of integrated 2D and 3D screen-reading.

No other population screening trials of integrated 2D and 3D mammography have reported final results (panel); however, an interim analysis of the Oslo trial17 a large population screening study has shown that integrated 2D and 3D mammography substantially increases detection of breast cancer. The Oslo study investigators screened women with both 2D and 3D mammography, but randomised reading strategies (with vs without 3D mammograms) and adjusted for the different screen-readers,17whereas we used sequential screen-reading to keep the same reader for each exam­ination. Our estimates for comparative cancer detection and for cancer detection rates are consistent with those of the interim analysis of the Oslo study.17 The applied recall methods differed between the Oslo study (which used an arbitration meeting to decide recall) and the STORM study (we recalled based on a decision by either screen-reader), yet both studies show that 3D mammog­raphy reduces false-positive recalls when added to standard mammography.

An editorial in The Lancet18 might indeed signal the closing of a chapter of debate about the benefits and harms of screening. We hope that our work might be the beginning of a new chapter for mammography screening: our findings should encourage new assessments of screening using 2D and 3D mammography and should factor several issues related to our study. First, we compared standard 2D mammography with integrated 2D and 3D mammography the 3D mammograms were not interpreted independently of the 2D mammograms therefore 3D mammography only (without the 2D images) might not provide the same results. Our experience with breast tomosynthesis and a review6 of 3D mammography underscore the importance of 2D images in integrated 2D and 3D screen-reading. The 2D images form the basis of the radiologist’s ability to integrate the information from 3D images with that from 2D images. Second, although most screening in STORM was incident screening, the substantial increase in cancer detection rate with integrated 2D and 3D mammography results from the enhanced sensitivity of integrated 2D and 3D screening and is probably also a result of a prevalence effect (ie, the effect of a first screening round with integrated 2D and 3D mammography). We did not assess the effect of repeat (incident) screening with integrated 2D and 3D mammography on cancer detection it might provide a smaller effect on cancer detection rates than what we report. Third, STORM was not designed to measure biological differences between the cancers detected at integrated 2D and 3D screening compared with those detected at both screen-reading phases. Descriptive analyses suggest that, generally, breast cancers detected only at integrated 2D and 3D screening had similar features (eg, histology, pathological tumour size, node status) as those detected at both screen-reading phases. Thus, some of the cancers detected only at 2D and 3D screening might represent early detection (and would be expected to receive screening benefit) whereas some might represent over-detection and a harm from screening, as for conventional screening mam mography.1,19 The absence of consensus about over-diagnosis in breast-cancer screening should not detract from the importance of our study findings to applied screening research and to screening practice; however, our trial was not done to assess the extent to which integrated 2D and 3D mam­mography might contribute to over-diagnosis.

The average dose of glandular radiation from the many low-dose projections taken during a single acquisition of 3D mammography is roughly the same as that from 2D mammography.6,20–22 Using integrated 2D and 3D en­tails both a 2D and 3D acquisition in one breast com­pression, which roughly doubles the radiation dose to the breast. Therefore, integrated 2D and 3D mammography for population screening might only be justifiable if improved outcomes were not defined solely in terms of improved detection. For example, it would be valuable to show that the increased detection with integrated 2D and 3D screening leads to reduced interval cancer rates at follow-up. A limitation of our study might be that data for interval cancers were not available; however, because of the paired design we used, future evaluation of interval cancer rates from our study will only apply to breast cancers that were not identified using 2D only or integrated 2D and 3D screening. We know of two patients from our study who have developed interval cancers (follow-up range 8–16 months). We did not get this information from cancer registries and follow-up was very short, so these data should be interpreted very cautiously, especially because interval cancers would be expected to occur in the second year of the standard 2 year interval between screening rounds. Studies of interval cancer rates after integrated 2D and 3D mammography would need to be randomised controlled trials and have a very large sample size. Additionally, the development of reconstructed 2D images from a 3D mammogram23 provides a timely solution to concerns about radiation by providing both the 2D and 3D images from tomosynthesis, eliminating the need for two acquisitions.

We have shown that integrated 2D and 3D mammog­raphy in population breast-cancer screening increases detection of breast cancer and can reduce false-positive recalls depending on the recall strategy. Our results do not warrant an immediate change to breast-screening practice, instead, they show the urgent need for random­ised controlled trials of integrated 2D and 3D versus 2D mammography, and for further translational research in breast tomosynthesis. We envisage that future screening trials investigating this issue will include measures of breast cancer detection, and will be designed to assess interval cancer rates as a surrogate endpoint for screening efficacy.

Contributors

SC had the idea for and designed the study, and collected and interpreted data. NH advised on study concepts and methods, analysed and interpreted data, searched the published work, and wrote and revised the report. DB and FC were lead radiologists, recruited participants, collected data, and commented on the draft report. MP, SB, PT, PB, PT, CF, and MV did the screen-reading, collected data, and reviewed the draft report. SM collected data and reviewed the draft report. PM planned the statistical analysis, analysed and interpreted data, and wrote and revised the report.

Conflicts of interest

SC, DB, FC, MP, SB, PT, PB, CF, MV, and SM received assistance from Hologic (Hologic USA; Technologic Italy) in the form of tomosynthesis technology and technical support for the duration of the study, and travel support to attend collaborators’ meetings. NH receives research support from a National Breast Cancer Foundation (NBCF Australia) Practitioner Fellowship, and has received travel support from Hologic to attend a collaborators’ meeting. PM receives research support through Australia’s National Health and Medical Research Council programme grant 633003 to the Screening & Test Evaluation Program.

 

References

1       Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012; 380: 1778–86.

2       Glasziou P, Houssami N. The evidence base for breast cancer screening. Prev Med 2011; 53: 100–102.

3       Autier P, Esserman LJ, Flowers CI, Houssami N. Breast cancer screening: the questions answered. Nat Rev Clin Oncol 2012; 9: 599–605.

4       Baker JA, Lo JY. Breast tomosynthesis: state-of-the-art and review of the literature. Acad Radiol 2011; 18: 1298–310.

5       Helvie MA. Digital mammography imaging: breast tomosynthesis and advanced applications. Radiol Clin North Am 2010; 48: 917–29.

6      Houssami N, Skaane P. Overview of the evidence on digital breast tomosynthesis in breast cancer detection. Breast 2013; 22: 101–08.

7   Wallis MG, Moa E, Zanca F, Leifland K, Danielsson M. Two-view and single-view tomosynthesis versus full-field digital mammography: high-resolution X-ray imaging observer study. Radiology 2012; 262: 788–96.

8   Bernardi D, Ciatto S, Pellegrini M, et al. Prospective study of breast tomosynthesis as a triage to assessment in screening. Breast Cancer Res Treat 2012; 133: 267–71.

9   Michell MJ, Iqbal A, Wasan RK, et al. A comparison of the accuracy of film-screen mammography, full-field digital mammography, and digital breast tomosynthesis. Clin Radiol 2012; 67: 976–81.

10 Skaane P, Gullien R, Bjorndal H, et al. Digital breast tomosynthesis (DBT): initial experience in a clinical setting. Acta Radiol 2012; 53: 524–29.

11 Pellegrini M, Bernardi D, Di MS, et al. Analysis of proportional incidence and review of interval cancer cases observed within the mammography screening programme in Trento province, Italy. Radiol Med 2011; 116: 1217–25.

12 Caumo F, Vecchiato F, Pellegrini M, Vettorazzi M, Ciatto S, Montemezzi S. Analysis of interval cancers observed in an Italian mammography screening programme (2000–2006). Radiol Med 2009; 114: 907–14.

13 Bernardi D, Ciatto S, Pellegrini M, et al. Application of breast tomosynthesis in screening: incremental effect on mammography acquisition and reading time. Br J Radiol 2012; 85: e1174–78.

14 American College of Radiology. ACR BI-RADS: breast imaging reporting and data system, Breast Imaging Atlas. Reston: American College of Radiology, 2003.

15  Lachenbruch PA. On the sample size for studies based on McNemar’s test. Stat Med 1992; 11: 1521–25.

16  Bonett DG, Price RM. Confidence intervals for a ratio of binomial proportions based on paired data. Stat Med 2006; 25: 3039–47.

17  Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology 2013; published online Jan 3. http://dx.doi.org/10.1148/ radiol.12121373.

18  The Lancet. The breast cancer screening debate: closing a chapter? Lancet 2012; 380: 1714.

19  Biesheuvel C, Barratt A, Howard K, Houssami N, Irwig L. Effects of study methods and biases on estimates of invasive breast cancer overdetection with mammography screening: a systematic review. Lancet Oncol 2007; 8: 1129–38.

20  Tagliafico A, Astengo D, Cavagnetto F, et al. One-to-one comparison between digital spot compression view and digital breast tomosynthesis. Eur Radiol 2012; 22: 539–44.

21  Tingberg A, Fornvik D, Mattsson S, Svahn T, Timberg P, Zackrisson S. Breast cancer screening with tomosynthesis—initial experiences. Radiat Prot Dosimetry 2011; 147: 180–83.

22  Feng SS, Sechopoulos I. Clinical digital breast tomosynthesis system: dosimetric characterization. Radiology 2012; 263: 35–42.

23  Gur D, Zuley ML, Anello MI, et al. Dose reduction in digital breast tomosynthesis (DBT) screening using synthetically reconstructed projection images: an observer performance study. Acad Radiol 2012; 19: 166–71.

A very good and down-to-earth comment on this article was made by Jules H Sumkin who disclosed that he is an unpaid member of SAB Hologic Inc and have a PI research agreement between University of Pittsburgh and Hologic Inc.

The results of the study by Stefano Ciatto and colleagues1 are consistent with recently published prospective,2,3 retrospective,4 and observational5 reports on the same topic. The study1 had limitations, including the fact that the same radiologist interpreted screens sequentially the same day without cross-balancing which examination was read first. Also, the false-negative findings for integrated 2D and 3D mammography, and therefore absolute benefit from the procedure, could not be adequately assessed because cases recalled by 2D mammography alone (141 cases) did not result in a single detection of an additional cancer while the recalls from the integrated 2D and 3D mammography alone (73 cases) resulted in the detection of 20 additional cancers. Nevertheless, the results are in strong agreement with other studies reporting of substantial performance improvements when the screening is done with integrated 2D and 3D mammography.

I disagree with the conclusion of the study with regards to the urgent need for randomised clinical trials of integrated 2D and 3D versus 2D mammography. First, to assess differences in mortality as a result of an imaging-based diagnostic method, a randomised trial will require several repeated screens by the same method in each study group, and the strong results from all studies to date will probably result in substantial crossover and self-selection biases over time. Second, because of the high survival rate (or low mortality rate) of breast cancer, the study will require long follow-up times of at least 10 years. In a rapidly changing environment in terms of improvements in screening technologies and therapeutic inter­ventions, the avoidance of biases is likely to be very difficult, if not impossible. The use of the number of interval cancers and possible shifts in stage at detection, while appropriately accounting for confounders, would be almost as daunting a task. Third, the imaging detection of cancer is only the first step in many management decisions and interventions that can affect outcome. The appropriate control of biases related to patient management is highly unlikely. The arguments above, in addition to the existing reports to date that show substantial improvements in cancer detection, particularly with the detection of invasive cancers, with a simultaneous reduction in recall rates, support the argument that a randomised trial is neither necessary nor warranted. The current technology might be obsolete by the time results of an appropriately done and analysed randomised trial is made public.

In order to better link the information given by “scientific” papers to the context of daily patients’ reality I suggest to spend some time reviewing few of the videos in the below links:

  1. The following group of videos is featured on a website by Siemens. Nevertheless, the presenting radiologists are leading practitioners who affects thousands of lives every year – What the experts say about tomosynthesis. – click on ECR 2013
  2. Breast Tomosynthesis in Practice – part of a commercial ad of the Washington Radiology Associates featured on the website of Diagnostic Imaging. As well, affects thousands of lives in the Washington area every year.

The pivotal questions yet to be answered are:

  1. What should be done in order to translate increase in sensitivity and early detection into decrease in mortality?

  2. What is the price of such increase in sensitivity in terms of quality of life and health-care costs and is it worth-while to pay?

An article that summarises positively the experience of introducing Tomosynthesis into routine screening practice was recently published on AJR:

Implementation of Breast Tomosynthesis in a Routine Screening Practice: An Observational Study

Stephen L. Rose1, Andra L. Tidwell1, Louis J. Bujnoch1, Anne C. Kushwaha1, Amy S. Nordmann1 and Russell Sexton, Jr.1

Affiliation: 1 All authors: TOPS Comprehensive Breast Center, 17030 Red Oak Dr, Houston, TX 77090.

Citation: American Journal of Roentgenology. 2013;200:1401-1408

 

ABSTRACT :

OBJECTIVE. Digital mammography combined with tomosynthesis is gaining clinical acceptance, but data are limited that show its impact in the clinical environment. We assessed the changes in performance measures, if any, after the introduction of tomosynthesis systems into our clinical practice.

MATERIALS AND METHODS. In this observational study, we used verified practice- and outcome-related databases to compute and compare recall rates, biopsy rates, cancer detection rates, and positive predictive values for six radiologists who interpreted screening mammography studies without (n = 13,856) and with (n = 9499) the use of tomosynthesis. Two-sided analyses (significance declared at p < 0.05) accounting for reader variability, age of participants, and whether the examination in question was a baseline were performed.

RESULTS. For the group as a whole, the introduction and routine use of tomosynthesis resulted in significant observed changes in recall rates from 8.7% to 5.5% (p < 0.001), nonsignificant changes in biopsy rates from 15.2 to 13.5 per 1000 screenings (p = 0.59), and cancer detection rates from 4.0 to 5.4 per 1000 screenings (p = 0.18). The invasive cancer detection rate increased from 2.8 to 4.3 per 1000 screening examinations (p = 0.07). The positive predictive value for recalls increased from 4.7% to 10.1% (p < 0.001).

CONCLUSION. The introduction of breast tomosynthesis into our practice was associated with a significant reduction in recall rates and a simultaneous increase in breast cancer detection rates.

Here are the facts in tables and pictures from this article

Table 1 AJR

Table 2-3 AJR

 

Table 4 AJR

 

p1 ajr

p2 ajr

Other articles related to the management of breast cancer were published on this Open Access Online Scientific Journal:

Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Introducing smart-imaging into radiologists’ daily practice.

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

Predicting Tumor Response, Progression, and Time to Recurrence

“The Molecular pathology of Breast Cancer Progression”

Personalized medicine gearing up to tackle cancer

What could transform an underdog into a winner?

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Nanotech Therapy for Breast Cancer

A Strategy to Handle the Most Aggressive Breast Cancer: Triple-negative Tumors

Breakthrough Technique Images Breast Tumors in 3-D With Great Clarity, Reduced Radiation

Closing the Mammography gap

Imaging: seeing or imagining? (Part 1)

Imaging: seeing or imagining? (Part 2)

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Could Teleradiology contribute to “cross-borders” standardization of imaging protocols in cancer management?

Writer: Dror Nir, PhD

Teleradiology is accepted as a legitimate medical service for several years now.  It has many clinical utilities worldwide, ranging from services for expert or second opinions to comprehensive remote management of radiology departments in hospitals. Rapid advances in web-technologies infrastructure eliminated the barriers related to the transfer, reading and reporting of radiology images from remote locations. Today’s main controversies are related to issues that are relevant also to “in-house” radiology departments; e.g. clinical governance, quality assessment, work-flow and medico-legal issues.

The concept of Teleradiology is as simple as plotted in this chart.

fig1

Images are automatically uploaded from the imaging system itself or from the institution’s PACS. Reports are sent to the “client” within few hours.

The value for the users goes well beyond mere image interpretation, for example:

  • On-site physicians have more time to spend with patients.
  • Offering of additional subspecialty/multidisciplinary expertise.
  • Comprehensive image-interpretation and reporting service at reduced time-span and reduced cost
  • Sharing images and reports with referring physicians and patients with no effort.

As an example for “cross-border” standardization of a major existing radiology service, let’s consider the use-case of centralized review of mammography images. I know, quite ambitious! And; politically very challenging!

But; seem to be technologically and clinically feasible, at least according to the below quoted publication:

Teleradiology with uncompressed digital mammograms: Clinical assessment

Julia Fruehwald-Pallamar, Marion Jantsch, Katja Pinker, Ricarda Hofmeister, Friedrich Semturs, Kathrin Piegler, Daniel Staribacher, Michael Weber, Thomas H. Helbich

published online 13 April 2012.

Abstract 

Purpose

The purpose of our study was to demonstrate the feasibility of sending uncompressed digital mammograms in a teleradiologic setting without loss of information by comparing image quality, lesion detection, and BI-RADS assessment.

Materials and methods

CDMAM phantoms were sent bidirectionally to two hospitals via the network. For the clinical aspect of the study, 200 patients were selected based on the BI-RAD system: 50% BI-RADS I and II; and 50% BI-RADS IV and V. Two hundred digital mammograms (800 views) were sent to two different institutions via a teleradiology network. Three readers evaluated those 200 mammography studies at institution 1 where the images originated, and in the two other institutions (institutions 2 and 3) where the images were sent. The readers assessed image quality, lesion detection, and BI-RADS classification.

Results

Automatic readout showed that CDMAM image quality was identical before and after transmission. The image quality of the 200 studies (total 600 mammograms) was rated as very good or good in 90–97% before and after transmission. Depending on the institution and the reader, only 2.5–9.5% of all studies were rated as poor. The congruence of the readers with respect to the final BI-RADS assessment ranged from 90% and 91% at institution 1 vs. institution 2, and from 86% to 92% at institution 1 vs. institution 3. The agreement was even higher for conformity of content (BI-RADS I or II and BI-RADS IV or V). Reader agreement in the three different institutions with regard to the detection of masses and calcifications, as well as BI-RADS classification, was very good (κ: 0.775–0.884). Results for interreader agreement were similar.

Conclusion

Uncompressed digital mammograms can be transmitted to different institutions with different workstations, without loss of information. The transmission process does not significantly influence image quality, lesion detection, or BI-RADS rating.

Keywords: Breast cancerImagingDigital mammographyTeleradiologyComparative studies

 

What could be the benefits from centralizing mammography interpretation through Teleradiology?

  • A baseline protocol that could enable pulling together large number of cases from different populations without having to worry about differences in practice and experience of reporters. This will enable better epidemiology studies of this disease.
  • Quantified measure, in real-time, of the relative quality of imaging between institutions could contribute to bringing all screening services to a maximal level.
  • Development of comprehensive training program for radiologists involved in mammography based screening of breast cancer.
  • Better information sharing between all players involved in the pathway of each individual patient could improve clinical decision making and patient’s support.
  • Lower costs of screening programs, disease treatment and follow-up.

Who could organize and carry out such an operation?

There are many reputable large university hospitals already offering Teleradiology services. They are already supported by government’s funds in addition to the fact that the service itself is carrying profits. I’m not listing any of these for obvious reasons, but; google “teleradiology” will bring you many results.

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Imaging of Non-tumorous and Tumorous Human Brain Tissues

Reporter and Curator: Dror Nir, PhD

The point of interest in the article I feature below is that it represents a potential building block in a future system that will use full-field optical coherence tomography during brain surgery to improve the accuracy of cancer lesions resection. The article is featuring promising results for differentiating tumor from normal brain tissue in large samples (order of 1–3 cm2) by offering images with spatial resolution comparable to histological analysis, sufficient to distinguish microstructures of the human brain parenchyma.  Easy to say, and hard to make…:) –> Intraoperative apparatus to guide the surgeon in real time during resection of brain tumors.

 

Imaging of non-tumorous and tumorous human brain tissues with full-field optical coherence tomography 

Open Access Article

Osnath Assayaga1Kate Grievea1Bertrand DevauxbcFabrice HarmsaJohan Palludbc,Fabrice ChretienbcClaude BoccaraaPascale Varletbc;  a Inserm U979 “Wave Physics For Medicine” ESPCI -ParisTech – Institut Langevin, 1 rue Jussieu, 75005, b France, Centre Hospitalier Sainte-Anne, 1 rue Cabanis 75014 Paris, France

c University Paris Descartes, France.

Abstract

A prospective study was performed on neurosurgical samples from 18 patients to evaluate the use of full-field optical coherence tomography (FF-OCT) in brain tumor diagnosis.

FF-OCT captures en face slices of tissue samples at 1 μm resolution in 3D to a penetration depth of around 200 μm. A 1 cm2 specimen is scanned at a single depth and processed in about 5 min. This rapid imaging process is non-invasive and requires neither contrast agent injection nor tissue preparation, which makes it particularly well suited to medical imaging applications.

Temporal chronic epileptic parenchyma and brain tumors such as meningiomas, low-grade and high-grade gliomas, and choroid plexus papilloma were imaged. A subpopulation of neurons, myelin fibers and CNS vasculature were clearly identified. Cortex could be discriminated from white matter, but individual glial cells such as astrocytes (normal or reactive) or oligodendrocytes were not observable.

This study reports for the first time on the feasibility of using FF-OCT in a real-time manner as a label-free non-invasive imaging technique in an intraoperative neurosurgical clinical setting to assess tumorous glial and epileptic margins.

Abbreviations

  • FF-OCT, full field optical coherence tomography;
  • OCT, optical coherence tomography

Keywords

Optical imaging; Digital pathology; Brain imaging; Brain tumor; Glioma

1. Introduction

1.1. Primary CNS tumors

Primary central nervous system (CNS) tumors represent a heterogeneous group of tumors with benign, malignant and slow-growing evolution. In France, 5000 new cases of primary CNS tumors are detected annually (Rigau et al., 2011). Despite considerable progress in diagnosis and treatment, the survival rate following a malignant brain tumor remains low and 3000 deaths are reported annually from CNS tumors in France (INCa, 2011). Overall survival from brain tumors depends on the complete resection of the tumor mass, as identified through postoperative imaging, associated with updated adjuvant radiation therapy and chemotherapy regimen for malignant tumors (Soffietti et al., 2010). Therefore, there is a need to evaluate the completeness of the tumor resection at the end of the surgical procedure, as well as to identify the different components of the tumor interoperatively, i.e. tumor tissue, necrosis, infiltrated parenchyma (Kelly et al., 1987). In particular, the persistence of non-visible tumorous tissue or isolated tumor cells infiltrating brain parenchyma may lead to additional resection.

For low-grade tumors located close to eloquent brain areas, a maximally safe resection that spares functional tissue warrants the current use of intraoperative techniques that guide a more complete tumor resection. During awake surgery, speech or fine motor skills are monitored, while cortical and subcortical stimulations are performed to identify functional areas (Sanai et al., 2008). Intraoperative MRI provides images of the surgical site as well as tomographic images of the whole brain that are sufficient for an approximate evaluation of the abnormal excised tissue, but offers low resolution (typically 1 to 1.5 mm) and produces artifacts at the air-tissue boundary of the surgical site.

Histological and immunohistochemical analyses of neurosurgical samples remain the current gold standard method used to analyze tumorous tissue due to advantages of sub-cellular level resolution and high contrast. However, these methods require lengthy (12 to 72 h), complex multiple steps, and use of carcinogenic chemical products that would not be technically possible intra-operatively. In addition, the number of histological slides that can be reviewed and analyzed by a pathologist is limited, and it defines the number and size of sampled locations on the tumor, or the surrounding tissue.

To obtain histology-like information in a short time period, intraoperative cytological smear tests are performed. However tissue architecture information is thereby lost and the analysis is carried out on only a limited area of the sample (1 mm × 1 mm).

Intraoperative optical imaging techniques are recently developed high resolution imaging modalities that may help the surgeon to identify the persistence of tumor tissue at the resection boundaries. Using a conventional operating microscope with Xenon lamp illumination gives an overall view of the surgical site, but performance is limited by the poor discriminative capacity of the white light illumination at the surgical site interface. Better discrimination between normal and tumorous tissues has been obtained using fluorescence properties of tumor cells labeled with preoperatively administered 5-ALA. Tumor tissue shows a strong ALA-induced PPIX fluorescence at 635 nm and 704 nm when the operative field is illuminated with a 440 nm-filtered lamp. More complete resections of high-grade gliomas have been demonstrated using 5-ALA fluorescence guidance (Stummer et al., 2000), however brain parenchyma infiltrated by isolated tumor cells is not fluorescent, reducing the interest of this technique when resecting low-grade gliomas.

Refinement of this induced fluorescence technique has been achieved using a confocal microscope and intraoperative injection of sodium fluorescein. A 488 nm laser illuminates the operative field and tissue contact analysis is performed using a handheld surgical probe (field of view less than 0.5 × 0.5 mm) which scans the fluorescence of the surgical interface at the 505–585 nm band. Fluorescent isolated tumor cells are clearly identified at depths from 0 to 500 μm from the resection border (Sanai et al., 2011), demonstrating the potential of this technique in low-grade glioma resection.

Reviewing the state-of-the-art, a need is identified for a quick and reliable method of providing the neurosurgeon with architectural and cellular information without the need for injection or oral intake of exogenous markers in order to guide the neurosurgeon and optimize surgical resections.

1.2. Full-field optical coherence tomography

Introduced in the early 1990s (Huang et al., 1991), optical coherence tomography (OCT) uses interference to precisely locate light deep inside tissue. The photons coming from the small volume of interest are distinguished from light scattered by the other parts of the sample by the use of an interferometer and a light source with short coherence length. Only the portion of light with the same path length as the reference arm of the interferometer, to within the coherence length of the source (typically a few μm), will produce interference. A two-dimensional B-scan image is captured by scanning. Recently, the technique has been improved, mainly in terms of speed and sensitivity, through spectral encoding (De Boer et al., 2003Leitgeb et al., 2003 and Wojtkowski et al., 2002).

A recent OCT technique called full-field optical coherence tomography (FF-OCT) enables both a large field of view and high resolution over the full field of observation (Dubois et al., 2002 and Dubois et al., 2004). This allows navigation across the wide field image to follow the morphology at different scales and different positions. FF-OCT uses a simple halogen or light-emitting diode (LED) light source for full field illumination, rather than lasers and point-by-point scanning components required for conventional OCT. The illumination level is low enough to maintain the sample integrity: the power incident on the sample is less than 1 mW/mm2 using deep red and near infrared light. FF-OCT provides the highest OCT 3D resolution of 1.5 × 1.5 × 1 μm3 (X × Y × Z) on unprepared label-free tissue samples down to depths of approximately 200 μm–300 μm (tissue-dependent) over a wide field of view that allows digital zooming down to the cellular level. Interestingly, it produces en face images in the native field view (rather than the cross-sectional images of conventional OCT), which mimic the histology process, thereby facilitating the reading of images by pathologists. Moreover, as for conventional OCT, it does not require tissue slicing or modification of any kind (i.e. no tissue fixation, coloration, freezing or paraffin embedding). FF-OCT image acquisition and processing time is less than 5 min for a typical 1 cm2 sample (Assayag et al., in press) and the imaging performance has been shown to be equivalent in fresh or fixed tissue (Assayag et al., in press and Dalimier and Salomon, 2012). In addition, FF-OCT intrinsically provides digital images suitable for telemedicine.

Numerous studies have been published over the past two decades demonstrating the suitability of OCT for in vivo or ex vivo diagnosis. OCT imaging has been previously applied in a variety of tissues such as the eye (Grieve et al., 2004 and Swanson et al., 1993), upper aerodigestive tract (Betz et al., 2008Chen et al., 2007 and Ozawa et al., 2009), gastrointestinal tract (Tearney et al., 1998), and breast tissue and lymph nodes (Adie and Boppart, 2009Boppart et al., 2004Hsiung et al., 2007Luo et al., 2005Nguyen et al., 2009Zhou et al., 2010 and Zysk and Boppart, 2006).

In the CNS, published studies that evaluate OCT (Bizheva et al., 2005Böhringer et al., 2006Böhringer et al., 2009Boppart, 2003 and Boppart et al., 1998) using time-domain (TD) or spectral domain (SD) OCT systems had insufficient resolution (10 to 15 μm axial) for visualization of fine morphological details. A study of 9 patients with gliomas carried out using a TD-OCT system led to classification of the samples as malignant versus benign (Böhringer et al., 2009). However, the differentiation of tissues was achieved by considering the relative attenuation of the signal returning from the tumorous zones in relation to that returning from healthy zones. The classification was not possible by real recognition of CNS microscopic structures. Another study showed images of brain microstructures obtained with an OCT system equipped with an ultra-fast laser that offered axial and lateral resolution of 1.3 μm and 3 μm respectively (Bizheva et al., 2005). In this way, it was possible to differentiate malignant from healthy tissue by the presence of blood vessels, microcalcifications and cysts in the tumorous tissue. However the images obtained were small (2 mm × 1 mm), captured on fixed tissue only and required use of an expensive large laser thereby limiting the possibility for clinical implementation.

Other studies have focused on animal brain. In rat brain in vivo, it has been shown that optical coherence microscopy (OCM) can reveal neuronal cell bodies and myelin fibers (Srinivasan et al., 2012), while FF-OCT can also reveal myelin fibers (Ben Arous et al., 2011), and movement of red blood cells in vessels (Binding et al., 2011).

En face images captured with confocal reflectance microscopy can closely resemble FF-OCT images. For example, a prototype system used by Wirth et al. (2012) achieves lateral and axial resolution of 0.9 μm and 3 μm respectively. However small field size prevents viewing of wide-field architecture and slow acquisition speed prohibits the implementation of mosaicking. In addition, the poorer axial resolution and lower penetration depth of confocal imaging in comparison to FF-OCT limit the ability to reconstruct cross-sections from the confocal image stack.

This study is the first to analyze non-tumorous and tumorous human brain tissue samples using FF-OCT.

2. Materials and methods

2.1. Instrument

The experimental arrangement of FF-OCT (Fig. 1A) is based on a configuration that is referred to as a Linnik interferometer (Dubois et al., 2002). A halogen lamp is used as a spatially incoherent source to illuminate the full field of an immersion microscope objective at a central wavelength of 700 nm, with spectral width of 125 nm. The signal is extracted from the background of incoherent backscattered light using a phase-shifting method implemented in custom-designed software. This study was performed on a commercial FF-OCT system (LightCT, LLTech, France).

 

Fig 1

Capturing “en face” images allows easy comparison with histological sections. The resolution, pixel number and sampling requirements result in a native field of view that is limited to about 1 mm2. The sample is moved on a high precision mechanical platform and a number of fields are stitched together (Beck et al., 2000) to display a significant field of view. The FF-OCT microscope is housed in a compact setup (Fig. 1B) that is about the size of a standard optical microscope (310 × 310 × 800 mm L × W × H).

2.2. Imaging protocol

All images presented in this study were captured on fresh brain tissue samples from patients operated on at the Neurosurgery Department of Sainte-Anne Hospital, Paris. Informed and written consent was obtained in all cases following the standard procedure at Sainte-Anne Hospital from patients who were undergoing surgical intervention. Fresh samples were collected from the operating theater immediately after resection and sent to the pathology department. A pathologist dissected each sample to obtain a 1–2 cm2 piece and made a macroscopic observation to orientate the specimen in order to decide which side to image. The sample was immersed in physiological serum, placed in a cassette, numbered, and brought to the FF-OCT imaging facility in a nearby laboratory (15 min distant) where the FF-OCT images were captured. The sample was placed in a custom holder with a coverslip on top (Fig. 1C, D). The sample was raised on a piston to rest gently against the coverslip in order to flatten the surface and so optimize the image capture. The sample is automatically scanned under a 10 × 0.3 numerical aperture (NA) immersion microscope objective. The immersion medium is a silicone oil of refractive index close to that of water, chosen to optimize index matching and slow evaporation. The entire area of each sample was imaged at a depth of 20 μm beneath the sample surface. This depth has been reported to be optimal for comparison of FF-OCT images to histology images in a previous study on breast tissue (Assayag et al., in press). There are several reasons for the choice of imaging depth: firstly, histology was also performed at approximately 20 μm from the edge of the block, i.e. the depth at which typically the whole tissue surface begins to be revealed. Secondly, FF-OCT signal is attenuated with depth due to multiple scattering in the tissue, and resolution is degraded with depth due to aberrations. The best FF-OCT images are therefore captured close to the surface, and the best matching is achieved by attempting to image at a similar depth as the slice in the paraffin block. It was also possible to capture image stacks down to several hundred μm in depth (where penetration depth is dependent on tissue type), for the purpose of reconstructing a 3D volume and imaging layers of neurons and myelin fibers. An example of such a stack in the cerebellum is shown as a video (Video 2) in supplementary material. Once FF-OCT imaging was done, each sample was immediately fixed in formaldehyde and returned to the pathology department where it underwent standard processing in order to compare the FF-OCT images to histology slides.

2.3. Matching FF-OCT to histology

The intention in all cases was to match as closely as possible to histology. FF-OCT images were captured 20 μm below the surface. Histology slices were captured 20 μm from the edge of the block. However the angle of the inclusion is hard to control and so some difference in the angle of the plane always exists when attempting matching. Various other factors that can cause differences stem from the histology process — fixing, dehydrating, paraffin inclusion etc. all alter the tissue and so precise correspondence can be challenging. Such difficulties are common in attempting to match histology to other imaging modalities (e.g. FF-OCT Assayag et al., in press; OCT Bizheva et al., 2005; confocal microscopy Wirth et al., 2012).

An additional parameter in the matching process is the slice thickness. Histology slides were 4 μm in thickness while FF-OCT optical slices have a 1 μm thickness. The finer slice of the FF-OCT image meant that lower cell densities were perceived on the FF-OCT images (in those cases where individual cells were seen, e.g. neurons in the cortex). This difference in slice thickness affects the accuracy of the FF-OCT to histology match. In order to improve matching, it would have been possible to capture four FF-OCT slices in 1 μm steps and sum the images to mimic the histology thickness. However, this would effectively degrade the resolution, which was deemed undesirable in evaluating the capacities of the FF-OCT method.

3. Results

18 samples from 18 adult patients (4 males, 14 females) of age range 19–81 years have been included in the study: 1 mesial temporal lobe epilepsy and 1 cerebellum adjacent to a pulmonary adenocarcinoma metastasis (serving as the non-tumor brain samples), 7 diffuse supratentorial gliomas (4 WHO grade II, 3 WHO grade III), 5 meningiomas, 1 hemangiopericytoma, and 1 choroid plexus papilloma. Patient characteristics are detailed in Table 1.

 

Table 1

3.1. FF-OCT imaging identifies myelinated axon fibers, neuronal cell bodies and vasculature in the human epileptic brain and cerebellum

The cortex and the white matter are clearly distinguished from one another (Fig. 2). Indeed, a subpopulation of neuronal cell bodies (Fig. 2B, C) as well as myelinated axon bundles leading to the white matter could be recognized (Fig. 2D, E). Neuronal cell bodies appear as dark triangles (Fig. 2C) in relation to the bright surrounding myelinated environment. The FF-OCT signal is produced by backscattered photons from tissues of differing refractive indices. The number of photons backscattered from the nuclei in neurons appears to be too few to produce a signal that allows their differentiation from the cytoplasm, and therefore the whole of the cell body (nucleus plus cytoplasm) appears dark.

Fig 2

 

Myelinated axons are numerous, well discernible as small fascicles and appear as bright white lines (Fig. 2E). As the cortex does not contain many myelinated axons, it appears dark gray. Brain vasculature is visible (Fig. 2F and G), and small vessels are distinguished by a thin collagen membrane that appears light gray. Video 1 in supplementary material shows a movie composed of a series of en face 1 μm thick optical slices captured over 100 μm into the depth of the cortex tissue. The myelin fibers and neuronal cell bodies are seen in successive layers.

The different regions of the human hippocampal formation are easily recognizable (Fig. 3). Indeed, CA1 field and its stratum radiatum, CA4 field, the hippocampal fissure, the dentate gyrus, and the alveus are easily distinguishable. Other structures become visible by zooming in digitally on the FF-OCT image. The large pyramidal neurons of the CA4 field (Fig. 3B) and the granule cells that constitute the stratum granulosum of the dentate gyrus are visible, as black triangles and as small round dots, respectively (Fig. 3D).

 

Fig 3

In the normal cerebellum, the lamellar or foliar pattern of alternating cortex and central white matter is easily observed (Fig. 4A). By digital zooming, Purkinje and granular neurons also appear as black triangles or dots, respectively (Fig. 4C), and myelinated axons are visible as bright white lines (Fig. 4E). Video 2 in supplementary material shows a fly-through movie in the reconstructed axial slice orientation of a cortex region in cerebellum. The Purkinje and granular neurons are visible down to depths of 200 μm in the tissue.

 

Fig 4

3.2. FF-OCT images distinguish meningiomas from hemangiopericytoma in meningeal tumors

The classic morphological features of a meningioma are visible on the FF-OCT image: large lobules of tumorous cells appear in light gray (Fig. 5A), demarcated by collagen-rich bundles (Fig. 5B) which are highly scattering and appear a brilliant white in the FF-OCT images. The classic concentric tumorous cell clusters (whorls) are very clearly distinguished on the FF-OCT image (Fig. 5D). In addition the presence of numerous cell whorls with central calcifications (psammoma bodies) is revealed (Fig. 5F). Collagen balls appear bright white on the FF-OCT image (Fig. 5H). As the collagen balls progressively calcify, they are consumed by the black of the calcified area, generating a target-like image (Fig. 5H). Calcifications appear black in FF-OCT as they are crystalline and so allow no penetration of photons to their interior.

Fig 5

Mesenchymal non-meningothelial tumors such as hemangiopericytomas represent a classic differential diagnosis of meningiomas. In FF-OCT, the hemangiopericytoma is more monotonous in appearance than the meningiomas, with a highly vascular branching component with staghorn-type vessels (Fig. 6A, C).

Fig 6

3.3. FF-OCT images identify choroid plexus papilloma

The choroid plexus papilloma appears as an irregular coalescence of multiple papillas composed of elongated fibrovascular axes covered by a single layer of choroid glial cells (Fig. 7). By zooming in on an edematous papilla, the axis appears as a black structure covered by a regular light gray line (Fig. 7B). If the papilla central axis is hemorrhagic, the fine regular single layer is not distinguishable (Fig. 7C). Additional digital zooming in on the image reveals cellular level information, and some nuclei of plexus choroid cells can be recognized. However, cellular atypia and mitosis are not visible. These represent key diagnosis criteria used to differentiate choroid plexus papilloma (grade I) from atypical plexus papilloma (grade II).

Fig 7

3.4. FF-OCT images detect the brain tissue architecture modifications generated by diffusely infiltrative gliomas

Contrary to the choroid plexus papillomas which have a very distinctive architecture in histology (cauliflower-like aspect), very easily recognized in the FF-OCT images (Fig. 7A to G), diffusely infiltrating glioma does not present a specific tumor architecture (Fig. 8) as they diffusely permeate the normal brain architecture. Hence, the tumorous glial cells are largely dispersed through a nearly normal brain parenchyma (Fig. 8E). The presence of infiltrating tumorous glial cells attested by high magnification histological observation (irregular atypical cell nuclei compared to normal oligodendrocytes) is not detectable with the current generation of FF-OCT devices, as FF-OCT cannot reliably distinguish the individual cell nuclei due to lack of contrast (as opposed to lack of resolution). In our experience, diffuse low-grade gliomas (less than 20% of tumor cell density) are mistaken for normal brain tissue on FF-OCT images. However, in high-grade gliomas (Fig. 8G–K), the infiltration of the tumor has occurred to such an extent that the normal parenchyma architecture is lost. This architectural change is easily observed in FF-OCT and is successfully identified as high-grade glioma, even though the individual glial cell nuclei are not distinguished.

Fig 8

4. Discussion

We present here the first large size images (i.e. on the order of 1–3 cm2) acquired using an OCT system that offer spatial resolution comparable to histological analysis, sufficient to distinguish microstructures of the human brain parenchyma.

Firstly, the FF-OCT technique and the images presented here combine several practical advantages. The imaging system is compact, it can be placed in the operating room, the tissue sample does not require preparation and image acquisition is rapid. This technique thus appears promising as an intraoperative tool to help neurosurgeons and pathologists.

Secondly, resolution is sufficient (on the order of 1 μm axial and lateral) to distinguish brain tissue microstructures. Indeed, it was possible to distinguish neuron cell bodies in the cortex and axon bundles going towards white matter. Individual myelin fibers of 1 μm in diameter are visible on the FF-OCT images. Thus FF-OCT may serve as a real-time anatomical locator.

Histological architectural characteristics of meningothelial, fibrous, transitional and psammomatous meningiomas were easily recognizable on the FF-OCT images (lobules and whorl formation, collagenous-septae, calcified psammoma bodies, thick vessels). Psammomatous and transitional meningiomas presented distinct architectural characteristics in FF-OCT images in comparison to those observed in hemangiopericytoma. Thus, FF-OCT may serve as an intraoperative tool, in addition to extemporaneous examination, to refine differential diagnosis between pathological entities with different prognoses and surgical managements.

Diffuse glioma was essentially recognized by the loss of normal parenchyma architecture. However, glioma could be detected on FF-OCT images only if the glial cell density is greater than around 20% (i.e. the point at which the effect on the architecture becomes noticeable). The FF-OCT technique is therefore not currently suitable for the evaluation of low tumorous infiltration or tumorous margins. Evaluation at the individual tumor cell level is only possible by IDH1R132 immunostaining in IDH1 mutated gliomas in adults (Preusser et al., 2011). One of the current limitations of the FF-OCT technique for use in diagnosis is the difficulty in estimating the nuclear/cytoplasmic boundaries and the size and form of nuclei as well as the nuclear-cytoplasmic ratio of cells. This prevents precise classification into tumor subtypes and grades.

To increase the accuracy of diagnosis of tumors where cell density measurement is necessary for grading, perspectives for the technique include development of a multimodal system (Harms et al., 2012) to allow simultaneous co-localized acquisition of FF-OCT and fluorescence images. The fluorescence channel images in this multimodal system show cell nuclei, which increase the possibility of diagnosis and tumor grading direct from optical images. However, the use of contrast agents for the fluorescence channel means that the multimodal imaging technique is no longer non-invasive, and this may be undesirable if the tissue is to progress to histology following optical imaging. This is a similar concern in confocal microscopy where use of dyes is necessary for fluorescence detection (Wirth et al., 2012).

In its current form therefore, FF-OCT is not intended to serve as a diagnostic tool, but should rather be considered as an additional intraoperative aid in order to determine in a short time whether or not there is suspicious tissue present in a sample. It does not aim to replace histological analyses but rather to complement them, by offering a tool at the intermediary stage of intraoperative tissue selection. In a few minutes, an image is produced that allows the surgeon or the pathologist to assess the content of the tissue sample. The selected tissue, once imaged with FF-OCT, may then proceed to conventional histology processing in order to obtain the full diagnosis (Assayag et al., in press and Dalimier and Salomon, 2012).

Development of FF-OCT to allow in vivo imaging is underway, and first steps include increasing camera acquisition speed. First results of in vivo rat brain imaging have been achieved with an FF-OCT prototype setup, and show real-time visualization of myelin fibers (Ben Arous et al., 2011) and movement of red blood cells in vessels (Binding et al., 2011). To respond more precisely to surgical needs, it would be preferable to integrate the FF-OCT system into a surgical probe. Work in this direction is currently underway and preliminary images of skin and breast tissue have been captured with a rigid probe FF-OCT prototype (Latrive and Boccara, 2011).

In conclusion, we have demonstrated the capacity of FF-OCT for imaging of human brain samples. This technique has potential as an intraoperative tool for determining tissue architecture and content in a few minutes. The 1 μm3 resolution and wide-field down to cellular-level views offered by the technique allowed identification of features of non-tumorous and tumorous tissues such as myelin fibers, neurons, microcalcifications, tumor cells, microcysts, and blood vessels. Correspondence with histological slides was good, indicating suitability of the technique for use in clinical practice for tissue selection for biobanking for example. Future work to extend the technique to in vivo imaging by rigid probe endoscopy is underway.

The following are the supplementary data related to this article.

Video 1.  Shows a movie composed of a series of en face 1 μm thick optical slices captured over 100 μm into the depth of the cortex tissue. The myelin fibers and neuronal cell bodies are seen in successive layers. Field size is 800 μm × 800 μm.

Video 2.  Shows a fly-through movie in the reconstructed cross-sectional orientation showing 1 μm steps through a 3D stack down to 200 μm depth in cerebellum cortical tissue. Purkinje and granular neurons are visible as dark spaces. Field size is 800 μm × 200 μm.

Acknowledgments

The authors wish to thank LLTech SAS for use of the LightCT Scanner.

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Large field, high resolution full field optical coherence tomography: a pre-clinical study of human breast tissue and cancer assessment

Technology in Cancer Research & Treatment TCRT Express, 1 (1) (2013), p. e600254http://dx.doi.org/10.7785/tcrtexpress.2013.600254

Beck et al., 2000

Beck et al.

Computer-assisted visualizations of neural networks: expanding the field of view using seamless confocal montaging

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Ben Arous et al.

Single myelin fiber imaging in living rodents without labeling by deep optical coherence microscopy

Journal of Biomedical Optics, 16 (11) (2011), p. 116012

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C.S. Betz et al.

A set of optical techniques for improving the diagnosis of early upper aerodigestive tract cancer

Medical Laser Application, 23 (2008), pp. 175–185

Binding et al., 2011

Binding et al.

Brain refractive index measured in vivo with high-NA defocus-corrected full-field OCT and consequences for two-photon microscopy

Optics Express, 19 (6) (2011), pp. 4833–4847

Bizheva et al., 2005

Bizheva et al.

Imaging ex vivo healthy and pathological human brain tissue with ultra-high-resolution optical coherence tomography

Journal of Biomedical Optics, 10 (2005), p. 011006 http://dx.doi.org/10.1117/1.1851513

Böhringer et al., 2006

Böhringer et al.

Time domain and spectral domain optical coherence tomography in the analysis of brain tumor tissue

Lasers in Surgery and Medicine, 38 (2006), pp. 588–597 http://dx.doi.org/10.1002/lsm.20353

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Böhringer et al.

Imaging of human brain tumor tissue by near-infrared laser coherence tomography

Acta Neurochirurgica, 151 (2009), pp. 507–517 http://dx.doi.org/10.1007/s00701-009-0248-y

Boppart, 2003

Boppart

Optical coherence tomography: technology and applications for neuroimaging

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Ultrasound imaging as an instrument for measuring tissue elasticity: “Shear-wave Elastography” VS. “Strain-Imaging”

Writer and curator: Dror Nir, PhD

In the context of cancer-management, imaging is pivotal. For decades, ultrasound is used by clinicians to support every step in cancer pathways. Its popularity within clinicians is steadily increasing despite the perception of it being less accurate and less informative than CT and MRI. This is not only because ultrasound is easily accessible and relatively low cost, but also because advances in ultrasound technology, mainly the conversion into PC-based modalities allows better, more reproducible, imaging and more importantly; clinically-effective image interpretation.

The idea to rely on ultrasound’s physics in order to measure the stiffness of tissue lesions is not new. The motivation for such measurement has to do with the fact that many times malignant lesions are stiffer than non-malignant lesions.

The article I bring below; http://digital.studio-web.be/digitalMagazine?issue_id=254 by Dr. Georg Salomon and his colleagues, is written for lay-readers. I found it on one of the many portals that are bringing quasi-professional and usually industry-sponsored information on health issues; http://www.dieurope.com/ – The European Portal for Diagnostic Imaging. Note, that when it comes to using ultrasound as a diagnostic aid in urology, Dr. Georg Salomon is known to be one of the early adopters for new technologies and an established opinion leader who published many peer-review, frequently quoted, papers on Elastography.

The important take-away I would like to highlight for the reader: Quantified measure of tissue’s elasticity (doesn’t matter if is done by ShearWave or another “Elastography” measure implementation) is information that has real clinical value for the urologists who needs to decide on the right pathway for his patient!

Note: the highlights in the article below are added by me for the benefit of the reader.

Improvement in the visualization of prostate cancer through the use of ShearWave Elastography

by:

Dr Georg Salomon1 Dr Lars Budaeus1, Dr L Durner2 & Dr K Boe1

1. Martini-Clinic — Prostate Cancer Center University Hospital Hamburg Eppendorf Martinistrasse 52, 20253 Hamburg, Germany

2. Urologische Kilnik Dr. Castringius Munchen-Planegg Germeringer Str. 32, 82152 Planegg, Germany

Corresponding author; PD Dr. Georg Salomon

Associate Professor of Urology

Martini Clinic

Tel: 0049 40 7410 51300

gsalornon@uke.de

 

Prostate cancer is the most common cancer in males with more than 910,000 annual cases worldwide. With early detection, excellent cure rates can be achieved. Today, prostate cancer is diagnosed by a randomized transrectal ultrasound guided biopsy. However, such randomized “blind” biopsies can miss cancer because of the inability of conventional TRUS to visualize small cancerous spots in most cases.

Elastography has been shown to improve visualization of prostate cancer.

The innovative ShearWave Elastography technique is an automated, user-friendly and quantifiable method for the determination of prostatic tissue stiffness.

The detection of prostate cancer (PCA) has become easier thanks to Prostate Specific Anti­gen (PSA) testing; the diagnosis of PCA has been shifted towards an earlier stage of the disease.

Prostate cancer is, in more than 80 % of the cases, a heterogeneous and multifocal tumor. Conventional ultra­sound has limitations to accurately define tumor foci within the prostate. This is due to the fact that most PCA foci are isoechogenic, so in these cases there is no dif­ferentiation of benign and malignant tissue. Because of this, a randomized biopsy is performed under ultrasound guidance with at least 10 to 12 biopsy cores, which should represent all areas of the prostate. Tumors, however, can be missed by this biopsy regimen since it is not a lesion-targeted biopsy. When PSA is rising — which usually occurs in most men — the originally negative biopsy has to be repeated.

What urologists expect from imag­ing and biopsy procedures is the detection of prostate cancer at an early stage and an accurate description of all foci within the prostate with different (Gleason) grades of differentiation for best treatment options.

In the past 10 years a couple of new innovative ultrasound techniques (computerized, contrast enhanced and real time elastography) have been introduced to the market and their impact on the detection of early prostate cancer has been evaluated. The major benefit of elastography compared to the other techniques is its ability to provide visualization of sus­picious areas and to guide the biopsy needle, in real time, to the suspicious and potentially malignant area.

Ultrasound-based elastography has been investigated over the years and has had a lot of success for increasing the detection rate of prostate cancer or reducing the number of biopsy sam­ples required. [1-3]. Different compa­nies have used different approaches to the ultrasound elastography technique (strain elastography vs. shear wave elastography). Medical centers have seen an evolution in better image qual­ity with more stable and reproducible results from these techniques.

One drawback of real time strain elastography is that there is a sig­nificant learning curve to be climbed before reproducible elastograms can be generated. The technique has to be performed by compressing and then decompressing the ultrasound probe to derive a measurement of tissue displacement.

Today there are ultrasound scanners on the market, which have the ability to produce elastograms without this “manual” assistance: this technique is called shear-wave elastography. While the ultrasound probe is being inserted transrectally, the “elastograms” are generated automatically by the calcu­lation of shear wave velocity as the waves travel through the tissue being examined, thus providing measure­ments of tissue stiffness and not dis­placement measurements.

There are several different tech­niques for this type of elastography. The FibroScan system, which is not an ultrasound unit, uses shear waves (transient elastography) to evaluate the advancement of the stiffness of the liver. Another technique is Acous­tic Radiation Force Impulse or ARF1 technique, also used for the liver. These non-real-time techniques only provide a shear wave velocity estimation for a single region of interest and are not currently used in prostate imaging.

A shear wave technology that pro­vides specific quantification of tissue elasticity in real-time is ShearWave Elastography, developed by Super-Sonic Imagine. This technique mea­sures elasticity in kilopascals and can provide visual representation of tis­sue stiffness over the entire region of interest in a color-coded map on the ultrasound screen. On a split screen the investigator can see the conven­tional ultrasound B-mode image and the color-coded elastogram at the same time. This enables an anatomi­cal view of the prostate along with the elasticity image of the tissue to guide the biopsy needle.

In short, ShearWave Elastography (SWE) is a different elastography technique that can be used for several applications. It automatically gener­ates a real-time, reproducible, fully quantifiable color-coded image of tissue elasticity.

QUANTIFICATION OF TISSUE STIFFNESS Such quantification can help to increase the chance that a targeted biopsy is positive for cancer.

It has been shown that elastography-targeted biopsies have an up to 4.7 times higher chance to be positive for cancer than a randomized biopsy [4J. Shear-Wave Elastography can not only visual­ize the tissue stiffness in color but also quantify (in kPa) the stiffness in real time, for several organs including the prostate. Correas et al, reported that with tissue stiffness higher than 45 to 50 kPa the chance of prostate cancer is very high in patients undergoing a pros­tate biopsy. The data from Gorreas et al showed a sensitivity of 80 % and a high negative predictive value of up to 9096. Another group (Barr et A) achieved a negative predictive value of up to 99.6% with a sensitivity of 96.2% and specific­ity of 962%. With a cut-off of 4D kPa the positive biopsy rate for the ShearWave Elastography targeted biopsy was 50%, whereas for randomized biopsy it was 20.8 95. In total 53 men were enrolled in this study.

Our group used SWE prior to radical prostatectomy to determine if the Shear-Wave Elastography threshold had a high accuracy using a cutoff >55 kPa. (Fig 1)

We then compared the ShearWave results with the final histopathological results. [Figure I], Our results showed the accuracy was around 78 % for all tumor foci We were also able to verify that ShearWave Elastography targeted biopsies were more likely to be posi­tive compared to randomized biopsies. [Figures 2, 3]

F1

F2F3 

CONCLUSION

SWE is a non-invasive method to visualize prostate cancer foci with high accuracy, in a user-friendly way. As Steven Kaplan puts it in an edi­torial comment in the Journal of Urology 2013: “Obviously, large-scale studies with multicenter corroboration need to be performed. Nevertheless, SWE is a potentially promising modality to increase our efficiency in evaluating prostate diseases:’

 

REFERENCES

  1. Pallweln, L. et al-. Sonoelastography of the prostate: comparison with systematic biopsy findings in 492 patients. European journal of radiology, 2008. 65(2): p. 304-10.
  2. Pallwein, L., et al., Comparison of sono-elastography guided biopsy with systematic biopsy: Impact on prostate cancer detecton. European radiology, 2007_ 17.(9) p. 2278-85.
  3. Salomon, G., et al., Evaluation of prostate can cer detection with ultrasound real-time elas-tographyl a companion with step section path­ological analysis after radical prostatectomy. European urology, 2008. 5446): p. 135462-
  4. Aigner, F., at al., Value of real-time elastography targeted biopsy for prostate cancer detection in men with prostate specific antigen 125 ng/mi or greater and 4-00 ng/ml or Lass. The Journal of urology, 2010. 184{3): p. 813.7,

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

Imaging: seeing or imagining? (Part 1)

Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Today’s fundamental challenge in Prostate cancer screening

State of the art in oncologic imaging of Prostate.

From AUA2013: “HistoScanning”- aided template biopsies for patients with previous negative TRUS biopsies 

On the road to improve prostate biopsy

 

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EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE

Author-Writer: Dror Nir, PhD

 

 When reviewing the DETECTION OF PROSTATE CANCER section on the AUA website , The first thing that catches one’s attention is the image below; clearly showing two “guys” exploring with interest what could be a CT or MRI image…..

 fig 1

But, if you bother to read the review underneath this image regarding EARLY DETECTION OF PROSTATE CANCER: AUA GUIDELINE produced by an independent group that was commissioned by the AUA to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening; Panel Members: H. Ballentine Carter, Peter C. Albertsen, Michael J. Barry, Ruth Etzioni, Stephen J. Freedland, Kirsten Lynn Greene, Lars Holmberg, Philip Kantoff, Badrinath R. Konety, Mohammad Hassan Murad, David F. Penson and Anthony L. Zietman - You are bound to be left with a strong feeling that something is wrong!

The above mentioned literature review was done using rigorous approach.

“The AUA commissioned an independent group to conduct a systematic review and meta-analysis of the published literature on prostate cancer detection and screening. The protocol of the systematic review was developed a priori by the expert panel. The search strategy was developed and executed

by reference librarians and methodologists and spanned across multiple databases including Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Reviews, Ovid Cochrane Central Register of Controlled Trials and Scopus. Controlled vocabulary supplemented with keywords was used to search for the relevant concepts of prostate cancer, screening and detection. The search focused on DRE, serum biomarkers (PSA, PSA Isoforms, PSA kinetics, free PSA, complexed PSA, proPSA, prostate health index, PSA velocity, PSA

doubling time), urine biomarkers (PCA3, TMPRSS2:ERG fusion), imaging (TRUS, MRI, MRS, MR-TRUS fusion), genetics (SNPs), shared-decision making and prostate biopsy. The expert panel manually identified additional references that met the same search criteria”

While reading through the document, I was looking for the findings related to the roll of imaging in prostate cancer screening; see highlighted above. The only thing I found: “With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests.

This must mean that: Notwithstanding hundreds of men-years and tens of millions of dollars which were invested in studies aiming to assess the contribution of imaging to prostate cancer management, no convincing evidence to include imaging in the screening progress was found by a group of top-experts in a thorough and rigorously managed literature survey! And it actually  lead the AUA to declare that “Nothing new in the last 20 years”…..

My interpretation of this: It says-it-all on the quality of the clinical studies that were conducted during these years, aiming to develop an improved prostate cancer workflow based on imaging. I hope that whoever reads this post will agree that this is a point worth considering!

For those who do not want to bother reading the whole AUA guidelines document here is a peer reviewed summary:

Early Detection of Prostate Cancer: AUA Guideline; Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, Holmberg L, Kantoff P, Konety BR, Murad MH, Penson DF, Zietman AL; Journal of Urology (May 2013)”

It says:

“A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age<40; 40 to 54; 55 to 69; ≥70).

RESULTS: With the exception of prostate-specific antigen (PSA)-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and over treatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening.

CONCLUSIONS: The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. The entire guideline is available at www.AUAnet.org/education/guidelines/prostate-cancer-detection.cfm.”

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

From AUA2013: “Histoscanning”- aided template biopsies for patients with previous negative TRUS biopsies

Imaging-biomarkers is Imaging-based tissue characterization

On the road to improve prostate biopsy

State of the art in oncologic imaging of Prostate

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: 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?

Read Full Post »


Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging

 Reporter: Dror Nir, PhD

Early this year I have posted on: Whole-body imaging as cancer screening tool; answering an unmet clinical need? F-PET/CT was discussed in this post as a leading modality in that respect. Here I report on an article dedicated to the sources for misdiagnosis; i.e. false negatives and false positives when applying this technology:

Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging, Niamh M. Long and Clare S. Smith /Insights into Imaging© European Society of Radiology 201010.1007/s13244-010-0062-3

Abstract

Background

18F-FDG is a glucose analogue that is taken up by a wide range of malignancies. 18F-FDG PET-CT is now firmly established as an accurate method for the staging and restaging of various cancers. However, 18F-FDG also accumulates in normal tissue and other non-malignant conditions, and some malignancies do not take up F18-FDG or have a low affinity for the tracer, leading to false-positive and false-negative interpretations.

Methods

PET-CT allows for the correlation of two separate imaging modalities, combining both morphological and metabolic information. We should use the CT to help interpret the PET findings. In this article we will highlight specific false-negative and false-positive findings that one should be aware of when interpreting oncology scans.

Results

We aim to highlight post-treatment conditions that are encountered routinely on restaging scans that can lead to false-positive interpretations. We will emphasise the importance of using the CT component to help recognise these entities to allow improved diagnostic accuracy.

Conclusion

In light of the increased use of PET-CT, it is important that nuclear medicine physicians and radiologists be aware of these conditions and correlate the PET and CT components to avoid misdiagnosis, over staging of disease and unnecessary biopsies.

Introduction

[18F] 2-fluoro-2deoxy-D-glucose (18F-FDG) PET-CT imaging has become firmly established as an excellent clinical tool in the diagnosis, staging and restaging of cancer. 18F-FDG (a glucose analog) is taken up by cells via glucose transporter proteins. The glucose analog then undergoes phosphorylation by hexokinase to FDG-6 phosphate. Unlike glucose, FDG-phosphate does not undergo further metabolism and so becomes trapped in the cell as the cell membrane is impermeable to FDG-6 phosphate following phosphorylation [1].

Malignant tumors have a higher metabolic rate and generally express higher numbers of specific membrane transporter proteins than normal cells. This results in increased uptake of 18F-FDG by tumor cells and forms the basis of FDG-PET imaging [2]. Glucose however acts as a basic energy substrate for many tissues, and so 18F-FDG activity can be seen both physiologically and in benign conditions. In addition, not all tumors take up FDG [35]. The challenge for the interpreting physician is to recognize these entities and avoid the many pitfalls associated with 18F-FDG PET-CT imaging.

In this article we discuss false-positive and false-negative 18F-FDG PET-CT findings, common and atypical physiological sites of FDG uptake, and benign pathological causes of FDG uptake. We will focus on post-treatment conditions that can result in false-positive findings. We will highlight the importance of utilizing the CT component of the study, not only for attenuation correction but also in the interpretation of the study. The CT component of 18F-FDG PET-CT imaging can provide high-resolution anatomical information, which enables more accurate staging and assessment. For the purposes of this article, we refer to the descriptive terms “false-positive” and “false-negative” findings in the context of oncology imaging.

The authors acknowledge that there are recognized causes of FDG uptake that are not related to malignancy; however in this paper we refer to false-positive findings as FDG uptake that is not tumor related.

Patient preparation

Tumor uptake of FDG is reduced in the presence of raised serum glucose as glucose competes with FDG for uptake by the membrane transporter proteins. In order to prevent false-negative results, it is necessary for the patient to fast for at least 4–6 h prior to the procedure [6]. Induction of a euglycamic hypoinsulinaemic state also serves to reduce the uptake of glucose by the myocardium and skeletal muscle. In the fasting state, the decreased availability of glucose results in predominant metabolism of fatty acids by the myocardium. This reduces the intensity of myocardial uptake and prevents masking of metastatic disease within the mediastinum [6].

The radiotracer is administered intravenously (dose dependent on both the count rate capability of the system used and the patient’s weight), and the patient is left resting in a comfortable position during the uptake phase (60–90 min). Patient discomfort and anxiety can result in increased uptake in skeletal muscles of the neck and paravertebral regions. Muscular contraction immediately prior to or following injection can result in increased FDG activity in major muscle groups [6].

Patients are placed in a warm, quiet room with little stimulation, as speech during the uptake phase is associated with increased FDG uptake in the laryngeal muscles [7].

At our institution we perform the CT component with arms up except for head and neck studies where the arms are placed down by the side. This minimizes artifacts on CT. Depending on the type of cancer, oral contrast to label the bowel and intravenous contrast may also be given. The CT is performed with a full dose similar to a diagnostic CT, and lungs are analyzed following reconstruction with a lung algorithm. The PET scan is performed with 3–4 min per bed position; however the time per bed position will vary in different centers depending on both the dose of FDG administered and the specifications of the camera used for image acquisition. It is beyond the scope of this article to provide detailed procedure guidelines for 18F-FDG PET-CT imaging, and for this purpose we refer the reader to a comprehensive paper by Boellaard et al. [8].

Technical causes of false positives

Misregistration artifact

The evaluation of pulmonary nodules provides a unique challenge for combined PET-CT scanning due to differences in breathing patterns between CT and PET acquisition periods. CT imaging of the thorax is classically performed during a breath-hold; however PET images are acquired during tidal breathing, and this can contribute significantly to misregistration of pulmonary nodules on fused PET-CT images. Misregistration is particularly evident at the lung bases, which can lead to difficulty differentiating pulmonary nodules from focal liver lesions (Fig. 1) [9].

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Fig. 1

18F-FDG PET-CT performed in a 65-year-old male with colorectal cancer. On the coronal PET images, a focus of increased FDG uptake is seen at the right lung base (black arrow). Contrast CT does not show any pulmonary nodules but does demonstrate a liver metastasis in the superior aspect of the right lobe of the liver (yellow arrow)

Acquiring CT imaging of the thorax during quiet respiration can help to minimize misregistration artifacts. It is also important to correlate your PET and CT findings by scrolling up and down to make sure that lesions match.

Injected clot

A further diagnostic pitfall in staging of intrathoracic disease can be caused by injected clot. Injection of radioactive clot following blood withdrawal into the syringe at the time of radiotracer administration can result in pulmonary hotspots [10]. The absence of a CT correlate for a pulmonary hotspot should raise the possibility of injected clot; however this is a diagnosis of exclusion, and it is important to carefully evaluate the adjacent slices to ensure the increased radiotracer activity does not relate to misregistration of a pulmonary nodule or hilar lymph node. The area of abnormal radiotracer uptake should also be closely evaluated on subsequent restaging CT to ensure there has been no interval development of an anatomical abnormality in the region of previously diagnosed injected clot (Fig. 2) [11].

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Fig. 2

18F-FDG PET-CT performed in a 28-year-old male with an osteosarcoma of the femur. A focus of increased FDG uptake (yellow arrow) is identified in the left lower lobe with no CT correlate (a). A 3-month follow-up CT thorax again does not demonstrate any pulmonary nodules confirming that the uptake seen originally on the PET-CT was due to injected clot (b)

Injection artifact

Leakage of radiotracer into the subcutaneous tissues at the injection site or tissued injection can result in subcutaneous tracking of FDG along lymphatic channels in the arm. This can result in spurious uptake in axillary nodes distal to the injection site [12]. Careful attention must be paid to the technical aspects of the study to ensure accurate staging. Injection at the side contralateral to the site of disease is advised where feasible to allow differentiation between artifactual and metastatic uptake, particularly in breast cancer patients. The side of injection should also be clearly documented during administration of radiotracer, and this information should be available to the reader in order to ensure pathological FDG uptake is not spuriously attributed to injection artifact (Fig. 3).

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Fig. 3

18F-FDG PET-CT performed in a 56-year-old woman with colorectal cancer. Some low grade FDG uptake is identified in non-enlarged right axillary nodes (yellow arrow) consistent with injection artifact

Imaging of metallic implants

The use of CT for attenuation correction negates the need for traditional transmission attenuation correction, reducing scanning time. There are however technical factors relating to the use of CT imaging for attenuation correction, which lead to artefacts when imaging metal [9]. The presence of metal implants in the body produces streak artifact on CT imaging and degrades image quality. When CT images are used for attenuation correction, the presence of metal results in over attenuation of PET activity in this region and can result in artifactual ‘hot spots.’ Metal prostheses, dental fillings, indwelling ports and breast expanders and sometimes contrast media are common causes of streak artifact secondary to high photon absorption and can cause attenuation correction artifacts [9]. In order to avoid false positives, particularly when imaging metallic implants careful attenuation should be paid to the nonattenuation corrected images, which do not produce this artifact.

Sites of physiological FDG uptake

Physiological uptake in a number of organs is readily recognized and rarely confused with malignancy. These include cerebral tissue, the urinary system, liver and spleen. Approximately 20% of administered activity is renally excreted in the 2 h post-injection resulting in intense radiotracer activity in the renal collecting systems, ureters and bladder [13]. In order to minimize the intensity of renal activity, patients are advised to void prior to imaging. Moderate physiological FDG uptake is noted in the liver, spleen, GI tract and salivary glands. Uptake in the cecum and right colon tends to be higher than in the remainder of the colon due to the presence of glucose-avid lymphocytes [14].

Other sites of physiological FDG activity can be confused with malignancy. Examples include activity within brown fat, adrenal activity, uterus and ovaries.

Brown fat

FDG uptake in hyper-metabolic brown adipose tissue is well recognized as a potential source of false positive in 18F-FDG PET-CT imaging. The incidence of FDG uptake in brown fat has been reported as between 2.5–4% [1516].

Hypermetabolic brown fat is more commonly identified in children than in adults and is more prevalent in females than in males. It occurs more frequently in patients with low body mass index and in cold weather [15].

Glucose accumulation within brown fat is increased by sympathetic stimulation as brown fat is innervated by the sympathetic nervous system. In view of this, administration of oral propranolol is advised by some authors as it has been shown to reduce the uptake of FDG by brown fat [17]. This is not performed at our institution; however, attempts are made to reduce FDG uptake in brown fat by maintaining a warm ambient temperature and providing patients with blankets during the uptake phase.

The typical distribution of brown fat in a bilateral symmetric pattern in the supraclavicular and neck regions is rarely confused with malignancy. In cases where hypermetabolic brown fat is seen to surround lymph nodes, the CT images should be separately evaluated to allow morphological assessment of the lymph nodes. The classical CT features of pathological replacement of lymph nodes should be sought, namely increased short axis diameter, loss of the fatty hilum and loss of the normal concavity of the lymph node. If the morphology of the lymph node is entirely normal, malignancy can be confidently excluded and the increased uptake attributed to brown fat [18].

Atypical brown fat in the mediastinum can be misinterpreted as nodal metastases and has been identified in the paratracheal, paraoesophageal, prevascular regions, along the pericardium and in the interatrial septum. Extramediastinal sites of brown fat uptake include the paravertebral regions, perinephric, perihepatic and subdiaphragmatic regions and in the intraatrial septum [16].

The absence of an anatomical lesion on CT imaging in areas of FDG uptake should raise the possibility of brown fat to the reader. Careful evaluation of the CT images must be performed to confirm the presence of adipose tissue in the anatomical region correlating to the increased FDG activity on 18F-FDG PET before this activity be attributed to brown fat.

An awareness of the possibility of brown fat in atypical locations is vital to avoid overstaging, and correlation with CT imaging increases reader confidence in differentiating brown fat from malignancy (Fig. 4).

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Fig. 4

18F-FDG PET-CT surveillance scan performed in a 36-year-old male with a history of seminoma. Symmetrical uptake is noted in the neck, supraclavicular fossa and paravertebral regions consistent with typical appearance of brown fat activity (black arrow). Brown fat uptake is also seen in the left supradiaphragmatic region and left paraoesophageal region (yellow arrow) (a). 18F-FDG PET-CT performed in a 48-year-old male with a history of colorectal cancer. Increased FDG uptake is noted within brown fat associated with lipomatous hypertrophy of the intra-atrial septum (b)

Uterine and ovarian uptake

In premenopausal women endometrial uptake of FDG varies cyclically and is increased both at ovulation and during the menstrual phase of the cycle with mean SUV values of 3.5–5 [19]. Endometrial uptake in postmenopausal women is abnormal and warrants further investigation; however benign explanations for increased FDG uptake include recent curettage, uterine fibroids and endometrial polyps [19].

Benign ovarian uptake of FDG in premenopausal women can be associated with ovulation. In postmenopausal women, ovarian uptake of FDG should be further investigated (Fig. 5).

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Fig. 5

18F-FDG PET-CT performed in a 42-year-old premenopausal female with breast cancer. She was scanned during menstruation. FDG uptake is noted within metastatic right axillary nodes (black arrow). Increased FDG uptake is also noted within the endometrial canal of the uterus (yellow arrow), which is thickened on CT, consistent with active menstruation (a). 18F-FDG PET-CT performed in the same 42-year-old woman at a different stage in her menstrual cycle showing resolution of the previously identified uterine uptake (yellow arrow) (b)

Adrenal uptake

18F-FDG PET imaging is commonly used for evaluation of adrenal masses in patients with diagnosed malignancies. Similarly incidental adrenal lesions are commonly identified on staging 18F-FDG PET-CT imaging. The positive predictive value of 18F-FDG PET-CT evaluation of adrenal lesions has been reported as high as 95% with a similarly high negative predictive value of 94% [20].

Causes of false-positive adrenal lesions include angiomyolipoma, adrenal hyperplasia and adrenal adenomas (up to 5%) [2124]. FDG activity greater than that of the liver is generally associated with malignancy; however benign lesions have been reported with greater activity than liver [21].

Evaluation of the CT component can provide additional diagnostic information with identification of HU attenuation values of <10 on noncontrast CT for adrenal adenomas or fat-containing myelolipomata [21].

Symmetrical intense FDG activity with no identifiable abnormality on CT is associated with benign physiological FDG uptake (Fig. 6).

f6 f6-b

Fig. 6

18F-FDG PET-CT performed in a 50-year-old woman with inflammatory breast cancer. Diffuse increased FDG uptake is noted within the right breast (yellow arrow) and in a right axillary node (black arrow), consistent with malignancy (a). Increased symmetrical uptake is also noted within both adrenal glands with no abnormal correlate on CT (yellow arrow) (b). Post-chemotherapy PET-CT performed 5 months later demonstrates resolution of the activity within the breast, increased uptake in the bone marrow consistent with post treatment effect (black arrow) and persistent increased uptake in the adrenal glands (yellow arrow), confirming benign physiological activity (c)

Thyroid uptake

Thyroid uptake is incidentally identified on 18F-FDG PET imaging with a frequency of almost 4%, with a diffuse uptake pattern in roughly half of cases and a focal pattern in the remainder [22]. The majority of diffuse uptake represents chronic thyroiditis, multinodular goiter or Graves’ disease, whereas focal uptake is associated with a risk of malignancy that ranges from 30.9–63.6% in published studies [2223]. Focal thyroid uptake requires further investigation with ultrasound and tissue biopsy.

Uptake in the gastrointestinal tract

The pattern of physiological uptake within the GI tract is highly variable. Low-grade linear uptake is likely related to smooth muscle activity and swallowed secretions. More focal increased uptake in the distal esophagus is sometimes seen with Barrett’s esophagus. In view of this, referral for OGD may be reasonable in cases of increased uptake in the distal esophagus [1424].

The typical pattern of FDG uptake in the stomach is of low-grade activity in a J-shaped configuration. Small bowel typically demonstrates mild heterogeneous uptake throughout. Common pitfalls of small bowel evaluation relate to spuriously high uptake in underdistened or overlapping loops of bowel [1425].

Within the colon, FDG uptake is highly variable, however can be quite avid particularly in the cecum, right colon and rectosigmoid regions. Focal areas of FDG activity within the colon that are of greater intensity than background liver uptake should raise the suspicion of a colonic neoplasm (Fig. 7) [2526].

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Fig. 7

18F-FDG PET-CT restaging scan performed in a 65-year-old female with a history of breast cancer. Incidental focal uptake is identified in the ascending colon where some abnormal thickening is seen on the CT component (yellow arrow). Colonoscopy confirmed the presence of a T3 adenocarcinoma

In a review of over 3,000 patients’ focal areas of abnormal FDG uptake within the gastrointestinal tract (GIT) were identified in 3% of cases of staging 18F-FDG PET-CT studies.

Incidental malignant lesions were identified in 19% of these patients with pre-malignant lesions including adenomas in 42% of the patients [27]. In view of this endoscopy referral is recommended in the absence of a clear benign correlate for focal areas of avid uptake on CT imaging.

Treatment-related causes of false-positive uptake

There are a number of conditions that can occur in patients undergoing treatment for cancer. When imaging these patients to assess for response, we often see these treatment-related conditions. It is important to recognize the imaging features to avoid misdiagnosis.

Thymus/thymic hyperplasia

Thymic hyperplasia post-chemotherapy is a well-described phenomenon. It is generally seen in children and young adults at a median of 12 months post chemotherapy [28]. The presence of increased FDG uptake in the anterior mediastinum can be attributed to thymic hyperplasia by identification of a triangular soft tissue density seen retrosternally on CT with a characteristic bilobed anatomical appearance [29]. In the presence of thymic hyperplasia, there is generally preservation of the normal shape of the gland despite an increase in size [30].

Superior mediastinal extension of thymic tissue is an anatomical variant that has been described in children and young adults (Fig. 8).

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Fig. 8

A 3.5-year-old boy with abdominal Burkitt’s lymphoma. Coronal 18F-FDG PET scan obtained 5 months after completion of treatment shows increased activity in the thymus in an inverted V configuration and in superior thymic extension (white arrow). Note physiologic activity within the right neck in the sternocleidomastoid muscle (a). Axial CT image from the same 18F-FDG PET-CT study performed 5 months after treatment shows a nodule (white arrow) anteromedial to the left brachiocephalic vein (b). Axial fusion image shows that the FDG activity in the superior mediastinum corresponds to this enlarged nodule anteromedial to left brachiocephalic vein (white arrow) (c). Axial fusion image shows increased activity in an enlarged thymus consistent with thymic hyperplasia (white arrow; standardized uptake value 3.0) of similar intensity to activity in superior mediastinum (d)

It presents as a soft tissue nodule anteromedial to the left brachiocephalic vein and represents a remnant of thymic tissue along the path of migration in fetal life. In patients with thymic hyperplasia, a superior mediastinal nodule in this location may represent accessory thymic tissue. An awareness of this physiological variant is necessary to prevent misdiagnosis [28].

G-CSF changes

Granulocyte colony-stimulating factor is a glycoprotein hormone that regulates proliferation and differentiation of granulocyte precursors. It is used to accelerate recovery from chemotherapy-related neutropaenia in cancer patients. Intense increased FDG uptake is commonly observed in the bone marrow and spleen following GCSF therapy; however the bone marrow response to GCSF can be differentiated from pathological infiltration by its intense homogeneous nature without focally increased areas of FDG uptake. Increased FDG uptake attributable to GCSF uptake rapidly decreases following completion of therapy and generally resolves within a month (Fig. 9).

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Fig. 9

18F-FDG PET-CT performed in a 46-year-old male post four cycles of chemotherapy for lymphoma and 2 weeks post administration of G-CSF. Note the diffuse homogeneous increased uptake throughout the bone marrow and the increased uptake in the spleen (yellow arrow)

Marked uptake in the bone marrow can also be seen following chemotherapy, reflecting marrow activation [3132].

Radiation pneumonitis

Inflammatory morphological changes in the radiation field post-irradiation of primary or metastatic lung tumor can result in false-positive diagnosis. Radiation pneumonitis typically occurs following high doses of external beam radiotherapy (>40 Gy). In the acute phase (1–8 weeks) radiation pneumonitis is characterized by ground-glass opacities and patchy consolidation. This can commonly lead to a misdiagnosis of infection. Chronic CT appearances of fibrosis and traction bronchiectasis in the radiation field allow correct interpretation of increased FDG uptake as radiation pneumonitis as opposed to disease recurrence [3334]. Other organs are also sensitive to radiation, and persistent uptake due to inflammatory change can persist for up to 1 year. It is important to elicit a history of radiation from the patient and to correlate the increased uptake with the CT findings to avoid missing a disease recurrence (Fig. 10).

f 10

Fig. 10

18F18-FDG PET-CT performed in a 52-year-old male with newly diagnosed esophageal carcinoma. Increased FDG uptake is identified within the esophagus (black arrow) and an upper abdominal lymph node (yellow arrow), consistent with malignancy (a). 18F18-FDG PET-CT performed 6 weeks post-completion of radiotherapy for esophageal carcinoma. Linear increased uptake is identified along the mediastinum in the radiation port (black arrow). This corresponds to areas of ground-glass change on CT (yellow arrow) consistent with acute radiation change (b)

Infection

Bone marrow suppression places chemotherapy patients at increased risk of infection.

Inflammatory cells such as neutrophils and activated macrophages at the site of infection or inflammation actively accumulate FDG [35].

In the post-therapy setting it has been reported that up to 40% of FDG uptake occurs in non-tumor tissue [12]. Infection is one of the most common causes of false-positive 18F-FDG PET-CT findings post-chemotherapy. Chemotherapy patients are susceptible to a wide variety of infections, including upper respiratory chest infections, pneumonia, colitis and cholecystitis. Reactivation of tuberculous infection can occur in immunocompromised patients post,chemotherapy, and correlation with CT imaging can prevent misdiagnosis in suspected cases.

Atypical infections such as cryptococcosis and pneumocystis can also present as false-positives on FDG imaging (Fig. 11) [36].

f 11

Fig. 11

18F-FDG PET-CT performed in a 57-year-old male 2 weeks following chemotherapy for lung cancer. Increased FDG uptake is noted within the cecum (black arrow). On CT there is some thickening of the cecal wall and stranding of the pericecal fat (yellow arrow) consistent with typhilits

Surgery and radiotherapy

There are inherent challenges in the interpretation of 18F-FDG PET-CT imaging in the postoperative patient. Non-tumor-related uptake of FDG is frequently identified in post-operative wound sites, at colostomy sites or at the site of post-radiation inflammatory change. 18F-FDG PET-CT imaging during the early postoperative/post-radiotherapy period may result in overstaging of patients because of non-neoplastic uptake of FDG [12]. Careful evaluation of the CT component in this setting is vital as CT imaging can provide valuable additional information regarding benign inflammatory conditions commonly encountered in the postoperative setting such as abscesses or wound infection. These conditions are often readily apparent on CT, particularly when oral and/or IV contrast CT is administered.

The reader should also bear in mind that avid uptake of FDG at postoperative/post radiotherapy sites may mask malignant FDG uptake in neighboring structures. In order to minimize non-tumoral uptake of FDG, it is advisable to allow at least 6 weeks post-surgery or completion of radiotherapy prior to performing staging 18F-FDG PET-CT [24].

Talc pleurodesis

Talc pleurodesis is a commonly performed procedure for the treatment of persistent pneumothorax or pleural effusion. The fibrotic/inflammatory reaction results in increased FDG uptake on 18F-FDG PET imaging with corresponding high-density areas of pleural thickening on CT. SUV values of between 2–16.3 have been seen years after the procedure [37].

When increased FDG uptake is indentified in the pleural space in a patient with a known history of pleurodesis, correlation with CT is recommended to detect pleural thickening of increased attenuation that suggests talc rather than tumor.

It is extremely important that a comprehensive history with relevant surgical interventions is available to the reader in order to ensure accurate diagnosis and staging (Fig. 12).

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Fig. 12

18F-FDG PET-CT performed in a 69-year-old male with a history of non-Hodgkin’s lymphoma. The patient had a previous talc pleurodesis for a persistent left pleural effusion. Increased FDG activity is identified within the left pleura (black arrow). CT demonstrates a pleural effusion with high density material along the left pleural surface consistent with talc (yellow arrow)

Flare phenomenon

Bone healing is mediated by osteoblasts, and an early increase in osteoblast activity on successful treatment of metastatic disease has been described [38]. “Bone flare” refers to a disproportionate increase in bone lesion activity on isotope bone scan despite evidence of a therapeutic response to treatment in other lesions and has been well described in breast, prostate and lung tumors. ‘Flare phenomenon’ has also been described on 18F-FDG PET-CT in patients with lung and breast cancer who are receiving chemotherapy [39].

Differentiating between increased FDG uptake due to flare response and true disease progression may not be possible in the early post-treatment studies. While it is recognized that bone flare is a rare phenomenon, an increase in baseline skeletal activity and appearance of new bone lesions despite apparent response or stable disease elsewhere should be interpreted with caution to avoid erroneously suggesting progressive disease.

Osteonecrosis

Osteonecrosis or avascular necrosis has been well described as a complication of combination chemotherapy treatment, especially where it includes intermittent high-dose corticosteroids (e.g., lymphoma patients) [40]. Commonly encountered sites include the hip and less frequently the proximal humerus. Occasionally we can see a discrete entity known as jaw osteonecrosis. Patients receiving IV bisphosphonates for the management of bone metastases are at an increased risk of developing this [41]. The development of osteonecrosis in the mandible is frequently preceded by tooth extraction. Radiographic findings that may be visualized on CT include osteosclerosis, dense woven bone, thickened lamina dura and sub-periosteal bone deposition [42]. FDG uptake can be seen in areas of osteonecrosis (Fig. 13).

f 13

Fig. 13

18F-FDG PET-CT performed in a 46-year-old gentleman with a history of non-Hodgkin’s lymphoma. Increased FDG uptake is identified in the right proximal humerus (black arrow). CT of the area demonstrates a corresponding vague area of sclerosis (yellow arrow). Biopsy of the area yielded osteonecrosis with no evidence of metastatic disease

Insufficiency fractures

Pelvic insufficiency fractures have been described following irradiation for gynecological, colorectal, anal and prostate cancer. They commonly occur within 3–12 months post-radiation treatment, and osteoporosis is often a precipitating factor. FDG uptake in insufficiency fractures ranges from mild and diffuse to intense and heterogeneous. The maximum SUV values are variable with reported values of between 2.4–7.2 [43]. Differentiating insufficiency fractures from bone metastases can prove challenging; however they are often bilateral and occur in characteristic locations within the radiation field—sacral ala, pubic rami and iliac bones. Biopsy of insufficiency fractures can lead to irreparable damage and so careful correlation of 18F-FDG PET imaging with the CT component along with radiation history is vital for correct diagnosis. CT allows evaluation of the bone cortex and adjacent soft tissues, which can confirm the diagnosis of a pathological fracture or a metastatic deposit.

Follow-up of suspected insufficiency fractures demonstrates a reduction in FDG uptake over time (Fig. 14) [43].

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Fig. 14

18F-FDG PET-CT performed in a 46-year-old female, 3 years post-chemo-radiation for cervical carcinoma. Low grade FDG uptake is identified in the left acetabulum and right pubic bone (black arrow). CT demonstrates pathological fractures in these areas consistent with insufficiency fractures (yellow arrow)

Sarcoidosis

Sarcoidosis is a chronic multisystem disorder characterized by non-caseating granulomas and derangement of normal tissue architecture [36]. Sarcoidosis has been reported in association with a variety of malignancies either synchronously or post-chemotherapy. Aggregation of inflammatory cells post-chemotherapy is associated with accumulation of FDG, and the intensity of FDG uptake may correlate with disease activity [36].

When suspected disease recurrence presents with signs and symptoms compatible with sarcoidosis (i.e., mediastinal and bihilar lymphadenopathy), this must be excluded by clinical, radiological and pathological correlation to prevent mistreatment (Fig. 15).

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Fig. 15

18F-FDG PET-CT performed in a 67-year-old male for restaging of laryngeal carcinoma. Increased FDG uptake is noted in the left lower neck and left mediastinum (black arrow). CT demonstrates lymphadenopathy in these areas (yellow arrow), some of which are calcified. Biopsy of the left lower neck node confirmed sarcoidosis

FDG-PET negative tumors

There are a number of malignancies that can be FDG-PET negative. Examples include bronchoalveolar carcinoma and carcinoid tumors in the lung, renal cell carcinomas and hepatomas, mucinous tumors of the GIT and colon, and low grade lymphomas [34448]. Careful evaluation of the CT component of the study however will prevent a misdiagnosis (Fig. 16).

f 16

Fig. 16

18F-FDG PET-CT performed in a 52-year-old female with breast cancer and chronic hepatitis. On the CT component a hyper-enhancing mass is identified in segment 4 of the liver (yellow arrow). No increased FDG activity is identified in this area on the PET component. Biopsy of the mass confirmed the diagnosis of a hepatocellular carcinoma

Osteoblastic metastases

Bone metastases are diagnosed in up to 85% of patients with advanced breast cancer, leading to significant morbidity and mortality. Sclerotic bone metastases are commonly associated with breast carcinoma [49].18F-FDG PET imaging is superior to nuclear bone scan in detection of osteolytic breast metastases; however it commonly fails to diagnose osteoblastic or sclerotic metastases [50]. Review of bony windows on CT imaging allows identification of sclerotic metastases and ensures accurate staging of metastatic bone disease (Fig. 17).

f 17

Fig. 17

Staging 18F-FDG PET-CT performed in a 45-year-old female with newly diagnosed breast cancer. CT demonstrates multiple small sclerotic foci in the spine and pelvis (yellow arrow), consistent with bony metastases. These are FDG negative on the PET component of the study

Discussion/conclusion

18F-FDG PET imaging has dramatically changed cancer staging, and findings of restaging studies commonly effect changes in treatment protocols. 18F-FDG however is not tumor specific. As interpreting physicians we need to be aware of these false positives and false negatives. In this review we have outlined atypical physiological sites of FDG uptake along with common causes of FDG uptake in benign pathological conditions, many of which are treatment related. With 18F-FDG PET-CT we have the advantage of two imaging modalities. The PET component gives us functional information and the CT, anatomical data. We have discussed the importance of dual-modality imaging and correlation with CT imaging of the above conditions. Furthermore CT imaging provides important diagnostic information in evaluation of tumors that poorly concentrate FDG. In light of the increased reliance of 18F-FDG PET-CT for cancer staging, it is vital that radiologists and nuclear medicine physicians be aware of pitfalls in 18F-FDG PET-CT imaging and correlate PET and CT components to avoid misdiagnosis, overstaging of disease and unnecessary biopsies.

Other research papers related to the use of 18F-PET in management of cancer were published on this Scientific Web site:

State of the art in oncologic imaging of Lymphoma.

State of the art in oncologic imaging of Colorectal cancers.

State of the art in oncologic imaging of Prostate.

State of the art in oncologic imaging of lungs.

State of the art in oncologic imaging of breast.

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

 

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Yeung HW, Grewal RK, Gonen M, Schöder H, Larson SM (2003) Patterns of (18)F-FDG uptake in adipose tissue and muscle: a potential source of false-positives for PET. J Nucl Med 44(11):1789–1796PubMed

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Choi JY, Lee KS, Kim HJ, Shim YM, Kwon OJ, Park K, Baek CH, Chung JH, Lee KH, Kim BT (2006) Focal thyroid lesions incidentally identified by integrated 18 F-FDG PET/CT: clinical significance and improved characterization. J Nucl Med 47(4):609–615PubMed

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Imaging guided Cancer-Therapy – a Discipline in Need of Guidance.

 Author – Writer: Dror Nir, PhD

The use of imaging in cancer management is broadly established. During the past two decades, advancements in imaging; image quality, precision and reproducibility lead to introduction of localized, minimally invasive treatments of cancer lesions.

 A statement-paper, published online: 17 January 2013: Radiologists’ leading position in image-guided therapy, which presents the thoughts of the Image-Guided Therapy Working Group within the Research Committee of the European Society of Radiology, give hope that the policy-makers in the European radiology society are becoming aware of the need to guide this process.

Although the authors are addressing imaging guided therapy (IGT) in its broad sense, most of their examples are related to treatment of cancer. The main reason for provided for being concerned with what is happening in this domain is: “This means that the planning, performing and monitoring, as well as the control of the therapeutic procedure, are based and dependent on the “virtual reality” provided by imaging investigations.”

The most interesting points raised by the authors are:

 1. The realization that IGT is involving many “non-radiologist”, and this fact cannot be ignored: “This role is mainly driven by the sophisticated opportunities offered by medical computing and radiological image guidance with regard to precision and minimal invasiveness [2]. However, the impact of radiology on the regulatory medico-legal, technical and radioprotection issues in this field have not yet been defined. Since an increasing number of procedures will probably be performed by non-radiologists, several main questions have to be addressed:

  • How should the radiology training requirements for non-radiologists be provided?
  • How should the technical and radioprotection related responsibilities for radiological imaging systems used by non-radiologists be organised?
  • How should radiologists be involved in the practical routine use of non-radiological image-guided procedures in clinical practice?

Considering the almost pan-European medical reality with decreasing staff resources and increasing diversification and subspecialisation, radiologists have to stress the fact that within a cooperative, goal-oriented and multidisciplinary environment, the specialty-specific knowledge should confer upon radiologists a significant impact on the overall responsibility for all imaging-related processes in various non-radiological specialties (such as purchase, servicing, quality management, radiation protection and documentation). Furthermore, radiologists should take responsibility for the definition and compliance with the legal requirements regarding all radiological imaging, especially if non-radiologists have to be trained in the use of imaging technology for guidance of therapy.”

2. Quality assurance and service standards needs to be established; “Performing IGT necessitates specific quality management tools for establishing standards and maintaining levels of excellence…. A European task force group on IGT might be necessary to further develop certification guidelines and establish requirements for IGT practice according to known standards, focused on common recommendations and certification guidelines.”

3. Controlling the process of introducing new medical devices into this niche-market: “IGT research can be broadly divided into two categories, target specific research (e.g. the type of tumour or vascular lesion by imaging biomarkers) and technical research (e.g. evaluation of a new device or procedure). Understanding the efficacy and application of new and emerging technologies is a critical first step, which then leads to target-specific research. The focus of this research is aimed at understanding when, where and in whom the therapy can provide clear clinical benefit and how to use IGT in conjunction with, or as an alternative to, more established therapies. This also clearly includes research on the development and implementation of imaging biomarkers, defined as objectively measured indicators of normal biological processes, pathological changes, or responses to a therapeutic intervention [9]…..

4. An unusual remark is made in respect to the way new devices are introduced: “Clinical specialists who lack the knowledge and expertise required to champion IGT and who are often already over-committed in pursuing their own research goals often dominate committees in control of other funding streams….”

5. Clear recognition that “health-care costs” is of outmost importance: “Demonstration of the cost effectiveness of IGT methods of treatment and targeting with formal quantification of financial as well as patient benefit would encourage their wider adoption. In a broad perspective, health technology assessment (HTA) might be the way for the systematic evaluation of health-relevant IGT procedures and methods, the effectiveness, safety and economic viability of a health intervention, as well as its social, ethical, legal and organisational effects; and for providing a basis for decisions in the health system.”

 References

1.

Solomon SB, Silverman SG (2010) Imaging in interventional oncology. Radiology 257(3):624–40PubMedCrossRef

2.

Levy MA, Rubin DL (2011) Current and future trends in imaging informatics for oncology. Cancer J 17(4):203–10PubMedCrossRef

3.

Council Directive 97/43 Euratom, on health protection of individuals against the dangers of ionizing radiation in relation to medical exposure, and repealing Directive 84/466 Euratom, 1997

4.

DIMOND. Measures for optimising radiological information and dose in digital imaging and interventional radiology. European Commission. Fifth Framework Programme. 1998–2002

5.

SENTINEL. Safety and efficacy for new techniques and imaging using new equipment to support European legislation. European Coordination Action. 2005–2007

6.

http://www.sirweb.org/about-us/IRSocietiesAroundTheWorld.shtml

7.

UNSCEAR (2000) Sources and effects of ionising radiation. United Nations Scientific Committee on the Effects of Atomic Radiation Report to the General Assembly with Scientific Annexes

8.

The 2007 recommendations of the international commission on radiological protection

9.

European Society of Radiology (2010) White paper on imaging biomarkers. Insights Imaging 1(2):42–45CrossRef

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e-Recognition via Friction-free Collaboration over the Internet: “Open Access to Curation of Scientific Research”

Curator: Aviva Lev-Ari, PhD, RN

Journal Site Statistics UPDATED on 3/5/2014

Scientific Journal Site Statistics

Date

Views to Date

# of articles

NIH Clicks

Nature Clicks

6/24/2013

 199,857

 1,034

 1,275

 661

 7/29/2013  217,356  1,138  1,389  705
 12/1/2013  287,645  1,428  1,676  828
 2/09/2014  325,039  1,665  1,793  892

 3/05/2014  338,938  1,717  1,830  965
 4/05/2014        

Top Authors for all days ending 2014-03-05 (Summarized)

AUTHOR ID

VIEWS

2012pharmaceutical

108,048

larryhbern

47,682

tildabarliya

18,998

Dr. Sudipta Saha

14,221

Dror Nir

9,855

sjwilliamspa

9,347

ritusaxena

9,339

aviralvatsa

4,917

zraviv06

2,654

Demet Sag, Ph.D., CRA, GCP

2,355

anamikasarkar

2,210

pkandala

1,855

zs22

1,519

Alan F. Kaul, PharmD., MS, MBA, FCCP

1,363

megbaker58

1,048

Aashir Awan, Phd

831

jdpmdphd

401

UPDATED on 10/14/2013 

Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation

UPDATED on 4/8/2013

This article has three parts.

Part 1,  presents a pioneering experience in Curation of Scientific Research of three forms:

Part 2, presents Views of two Curators on the transformation of Scientific Publishing and the functioning of the Scientific AGORA (market place in the Ancient Greek CIty of Athena).

Part 3, presents the

“Beall’s list” a blacklist of “predatory” journals: Scientific Articles to be Accepted for Publications followed by a Bill to Pay for been Published

Part One

e-Recognition for Author Views is presented below of a pioneering launch of the ONE and ONLY web-based Open Access Online Scientific Journal on frontiers in Biomedical Technologies, Genomics, Biological SciencesHealthcare Economics, Pharmacology, Pharmaceutical & Medicine.

Friction-free Collaboration over the Internet: An Equity Sharing Venture for “Open Access to Curation of Scientific Research” launched THREE TYPES of Scientific Research Sharing

Type 1:

“Open Access to Curation of Scientific Research - Online Scientific Journal

 http://pharmaceuticalintelligence.com

The venture, Leaders in Pharmaceutical Business Intelligence, operates as an online scientific intellectual EXCHANGE – an Open Access Online Scientific Journal for curation and reporting on frontiers in Biomedical, Genomics, Biological SciencesHealthcare Economics, Pharmacology, Pharmaceutical & Medicine. The website,  http://pharmaceuticalintelligence.com , is a scientific, medical and business multi expert authoring environment  in several domains of  LIFE SCIENCES, PHARMACEUTICAL, HEALTHCARE & MEDICINE INDUSTRIES.

http://pharmaceuticalintelligence.com/open-access-scientific-journal/about/

http://pharmaceuticalintelligence.com/contributors-biographies/

http://pharmaceuticalintelligence.com/contributors-biographies/aviva-lev-ari/

Our organic in growth ONTOLOGY includes ~ 90 Research Categories, i.e.,

  •  Advanced Drug Manufacturing Technology
  •  Alzheimer’s Disease
    •  Etiology
    •  Medical Device Therapies for Altzheimer’s disease
    •  Pharmacotherapy
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  •  BioSimilars
  •  Bone Disease and Musculoskeletal Disease
  •  CANCER BIOLOGY & Innovations in Cancer Therapy
  •  Cancer Prevention: Research & Programs
  •  Cardiovascular Pharmaceutical Genomics
  •  Cell Biology, Signaling & Cell Circuits
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  •  Chemical Biology and its relations to Metabolic Disease
  •  Chemical Genetics
  •  Coagulation Therapy and Internal Bleeding
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  •  Disease Biology, Small Molecules in Development of Therapeutic Drugs
  •  Drug Delivery Platform Technology
  •  Ecosystems & Industrial Concentration in the Medical Device Sector
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    •  Massachusetts Niche Suppliers and National Leaders
  •  FDA Regulatory Affairs
    •  FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning – GCP, GLP, ISO 14155
    •  ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics
  •  Frontiers in Cardiology
    •  Medical Devices
      •  Stents & Tools
      •  Valves & Tools
    •  Pharmacotherapy of Cardiovascular Disease
      •  HTN
      •  HTN in Youth
      •  Resident-cell-based
    •  Procedures
      •  Aortic Valve: TAVI, TAVI vs Open Heart Surgery
      •  CABG
      •  Mitral Valve: Repair and Replacement
      •  PCI
      •  Renal Denervation
  •  Genome Biology
  •  Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics
  •  Genomic Testing: Methodology for Diagnosis
  •  Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics
  •  Health Economics and Outcomes Research
  •  Health Law & Patient Safety
  •  HealthCare IT
  •  Human Immune System in Health and in Disease
  •  Human Sensation and Cellular Transduction: Physiology and Therapeutics
  •  Imaging-based Cancer Patient Management
  •  Infectious Disease & New Antibiotic Targets
  •  Innovations in Neurophysiology & Neuropsychology
  •  International Global Work in Pharmaceutical
  •  Interviews with Scientific Leaders
  •  Liver & Digestive Diseases Research
  •  Medical and Population Genetics
  •  Medical Devices R&D Investment
  •  Medical Imaging Technology, Image Processing/Computing, MRI
  •  Metabolomics
  •  Molecular Genetics & Pharmaceutical
  •  Nanotechnology for Drug Delivery
  •  Nitric Oxide in Health and Disease
  •  Nutrigenomics
  •  Nutrition
    •  Nutritional Supplements: Atherogenesis, lipid metabolism
  •  Origins of Cardiovascular Disease
    •  Atherogenic Processes & Pathology
  •  Pain: Etiology, Genetics & Innovations in Treatment
  •  Patient Experience: Personal Memories of Invasive Medical Intervantion
  •  Personalized Medicine & Genomic Research
  •  Pharmaceutical Analytics
  •  Pharmaceutical Industry Competitive Intelligence
  •  Pharmaceutical R&D Investment
  •  Pharmacogenomics
  •  Population Health Management, Genetics & Pharmaceutical
  •  Population Health Management, Nutrition and Phytochemistry
  •  Proteomics
  •  Regulated Clinical Trials: Design, Methods, Components and IRB related issues
  •  Reproductive Biology & Bio Instrumentation
  •  Scientist: Career considerations
  •  Statistical Methods for Research Evaluation
  •  Stem Cells for Regenerative Medicine
  •  Systemic Inflammatory Response Related Disorders
  •  Technology Transfer: Biotech and Pharmaceutical

Open Access Online Scientific Journal Site Statistics: Site Launched in February 2012, first post Published on 4/30/2012

http://pharmaceuticalintelligence.com/2012/04/30/93/

On 4/2/2013, less then one year since the first post was published as a CURATED article, we achieved the following results:

150,339 Views

766 Posts

87 Categories

3,908 Tags

3,706 Comments

Referrer Views
Search Engines 43,238
linkedin.com 9,865
Google 2,171
Facebook 1,591

URL    Clicks

ncbi.nlm.nih.gov    1,014

nature.com    513

genomeweb.com    215

medicregister.com    177

sciencedirect.com    156

pnas.org    145

nejm.org    125

Author        Views

2012pharmaceutical        51,214 <<<<—- Aviva

larryhbern    Following    19,819

tildabarliya        6,924

Dr. Sudipta Saha    Following    6,859

ritusaxena    Following    5,795

Dror Nir    Follow    4,190

sjwilliamspa    Following    3,369

aviralvatsa    Following    3,216

anamikasarkar    Following    1,682

pkandala    Follow    1,595

Alan F. Kaul, PharmD., MS, MBA, FCCP    Following    1,068

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Type 2:

“Open Access to Curation of Scientific Research” – BioMed e-Books Series

http://pharmaceuticalintelligence.com/biomed-e-books/

Launch on Amazon-KINDLE, KINDLE FIRE: 2013, 2014

Eight Authors: 40 articles — Any day on Amazon’s e-Books List

Volume 1: Seven Authors, 29 articles

Volume 2: Six Authors, 28 articles

Volume 3: Eight Authors, 43 articles

Volume 1: Eight Authors, 154 articles [65 posts by Larry, 56 posts by Aviva]

Volume 2: [Work-in-Progress]

Volume 3: [Work-in-Progress]

Type 3:

“Open Access to Curation of Scientific Research” - Scoop.it!

medical imaging of the heart

Cardiovascular Disease: Pharmaco-therapy

Drug Therapy for Heart Disease 

Curated by Aviva Lev-Ari, PhD, RN

“Open Access to Curation of Scientific Research” – Articles on this Topic covered in http://pharmaceuticalintelligence.com

“Open Access Publishing” is becoming the mainstream model: “Academic Publishing” has changed Irrevocably

http://pharmaceuticalintelligence.com/2012/10/25/open-access-publishing-is-becoming-the-mainstream-model-academic-publishing-has-changed-irrevocably/

Digital Publishing Promotes Science and Popularizes it by Access to Scientific 

Open-Access Publishing in Genomics

http://pharmaceuticalintelligence.com/2013/01/14/open-access-publishing-in-genomics/

Part Two

Comprehensive analysis of the phenomena of “Open Access to Curation of Scientific Research” is presented below by two curated articles:

Views of Thomas Lin, NYT, 1/17/2012 - Cracking Open the Scientific Process

A GLOBAL FORUM Ijad Madisch, 31, a virologist and computer scientist, founded ResearchGate, a Berlin-based social networking platform for scientists that has more than 1.3 million members.
Published: January 16, 2012 

The New England Journal of Medicine marks its 200th anniversary this year with a timeline celebrating the scientific advances first described in its pages: the stethoscope (1816), the use of ether foranesthesia (1846), and disinfecting hands and instruments before surgery (1867), among others.

Timothy Fadek for The New York Times

LIKE, FOLLOW, COLLABORATE A staff meeting at ResearchGate. The networking site, modeled after Silicon Valley startups, houses 350,000 papers.

For centuries, this is how science has operated — through research done in private, then submitted to science and medical journals to be reviewed by peers and published for the benefit of other researchers and the public at large. But to many scientists, the longevity of that process is nothing to celebrate.

The system is hidebound, expensive and elitist, they say. Peer review can take months, journal subscriptions can be prohibitively costly, and a handful of gatekeepers limit the flow of information. It is an ideal system for sharing knowledge, said the quantum physicist Michael Nielsen, only “if you’re stuck with 17th-century technology.”

Dr. Nielsen and other advocates for “open science” say science can accomplish much more, much faster, in an environment of friction-free collaboration over the Internet. And despite a host of obstacles, including the skepticism of many established scientists, their ideas are gaining traction.

Open-access archives and journals like arXiv and the Public Library of Science (PLoS) have sprung up in recent years. GalaxyZoo, a citizen-science site, has classified millions of objects in space, discovering characteristics that have led to a raft of scientific papers.

On the collaborative blog MathOverflow, mathematicians earn reputation points for contributing to solutions; in another math experiment dubbed the Polymath Project, mathematicians commenting on the Fields medalistTimothy Gower’s blog in 2009 found a new proof for a particularly complicated theorem in just six weeks.

And a social networking site called ResearchGate — where scientists can answer one another’s questions, share papers and find collaborators — is rapidly gaining popularity.

Editors of traditional journals say open science sounds good, in theory. In practice, “the scientific community itself is quite conservative,” said Maxine Clarke, executive editor of the commercial journal Nature, who added that the traditional published paper is still viewed as “a unit to award grants or assess jobs and tenure.”

Dr. Nielsen, 38, who left a successful science career to write “Reinventing Discovery: The New Era of Networked Science,” agreed that scientists have been “very inhibited and slow to adopt a lot of online tools.” But he added that open science was coalescing into “a bit of a movement.”

On Thursday, 450 bloggers, journalists, students, scientists, librarians and programmers will converge on North Carolina State University (and thousands more will join in online) for the sixth annual ScienceOnline conference. Science is moving to a collaborative model, said Bora Zivkovic, a chronobiology blogger who is a founder of the conference, “because it works better in the current ecosystem, in the Web-connected world.”

Indeed, he said, scientists who attend the conference should not be seen as competing with one another. “Lindsay Lohan is our competitor,” he continued. “We have to get her off the screen and get science there instead.”

Facebook for Scientists?

“I want to make science more open. I want to change this,” said Ijad Madisch, 31, the Harvard-trained virologist and computer scientist behind ResearchGate, the social networking site for scientists.

Started in 2008 with few features, it was reshaped with feedback from scientists. Its membership has mushroomed to more than 1.3 million, Dr. Madisch said, and it has attracted several million dollars in venture capital from some of the original investors of Twitter, eBay and Facebook.

A year ago, ResearchGate had 12 employees. Now it has 70 and is hiring. The company, based in Berlin, is modeled after Silicon Valley startups. Lunch, drinks and fruit are free, and every employee owns part of the company.

The Web site is a sort of mash-up of Facebook, Twitter and LinkedIn, with profile pages, comments, groups, job listings, and “like” and “follow” buttons (but without baby photos, cat videos and thinly veiled self-praise). Only scientists are invited to pose and answer questions — a rule that should not be hard to enforce, with discussion threads about topics like polymerase chain reactions that only a scientist could love.

Scientists populate their ResearchGate profiles with their real names, professional details and publications — data that the site uses to suggest connections with other members. Users can create public or private discussion groups, and share papers and lecture materials. ResearchGate is also developing a “reputation score” to reward members for online contributions.

ResearchGate offers a simple yet effective end run around restrictive journal access with its “self-archiving repository.” Since most journals allow scientists to link to their submitted papers on their own Web sites, Dr. Madisch encourages his users to do so on their ResearchGate profiles. In addition to housing 350,000 papers (and counting), the platform provides a way to search 40 million abstracts and papers from other science databases.

In 2011, ResearchGate reports, 1,620,849 connections were made, 12,342 questions answered and 842,179 publications shared. Greg Phelan, chairman of the chemistry department at the State University of New York, Cortland, used it to find new collaborators, get expert advice and read journal articles not available through his small university. Now he spends up to two hours a day, five days a week, on the site.

Dr. Rajiv Gupta, a radiology instructor who supervised Dr. Madisch at Harvard and was one of ResearchGate’s first investors, called it “a great site for serious research and research collaboration,” adding that he hoped it would never be contaminated “with pop culture and chit-chat.”

Mike Peel

EVOLUTION Michael Nielsen, a quantum physicist, says that as online tools slowly catch on, open science is coalescing into “a bit of a movement.”

Travis Dove for The New York Times

COME TOGETHER Bora Zivkovic, a chronobiology blogger, is a founder of  the ScienceOnline conference.

Dr. Gupta called Dr. Madisch the “quintessential networking guy — if there’s a Bill Clinton of the science world, it would be him.”

The Paper Trade

Dr. Sönke H. Bartling, a researcher at the German CancerResearch Center who is editing a book on “Science 2.0,” wrote that for scientists to move away from what is currently “a highly integrated and controlled process,” a new system for assessing the value of research is needed. If open access is to be achieved through blogs, what good is it, he asked, “if one does not get reputation and money from them?”

Changing the status quo — opening data, papers, research ideas and partial solutions to anyone and everyone — is still far more idea than reality. As the established journals argue, they provide a critical service that does not come cheap.

“I would love for it to be free,” said Alan Leshner, executive publisher of the journal Science, but “we have to cover the costs.” Those costs hover around $40 million a year to produce his nonprofit flagship journal, with its more than 25 editors and writers, sales and production staff, and offices in North America, Europe and Asia, not to mention print and distribution expenses. (Like other media organizations, Science has responded to the decline in advertising revenue by enhancing its Web offerings, and most of its growth comes from online subscriptions.)

Similarly, Nature employs a large editorial staff to manage the peer-review process and to select and polish “startling and new” papers for publication, said Dr. Clarke, its editor. And it costs money to screen for plagiarism and spot-check data “to make sure they haven’t been manipulated.”

Peer-reviewed open-access journals, like Nature Communications and PLoS One, charge their authors publication fees — $5,000 and $1,350, respectively — to defray their more modest expenses.

The largest journal publisher, Elsevier, whose products include The Lancet, Cell and the subscription-based online archive ScienceDirect, has drawn considerable criticism from open-access advocates and librarians, who are especially incensed by its support for the Research Works Act, introduced in Congress last month, which seeks to protect publishers’ rights by effectively restricting access to research papers and data.

In an Op-Ed article in The New York Times last week,Michael B. Eisen, a molecular biologist at the University of California, Berkeley, and a founder of the Public Library of Science, wrote that if the bill passes, “taxpayers who already paid for the research would have to pay again to read the results.”

In an e-mail interview, Alicia Wise, director of universal access at Elsevier, wrote that “professional curation and preservation of data is, like professional publishing, neither easy nor inexpensive.” And Tom Reller, a spokesman for Elsevier, commented on Dr. Eisen’s blog, “Government mandates that require private-sector information products to be made freely available undermine the industry’s ability to recoup these investments.”

Mr. Zivkovic, the ScienceOnline co-founder and a blog editor for Scientific American, which is owned by Nature, was somewhat sympathetic to the big journals’ plight. “They have shareholders,” he said. “They have to move the ship slowly.”

Still, he added: “Nature is not digging in. They know it’s happening. They’re preparing for it.”

Science 2.0

Scott Aaronson, a quantum computing theorist at the Massachusetts Institute of Technology, has refused to conduct peer review for or submit papers to commercial journals. “I got tired of giving free labor,” he said, to “these very rich for-profit companies.”

Dr. Aaronson is also an active member of online science communities like MathOverflow, where he has earned enough reputation points to edit others’ posts. “We’re not talking about new technologies that have to be invented,” he said. “Things are moving in that direction. Journals seem noticeably less important than 10 years ago.”

Dr. Leshner, the publisher of Science, agrees that things are moving. “Will the model of science magazines be the same 10 years from now? I highly doubt it,” he said. “I believe in evolution.

“When a better system comes into being that has quality and trustability, it will happen. That’s how science progresses, by doing scientific experiments. We should be doing that with scientific publishing as well.”

Matt Cohler, the former vice president of product management at Facebook who now represents Benchmark Capital on ResearchGate’s board, sees a vast untapped market in online science.

“It’s one of the last areas on the Internet where there really isn’t anything yet that addresses core needs for this group of people,” he said, adding that “trillions” are spent each year on global scientific research. Investors are betting that a successful site catering to scientists could shave at least a sliver off that enormous pie.

Dr. Madisch, of ResearchGate, acknowledged that he might never reach many of the established scientists for whom social networking can seem like a foreign language or a waste of time. But wait, he said, until younger scientists weaned on social media and open-source collaboration start running their own labs.

“If you said years ago, ‘One day you will be on Facebook sharing all your photos and personal information with people,’ they wouldn’t believe you,” he said. “We’re just at the beginning. The change is coming.”

 SOURCE:

Views of Célya Gruson-Daniel, October 29, 2012, MyScienceWork

Monday, October 29, 2012 Célya Gruson-Daniel
The Internet now makes it possible to publish and share billions of data items every day, accessible to over 2 billion people worldwide.  This mass of information makes it difficult, when searching, to extract the relevant and useful information from the background noise. It should be added that these searches are time-consuming and can take much longer than the time we actually have to spend on them. Today, Google and specialized search engines such as Google Scholar are based on established algorithms. But are these algorithms sufficiently in line with users’ needs? What if the web needed a human brain to select and put forward the relevant information and not just the information based on “popularity” and lexical and semantic operations?

This article is a translation of “Science et curation : nouvelle pratique du Web 2.0” available at:http://blog.mysciencework.com/2012/02/03/science-et-curation-nouvelle-pratique-du-web-2-0.html It was translated from French into English by Mayte Perea López.

Curation on the World Wide Web ©Beboy-Fotolia

Web 2.0: New practices, new uses

To address this need, human intermediaries, empowered by the participatory wave of web 2.0, naturally started narrowing down the information and providing an angle of analysis and some context. They are bloggers, regular Internet users or community managers – a new type of profession dedicated to the web 2.0. A new use of the web has emerged, through which the information, once produced, is collectively spread and filtered by Internet users who create hierarchies of information. This “popularization of the web”therefore paves the way to a user-centered Internet that plays a more active role in finding means to improve the dissemination of information and filter it with more relevance. Today, this new practice has also been categorized and is known as curation.

The term “curation” was borrowed from the world of fine arts. Curators are responsible for the exhibitions held in museums and galleries. They build these exhibitions and act as intermediaries between the public and works of art. In contemporary art, the curator’s role is also to interpret works of art and discover new artists and trends of the moment. In a similar way on the web, the tasks performed by content curators include the search, selection, analysis, editorial work and dissemination of information. Curators can also share online the most relevant information on a specific subject. Instead of acting as mere echo chambers, they provide some context for their searches. For example, they address niche topics and themes that do not stand out in a traditional search. They prioritize the information and are able to find new means of presenting it, new types of visualizationTheir role is, therefore, to find new formats, faster and more direct means of consultation for Internet users, in a context in which the time we spend reading the information is more and more limited. Curation on the web has a social and relational dimension that plays a central role in the curator’s work. Anyone can act as a curator and personalize information, providing an angle that he or she invites us to discover. This means that curation can be carried out by individuals who do not have an institutional footing. The expression “powered by people” exemplifies this possibility of democratizing information searches.

The world of scientific research and culture is no exception to this movement. The web 2.0 offers the scientific community and its surrounding spheres the opportunity to discover new tools that transform practices and uses, not only of researchers, but also of all the actors of scientific and technical culture (STC).

©Zothen-Fotolia

Curation: an Essential Practice to Manage “Open Science”

The web 2.0 gave birth to new practices motivated by the will to have broader and faster cooperation in a more free and transparent environment. We have entered the era of an “open” movement: “open data”, “open software”, etc. In science, expressions like “open access” (to scientific publications and research results) and “open science” are used more and more often.

The concept of “open science” emerged from the web and created bigger and bigger niches all around the planet. Open science and its derivatives such as open access make us dream of an era of open, collective expertise and innovation on an international scale. This catalyst in the field of science is only possible on one condition: that it be accompanied by the emergence of a reflection on the new practices and uses that are essential to its conservation and progress. Sharing information and data at the international level is very demanding in terms of management and organization. As a result, curation has established itself in the realm of science and technology, both in the research community and in the world of scientific and technical culture.

Curation: Collaborative Bibliographic Management for the Researcher 2.0

In the world of research, curation appears as a logical extension of the literature review and bibliographic search, the pillars of a researcher’s work. Curation on the web has brought a new dimension to this work of organizing and prioritizing information. It makes it easier for researchers to collaborate and share, while also bringing to light some works that had previously remained in the shadows.

Mendeley and Zotero are both search and bibliographic management tools that assist you in the creation of an online library. Thus, it is possible to navigate in this mass of bibliographic data, referenced by the researcher, through multiple gateways: keywords, authors’ names, date of publication, etc. In addition, these programs make it possible to generate automatically article bibliographies in the formats specified by each scientific journal. What is new about these tools, apart from the “logistical” aid they provide, is that they are based on collaboration and sharing. Mendeley and Zotero let you create private or public groups. These groups make it possible to share a bibliography with other researchers. They also give access to discussion forums that are useful for sharing with international researchers. Other tools like EndNote and Papersexist, but these paid softwares are less collaborative.

New platforms, real scientific social networks, have also appeared. The leading platform ResearchGate was founded in 2008 and now counts 1.9 million users (august 2012). It is an online search platform, but it is used above all for social interaction. Researchers can create a profile and discussion groups, make their work available online, job hunt, etc. Other professional social networks for researchers have emerged, among them MyScienceWork, which is devoted to open access.

Curation, in the era of open science, accelerates the dissemination of information and provides access to the most relevant parts. Post-publication comments add value to the content. Apart from the benefits for the community, these new practices change the role of researchers in society by offering them new public spaces for expression. Curation on the web opens the way towards the development of an e-reputation and a new form of celebrity in the world of international science. It gives everyone the opportunity to show the cornerstones of their work in the same way that the research notebooks of Hypothèses.orgwere used in Humanities and Social Sciences. This system based on the dual role of “observer/observed” may also impose limits on researchers who would have to be more thorough in the choice of the articles they list.

Have we entered the era of the “researcher 2.0”? Undoubtedly, even if it is still limited to a small group of people. The tools described above are widely used for bibliographic management but their collaborative function is still less used. It is difficult to change researchers’ practices and attitudes. To move from a closed science to an open science in a world of cutthroat competition, researchers will have to grope their way along. These new means of sharing are still sometimes perceived as a threat to the work of researchers or as an excessively long and tedious activity.

Curation and Scientific and Technical Culture: Creating Hybrid Networks

Another area, where there are most likely fewer barriers, is scientific and technical culture. This broad term involves different actors such as associations, companies, universities’ communication departments, CCSTI (French centers for scientific, technical and industrial culture), journalists, etc. A number of these actors do not limit their work to popularizing the scientific data; they also consider they have an authentic mission of “culturing” science. The curation practice thus offers a better organization and visibility to the information. The sought-after benefits will be different from one actor to the next. University communication departments are using the web 2.0 more and more to promote their values; this is the case, for example, for the FrenchUniversité Paris 8. For companies, curation offers the opportunity to become a reference on the themes related to their corporate identity. MyScienceWork, for example, began curating three collections surrounding the key themes of its project. The key topics of its identity are essentially open accessnew uses and practices of the web 2.0 in the world of science and “women in science”. It is essential to keep abreast of the latest news coming from large institutions and traditional media, but also to take into account bloggers’ articles and links that offer a different viewpoint.

Some tools have also been developed in order to meet the expectations of these various users. Pearltreesand Scoopit are non-specialized curation tools that are widely used by the world of Scientific and Technical Culture. Pearltrees offers a visual representation in which each listed page is presented as a pearl connected to the others through branches. The result: a prioritized data tree. These mindmaps can be shared with one’s contacts. A good example of this is the work done by Sébastien Freudenthal, who uses this tool on a daily basis and offers rich content listed by theme in the field of Sciences and Web. Scoopit offers a more traditional presentation with a nice page layout that looks like a magazine. It enables you to list articles quickly and almost automatically, thanks to a plugin, and also to share them. A special tool for the “world” of Technical and Scientific Culture is the social network of scientific culture Knowtex that, in addition to its referencing and links assessment functions, seeks to create a space interconnecting journalists, artists, communicators, designers, bloggers, researchers, etc.

These different tools are used on a daily basis by various actors of technical and scientific culture, but also by researchers, teachers, etc. They gather these communities around a shared practice and favor multiple conversations. The development of these hybrid networks is surely a cornerstone in the building of open science, encouraging the creation of new ties between science and society that go beyond the traditional geographical limits.

Un grand merci à Antoine Blanchard pour sa participation et relecture de l’article.

Find out more:

« Curation is the new research, »… et le nouveau média, Benoit Raphael, 2011http://benoitraphael.com/2011/01/17/curation-is-the-new-search/

La curation : la révolution du webjournalisme?, non-fiction.fr http://www.nonfiction.fr/article-4158-la_curation__la_revolution_du_webjournalisme_.htm

La curation : les 10 raisons de s’y intéresser, Pierre Tran http://pro.01net.com/editorial/529947/la-curation-les-10-raisons-de-sy-interesser/

Curation : quelle valeur pour les entreprises, les médias, et sa « marque personnelle »?, Marie-Laure Vie http://marilor.posterous.com/curation-et-marketing-de-linformation

Cracking Open the Scientific Process, Thomas Lin, New York Times http://www.nytimes.com/2012/01/17/science/open-science-challenges-journal-tradition-with-web-collaboration.html?_r=4&pagewanted=1

La « massification » du web transforme les relations sociales, Valérie Varandat, INRIA http://www.inria.fr/actualite/actualites-inria/internet-du-futur

Internet a révolutionné le métier de chercheur, AgoraVoxhttp://www.agoravox.fr/actualites/technologies/article/internet-a-revolutionne-le-metier-103514

Gérer ses références numériques, Université de Genèvehttp://www.unige.ch/medecine/udrem/Unit/actualites/biblioManager.html

Notre liste Scoop-it : Scientific Social Network, MyScienceWork

SOURCE:

In French:

Summary

This article has two parts, the first presents a pioneering experience in Curation of Scientific Research in an Open Access Online Scientific Journal,  in a BioMed e-Books Series and in curation of a Scoop.it! Journal on Medical Imaging.

The second Part, presents Views of two Curators on the transformation of Scientific Publishing and the functioning of the Scientific AGORA (market place in the Ancient Greek CIty of Athena).

The CHANGES described above are irrevocable and foster progress of civilization by provision of ACCESS to the Scientific Process and Resources via collaboration among peers.

Part Three

SOURCE:

http://www.nytimes.com/2013/04/08/health/for-scientists-an-exploding-world-of-pseudo-academia.html?pagewanted=1&_r=0&emc=eta1 

Scientific Articles Accepted (Personal Checks, Too)

Kevin Moloney for The New York Times

Jeffrey Beall, a research librarian at the University of Colorado at Denver, has developed a blacklist of “predatory” journals.

By 

Published: April 7, 2013

The scientists who were recruited to appear at a conference called Entomology-2013 thought they had been selected to make a presentation to the leading professional association of scientists who study insects.

But they found out the hard way that they were wrong. The prestigious, academically sanctioned conference they had in mind has a slightly different name: Entomology 2013 (without the hyphen). The one they had signed up for featured speakers who were recruited by e-mail, not vetted by leading academics. Those who agreed to appear were later charged a hefty fee for the privilege, and pretty much anyone who paid got a spot on the podium that could be used to pad a résumé.

“I think we were duped,” one of the scientists wrote in an e-mail to the Entomological Society.

Those scientists had stumbled into a parallel world of pseudo-academia, complete with prestigiously titled conferences and journals that sponsor them. Many of the journals and meetings have names that are nearly identical to those of established, well-known publications and events.

Steven Goodman, a dean and professor of medicine at Stanford and the editor of the journal Clinical Trials, which has its own imitators, called this phenomenon “the dark side of open access,” the movement to make scholarly publications freely available.

The number of these journals and conferences has exploded in recent years as scientific publishing has shifted from a traditional business model for professional societies and organizations built almost entirely on subscription revenues to open access, which relies on authors or their backers to pay for the publication of papers online, where anyone can read them.

Open access got its start about a decade ago and quickly won widespread acclaim with the advent of well-regarded, peer-reviewed journals like those published by the Public Library of Science, known as PLoS. Such articles were listed in databases like PubMed, which is maintained by the National Library of Medicine, and selected for their quality.

But some researchers are now raising the alarm about what they see as the proliferation of online journals that will print seemingly anything for a fee. They warn that nonexperts doing online research will have trouble distinguishing credible research from junk. “Most people don’t know the journal universe,” Dr. Goodman said. “They will not know from a journal’s title if it is for real or not.”

Researchers also say that universities are facing new challenges in assessing the résumés of academics. Are the publications they list in highly competitive journals or ones masquerading as such? And some academics themselves say they have found it difficult to disentangle themselves from these journals once they mistakenly agree to serve on their editorial boards.

The phenomenon has caught the attention of Nature, one of the most competitive and well-regarded scientific journals. In a news report published recently, the journal noted “the rise of questionable operators” and explored whether it was better to blacklist them or to create a “white list” of those open-access journals that meet certain standards. Nature included a checklist on “how to perform due diligence before submitting to a journal or a publisher.”

Jeffrey Beall, a research librarian at the University of Colorado in Denver, has developed his own blacklist of what he calls “predatory open-access journals.” There were 20 publishers on his list in 2010, and now there are more than 300. He estimates that there are as many as 4,000 predatory journals today, at least 25 percent of the total number of open-access journals.

“It’s almost like the word is out,” he said. “This is easy money, very little work, a low barrier start-up.”

Journals on what has become known as “Beall’s list” generally do not post the fees they charge on their Web sites and may not even inform authors of them until after an article is submitted. They barrage academics with e-mail invitations to submit articles and to be on editorial boards.

One publisher on Beall’s list, Avens Publishing Group, even sweetened the pot for those who agreed to be on the editorial board of The Journal of Clinical Trails & Patenting, offering 20 percent of its revenues to each editor.

One of the most prolific publishers on Beall’s list, Srinubabu Gedela, the director of the Omics Group, has about 250 journals and charges authors as much as $2,700 per paper. Dr. Gedela, who lists a Ph.D. from Andhra University in India, says on his Web site that he “learnt to devise wonders in biotechnology.”

Another Beall’s list publisher, Dove Press, says on its Web site, “There are no limits on the number or size of the papers we can publish.”

Open-access publishers say that the papers they publish are reviewed and that their businesses are legitimate and ethical.

“There is no compromise on quality review policy,” Dr. Gedela wrote in an e-mail. “Our team’s hard work and dedicated services to the scientific community will answer all the baseless and defamatory comments that have been made about Omics.”

But some academics say many of these journals’ methods are little different from spam e-mails offering business deals that are too good to be true.

Paulino Martínez, a doctor in Celaya, Mexico, said he was gullible enough to send two articles in response to an e-mail invitation he received last year from The Journal of Clinical Case Reports. They were accepted. Then came a bill saying he owed $2,900. He was shocked, having had no idea there was a fee for publishing. He asked to withdraw the papers, but they were published anyway.

“I am a doctor in a hospital in the province of Mexico, and I don’t have the amount they requested,” Dr. Martínez said. The journal offered to reduce his bill to $2,600. Finally, after a year and many e-mails and a phone call, the journal forgave the money it claimed he owed.

Some professors listed on the Web sites of journals on Beall’s list, and the associated conferences, say they made a big mistake getting involved with the journals and cannot seem to escape them.

Thomas Price, an associate professor of reproductive endocrinology and fertility at the Duke University School of Medicine, agreed to be on the editorial board of The Journal of Gynecology & Obstetrics because he saw the name of a well-respected academic expert on its Web site and wanted to support open-access journals. He was surprised, though, when the journal repeatedly asked him to recruit authors and submit his own papers. Mainstream journals do not do this because researchers ordinarily want to publish their papers in the best journal that will accept them. Dr. Price, appalled by the request, refused and asked repeatedly over three years to be removed from the journal’s editorial board. But his name was still there.

“They just don’t pay any attention,” Dr. Price said.

About two years ago, James White, a plant pathologist at Rutgers, accepted an invitation to serve on the editorial board of a new journal, Plant Pathology & Microbiology, not realizing the nature of the journal. Meanwhile, his name, photograph and résumé were on the journal’s Web site. Then he learned that he was listed as an organizer and speaker on a Web site advertising Entomology-2013.

“I am not even an entomologist,” he said.

He thinks the publisher of the plant journal, which also sponsored the entomology conference, — just pasted his name, photograph and résumé onto the conference Web site. At this point, he said, outraged that the conference and journal were “using a person’s credentials to rip off other unaware scientists,” Dr. White asked that his name be removed from the journal and the conference.

Weeks went by and nothing happened, he said. Last Monday, in response to this reporter’s e-mail to the conference organizers, Jessica Lincy, who said only that she was a conference member, wrote to explain that the conference had “technical problems” removing Dr. White’s name. On Tuesday, his name was gone. But it remained on the Web site of the journal.

Dr. Gedela, the publisher of the journals and sponsor of the conference, said in an e-mail on Thursday that Dr. Price and Dr. White’s names remained on the Web sites “because of communication gap between the EB member and the editorial assistant,” referring to editorial board members. That day, their names were gone from the journals’ Web sites.

“I really should have known better,” Dr. White said of his editorial board membership, adding that he did not fully realize how the publishing world had changed. “It seems like the Wild West now.”

This article has been revised to reflect the following correction:

Correction: April 8, 2013

An earlier version of this article misstated the name of a city in Mexico that is home to a doctor who sent articles to a pseudo-academic journal. It is Celaya, not Ceyala.

SOURCE:

http://www.nytimes.com/2013/04/08/health/for-scientists-an-exploding-world-of-pseudo-academia.html?pagewanted=1&_r=0&emc=eta1 

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