Optical innovations in surgery.

BACKGROUND: In the past decade, there has been a major drive towards clinical translation of optical and, in particular, fluorescence imaging in surgery. In surgical oncology, radical surgery is characterized by the absence of positive resection margins, a critical factor in improving prognosis. Fluorescence imaging provides the surgeon with reliable and real-time intraoperative feedback to identify surgical targets, including positive tumour margins. It also may enable decisions on the possibility of intraoperative adjuvant treatment, such as brachytherapy, chemotherapy or emerging targeted photodynamic therapy (photoimmunotherapy). METHODS: This article reviews the use of optical imaging for intraoperative guidance and decision-making. RESULTS: Image-guided cancer surgery has the potential to be a powerful tool in guiding future surgical care. Photoimmunotherapy is a theranostic concept (simultaneous diagnosis and treatment) on the verge of clinical translation, and is highlighted as an effective combination of image-guided surgery and intraoperative treatment of residual disease. Multispectral optoacoustic tomography, a technique complementary to optical image-guided surgery, is currently being tested in humans and is anticipated to have great potential for perioperative and postoperative application in surgery. CONCLUSION: Significant advances have been achieved in real-time optical imaging strategies for intraoperative tumour detection and margin assessment. Optical imaging holds promise in achieving the highest percentage of negative surgical margins and in early detection of micrometastastic disease over the next decade.

Real-time near infrared fluorescence (NIRF) intra-operative imaging in ovarian cancer using an α(v)ß(3-)integrin targeted agent.

BACKGROUND: In ovarian cancer, optimal cytoreductive surgery is of the utmost importance for long-term survival. The ability to visualize minuscule tumor deposits is important to ensure complete resection of the tumor. The purpose of our study was to estimate the in vivo sensitivity, specificity and diagnostic accuracy of an intra-operative fluorescence imaging system combined with an α(v)ß(3)-integrin targeted near-infrared fluorescent probe. METHOD: Tumor bearing mice were injected intravenously with a fluorescent probe targeting α(v)ß(3) integrins. Fluorescent spots and non-fluorescent tissue were identified and resected. Standard histopathology and fluorescence microscopy were used as gold-standard for tumor detection. RESULTS: Fifty-eight samples excised with support of intra-operative image-guided surgery were analyzed. The mean target to background ratio was 2.2 (SD 0.5). The calculated sensitivity of the imaging system was 95%, and the specificity was 88% with a diagnostic accuracy of 96.5%. CONCLUSION: Near-infrared image-guided surgery in this model has a high diagnostic accuracy and a fair target to background ratio that supports the development towards clinical translation of α(v)ß(3)-integrin targeted imaging.

Near-infrared fluorescence (NIRF) imaging in breast-conserving surgery: assessing intraoperative techniques in tissue-simulating breast phantoms.

PURPOSE: Breast-conserving surgery (BCS) results in tumour-positive surgical margins in up to 40% of the patients. Therefore, new imaging techniques are needed that support the surgeon with real-time feedback on tumour location and margin status. In this study, the potential of near-infrared fluorescence (NIRF) imaging in BCS for pre- and intraoperative tumour localization, margin status assessment and detection of residual disease was assessed in tissue-simulating breast phantoms. METHODS: Breast-shaped phantoms were produced with optical properties that closely match those of normal breast tissue. Fluorescent tumour-like inclusions containing indocyanine green (ICG) were positioned at predefined locations in the phantoms to allow for simulation of (i) preoperative tumour localization, (ii) real-time NIRF-guided tumour resection, and (iii) intraoperative margin assessment. Optical imaging was performed using a custom-made clinical prototype NIRF intraoperative camera. RESULTS: Tumour-like inclusions in breast phantoms could be detected up to a depth of 21 mm using a NIRF intraoperative camera system. Real-time NIRF-guided resection of tumour-like inclusions proved feasible. Moreover, intraoperative NIRF imaging reliably detected residual disease in case of inadequate resection. CONCLUSION: We evaluated the potential of NIRF imaging applications for BCS. The clinical setting was simulated by exploiting tissue-like breast phantoms with fluorescent tumour-like agarose inclusions. From this evaluation, we conclude that intraoperative NIRF imaging is feasible and may improve BCS by providing the surgeon with imaging information on tumour location, margin status, and presence of residual disease in real-time. Clinical studies are needed to further validate these results.

Bioluminescence as gold standard for validation of optical imaging modalities in peritoneal carcinomatosis animal models.

BACKGROUND: The outcome of cytoreductive surgery in patients with peritoneal carcinomatosis is influenced by incomplete resection as a result of inadequate detection of a tumor, i.e. residual disease. The future perspective of complete resection, made possible by application of intraoperative near-infrared fluorescence imaging (NIRF), led to the development and validation of a bioluminescent colorectal peritoneal carcinomatosis xenograft rat model to act as the gold standard for the evaluation of new optical imaging modalities. METHODS: Twenty nude rats were inoculated intraperitoneally with 2 × 10(6) luciferase-labeled human colorectal tumor cells (HT-29-luc-D6). The peritoneal carcinomatosis index (PCI) was estimated using visual observation (PCI-VO) and VO combined with bioluminescence imaging (PCI-BLI). Subsequently, the BL images were presented, and residual tumor tissue was localized by PCI-BLI scoring and compared with the PCI-VO. RESULTS: BLI revealed additional tumor tissue, confirmed by HE staining, compared to VO alone in 7 out of 8 rats (p < 0.02). CONCLUSION: The developed model turned out to be suitable. The use of BLI for tumor detection was more sensitive compared to VO alone. In this model, BLI significantly detected residual disease, and therefore, BLI can be denominated as the gold standard for the evaluation of optical imaging modalities like NIRF.

Surgeons lack predictive accuracy for anastomotic leakage in gastrointestinal surgery.

BACKGROUND: The dramatic clinical consequences of anastomotic leakage in gastrointestinal surgery can be reduced by a diverting stoma or drainage of the peri-anastomotic area. Currently, the surgeons' clinical judgement is of major importance in decision making, but reliable data of the diagnostic accuracy are lacking. In this prospective clinical study, the surgeons' predictive accuracy for anastomotic leakage was evaluated. MATERIALS AND METHODS: In 191 patients undergoing colorectal resection with anastomosis, the risk for anastomotic leakage was determined by the surgeon on the basis of a visual analogue scale (VAS). This risk assessment was compared to the actual occurrence of anastomotic leakage post-operatively. RESULTS: A total of 26 (13.6%) patients showed anastomotic leakage. The surgeons' median predicted leakage rate was 7.1% in anastomoses >15 cm from the anal verge and 9.5%

Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children.

Quantitative genetic research suggests that reading disability is the quantitative extreme of the same genetic and environmental factors responsible for normal variation in reading ability. This finding warrants a quantitative trait locus (QTL) strategy that compares low versus high extremes of the normal distribution of reading in the search for QTLs associated with variation throughout the distribution. A low reading ability group (N=755) and a high reading group (N=747) were selected from a representative UK sample of 7-year-olds assessed on two measures of reading that we have shown to be highly heritable and highly genetically correlated. The low and high reading ability groups were each divided into 10 independent DNA pools and the 20 pools were assayed on 100 K single nucleotide polymorphism (SNP) microarrays to screen for the largest allele frequency differences between the low and high reading ability groups. Seventy five of these nominated SNPs were individually genotyped in an independent sample of low (N=452) and high (N=452) reading ability children selected from a second sample of 4258 7-year-olds. Nine of the seventy-five SNPs were nominally significant (P<0.05) in the predicted direction. These 9 SNPs and 14 other SNPs showing low versus high allele frequency differences in the predicted direction were genotyped in the rest of the second sample to test the QTL hypothesis. Ten SNPs yielded nominally significant linear associations in the expected direction across the distribution of reading ability. However, none of these SNP associations accounted for more than 0.5% of the variance of reading ability, despite 99% power to detect them. We conclude that QTL effect sizes, even for highly heritable common disorders and quantitative traits such as early reading disability and ability, might be much smaller than previously considered.

Generalist genes and the Internet generation: etiology of learning abilities by web testing at age 10.

A key translational issue for neuroscience is to understand how genes affect individual differences in brain function. Although it is reasonable to suppose that genetic effects on specific learning abilities, such as reading and mathematics, as well as general cognitive ability (g), will overlap very little, the counterintuitive finding emerging from multivariate genetic studies is that the same genes affect these diverse learning abilities: a Generalist Genes hypothesis. To conclusively test this hypothesis, we exploited the widespread access to inexpensive and fast Internet connections in the UK to assess 2541 pairs of 10-year-old twins for reading, mathematics and g, using a web-based test battery. Heritabilities were 0.38 for reading, 0.49 for mathematics and 0.44 for g. Multivariate genetic analysis showed substantial genetic correlations between learning abilities: 0.57 between reading and mathematics, 0.61 between reading and g, and 0.75 between mathematics and g, providing strong support for the Generalist Genes hypothesis. If genetic effects on cognition are so general, the effects of these genes on the brain are also likely to be general. In this way, generalist genes may prove invaluable in integrating top-down and bottom-up approaches to the systems biology of the brain.

Overlap and specificity of genetic and environmental influences on mathematics and reading disability in 10-year-old twins.

BACKGROUND: To what extent do genetic and environmental influences on reading disability overlap with those on mathematics disability? Multivariate genetic research on the normal range of variation in unselected samples has led to a Generalist Genes Hypothesis which posits that the same genes largely affect individual differences in these abilities in the normal range. However, little is known about the etiology of co-morbidity for the disability extremes of reading and mathematics. METHOD: From 2596 pairs of 10-year-old monozygotic and dizygotic twins assessed on a web-based battery of reading and mathematics tests, we selected the lowest 15% on reading and on mathematics. We conducted bivariate DeFries-Fulker (DF) extremes analyses to assess overlap and specificity of genetic and environmental influences on reading and mathematics disability defined by a 15% cut-off. RESULTS: Both reading and mathematics disability are moderately heritable (47% and 43%, respectively) and show only modest shared environmental influence (16% and 20%). There is substantial phenotypic co-morbidity between reading and mathematics disability. Bivariate DF extremes analyses yielded a genetic correlation of .67 between reading disability and mathematics disability, suggesting that they are affected largely by the same genetic factors. The shared environmental correlation is .96 and the non-shared environmental correlation is .08. CONCLUSIONS: In line with the Generalist Genes Hypothesis, the same set of generalist genes largely affects mathematical and reading disabilities. The dissociation between the disabilities occurs largely due to independent non-shared environmental influences.

'Generalist genes' and mathematics in 7-year-old twins.

Mathematics performance at 7 years as assessed by teachers using UK national curriculum criteria has been found to be highly heritable. For almost 3000 pairs of 7-year-old same-sex twins, we used multivariate genetic analysis to investigate the extent to which these genetic effects on mathematics performance overlap with genetic effects on reading and general intelligence (g) as predicted by the 'generalist genes' hypothesis. We found substantial genetic overlap between mathematics and reading (genetic correlation=0.74) and between mathematics and g (0.67). These findings support the 'generalist genes' hypothesis that most of the genes that contribute to individual differences in mathematics are the same genes that affect reading and g. Nonetheless, the genetic correlations are less than unity and about a third of the genetic variance on mathematics is independent of reading and g, suggesting that there are also some genes whose effects are specific to mathematics.