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Nanotheranostics 2022; 6(3): 243-255. [Abstract] [Full text] [PDF]
Nanotheranostics
International Journal of Biological Sciences
International Journal of Medical Sciences
Journal of Cancer
Global reach, higher impact
Theranostics 2018; 8(19):5336-5347. doi:10.7150/thno.27384 This issue
Recommendations for reporting on emerging optical imaging agents to promote clinical approval
Willemieke S. Tummers1,2, Jason M Warram3, Nynke S. van den Berg4, Sarah E. Miller4, Rutger-Jan Swijnenburg2, Alexander L. Vahrmeijer2, Eben L. Rosenthal4
1. Department of Radiology, Molecular Imaging Program, Stanford University, Stanford, CA.
2. Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
3. Department of Otolaryngology, University of Alabama at Birmingham, AL
4. Department of Otolaryngology, Stanford University, Stanford, CA.
✉ Corresponding author: E.L. Rosenthal, MD. Professor of Otolaryngology and Radiology, Ann & John Doerr Medical Director, Stanford Cancer Center, Stanford, CA. Tel: 650 723 4250; Fax: 650 723 2225; E-mail:elredu
This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Tummers WS, Warram JM, van den Berg NS, Miller SE, Swijnenburg RJ, Vahrmeijer AL, Rosenthal EL. Recommendations for reporting on emerging optical imaging agents to promote clinical approval. Theranostics 2018; 8(19):5336-5347. doi:10.7150/thno.27384. Available from https://www.thno.org/v08p5336.htm
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Intraoperative fluorescence imaging is particularly well-suited for surgical applications due to its inherently high sensitivity, resolution, and ability to provide images in real-time. To date, the intraoperative observation of fluorescence has largely been subjective. With the need to show objective evidence in order to demonstrate the benefit of this technique, quantitative data needs to be provided to overseeing regulatory bodies. Standardization of fluorescence imaging protocols would improve reproducibility and minimize inter- and intra-institution variance. This would allow studies to be conducted using the same injection techniques, imaging times, reconstruction methods, and analyses. Here, we provide recommendations for standardized methodologies with the goal of setting a minimum requirement for reporting fluorescence-guided surgery results based on both qualitative and (semi-) quantitative data collection. Clinical trials using fluorescence-guided surgery should present results of three critical elements; 1) intra-operative imaging, 2) specimen mapping and pathology correlation, and 3) target validation. Qualitative analyses should consist of a bright field image, black-and-white fluorescence image, pseudo-colored fluorescence overlay image, and/or heat-map whereby fluorescence signal intensity differences are displayed on a color spectrum. Quantitative analyses should include 1) intraoperative data (consisting of images or video, raw numeric values and ratios); 2) specimen mapping, for correlation of fluorescence with the presence of disease (performed using fresh tissue); and 3) target validation (designed to determine fluorescence intensity relative to receptor density of a specific area). Including the aforementioned methods of both qualitative and quantitative analyses will ensure that trial results are comparable and could be collated in future studies to expedite FDA approval.
Keywords: Optical imaging, fluorescence, clinical trial, standardization, result reporting
An incremental improvement in oncologic surgical outcomes can be obtained by successful identification of visually occult disease and tumor-positive margins during surgery, which will have a significant impact on overall cancer survival. Interest in cancer-specific intraoperative molecular imaging has undergone rapid growth. This substantial interest is not surprising considering the robust potential of the technique to achieve subclinical tumor-detection and improved surgical guidance. Fluorescence-guided surgery (FGS) is particularly well-suited for surgical applications due to its inherently high sensitivity, resolution, and ability to provide images in real-time [1]. In recent years, the number of early phase clinical trials using FGS has drastically risen, and shifted towards the use of dyes emitting in the near-infrared rather than in the visible part of the light spectrum. An example of a commonly used near-infrared fluorescent (NIRF) dye is indocyanine green (ICG). ICG achieves its tumor-targeting through "second window imaging," which is based on the enhanced permeability and retention (EPR) effect [2, 3]. While safe, ICG is a non-specific agent that is rapidly cleared by the liver and excreted in bile. Currently, most strategies use a NIRF dye that is conjugated to a targeting vehicle directed against a tissue of interest, such as a tumor-specific agent, and this combination permits optimal cancer-specific detection [4, 5]. However, human testing using such novel NIRF-guided surgical agents has thus far only been conducted in early phase trials to establish safety and efficacy [6-13]. These trials are unable to show benefit over the current standard-of-care; larger phase II/III trials are needed to demonstrate superiority prior to obtaining regulatory approval and wide-spread adoption into practice. Early stage clinical trials are crucial to providing data to support in vivo application, surgical specimen mapping, and target validation. These three elements should be evaluated using a standardized methodology that can be used to advance these technologies through regulatory pathways into routine clinical use.
Positron emission tomography (PET) imaging represents a clear precedent for the introduction of standardization into FGS. Since its establishment in 1984, numerous articles have been published describing the need for standardization of the technology with regards to clinical application [14-16]. These studies showed that strict standardization of all aspects of imaging and data analysis is required to obtain quantitative, accurate, reliable, precise and reproducible results. Similarly, multiple studies have been performed investigating the concordance of PET results obtained at different institutions [15, 17, 18]. Developing a standardized approach will minimize variability between studies in addition to facilitating the development of multicenter studies, thus allowing for direct comparison of results within and between clinical trials. Moreover, it can potentially allow for future direct translation of results to other centers.
Although often difficult to test in clinical trials, the qualitative representation of fluorescence imaging data is critical, as surgeons make intraoperative decisions based on their own interpretation of images generated and displayed by the imaging device. To be valuable, high-resolution images need to be generated in real-time, without delayed image processing. In many cases, the value and objectivity of qualitative data is questioned, though in the case of FGS its representation is of the utmost importance to the technology's implementation and utility.
Simultaneously, quantitative data plays a key role in the analysis of FGS clinical trials. Currently, quantitative data is difficult to generate as compared to qualitative data, and since FGS is primarily a visual tool for the surgeon, the use of quantitative data has been less emphasized in the first early phase clinical trials. However, with the need to show objective evidence to demonstrate the superiority of FGS techniques, quantitative data should also be provided to the regulatory bodies.
Here, we propose a methodology for reporting results from fluorescence-guided oncologic surgery studies (Figure 1). Our proposed method is based on the minimum requirements for the presented data from all phases of a clinical trial, including intraoperative imaging, ex vivo imaging, and pathologic correlation, which should be represented using both qualitative and quantitative data.
In vivo fluorescence quantification is challenging, since the measured fluorescence depends not only on the concentration of the imaging agent, but on multiple parameters, such as intrinsic autofluorescence of tissue, the sensitivity of the imaging device, the absorption and scattering properties of the tissue, and photobleaching. All these parameters can influence the accuracy of quantification [19-21]. Standardization of quantification in fluorescence imaging protocols would improve reproducibility and minimize inter- and intra-institution variance, and studies should be conducted using the same injection technique, imaging time, reconstruction method, and analysis [14]. Such strategies are critical for reproducibility in multi-institutional clinical trials but are not easy to achieve. Use of phantoms will be beneficial to determine how well individual cameras and centers perform in the technical aspects of image acquisition, data processing, and analysis [22]. In multicenter studies using PET imaging, the submission of a phantom scan is usually required periodically for scanner calibration and reproducibility [23].
Perhaps the largest research effort to quantify fluorescence in vivo has been focused on the measurement of photosensitizer concentration prior to and during photodynamic therapy (PDT) [20, 21, 24, 25]. Because the effect of PDT depends directly on the concentration of sensitizer used, there is a high need for measuring this quantity quickly and noninvasively [20]. Kim et al. described a noninvasive in vivo method to determine fluorophore concentration in neurosurgery using 5-ALA [19]. Using a fiber-optic probe, the fluorophore concentration is calculated from the quantitative fluorescence spectrum, which is the fluorescence emission spectrum corrected for optical attenuation of the tissue, thus quantifying the observed fluorescence [19]. These handheld fiber-optic probes need to simultaneously collect tissue fluorescence and diffuse reflectance spectra in vivo [26]. The method is performed using specific fiber-optic probes that touch the tissue, which requires a separate device in combination with the fluorescence camera for intra-operative navigation. Another complicating factor of this method is the need to identify the optical properties of tissues and the variation of these properties, which are mostly unknown [26].
Standardized assessment of reporting results in fluorescence-guided oncologic surgical trials for all aspects of the clinical trial: intraoperative imaging, ex vivo imaging and pathologic assessment. During the intraoperative assessment, focus should remain on imaging at predetermined timepoints intraoperatively. Ex vivo imaging will ensure exact tumor mapping to correlate imaging results to pathology. During pathologic assessment the focus should be on confirmation of fluorophore targeting to tumor tissue [adapted with permission from [48], copyright 2018].
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Achieving absolute in vivo quantification is unlikely, since the current fluorescence imaging systems are not equipped to generate quantified imaging data, but a semi-quantification of the fluorescence signal should be possible. Similar to PET imaging, where maximum standard uptake values (SUVmax) are calculated based on the administered radioisotope dose and the patient weight, one can also calculate fluorescence signal uptake values by correcting for tissue surface area [27]. In fluorescence imaging, only fluorescence arising from <1 cm depth will contribute to the measured signal. Therefore, signal should be corrected for surface area since corrections either for weight or volume will not necessarily generate a representative value. Consequently, it is recommended for fluorescence imaging to provide standardized reports on surface area-adjusted values where feasibly measured by ex vivo imaging. For example, adjusted from the formula for SUV values, mean fluorescence intensity (MFI) could be calculated as MFIcorrected = fluorescence intensity of tissue of interest / (injected dose/surface area of the tissue) [28].
As described above, quantification of fluorescence signal is still in its infancy. Ultimately, it is expected that this objective measure is going to play a major role in providing evidence of patient benefit. Next to the extensive investments in novel agents and clinical cameras, innovative solutions are being developed for the quantification of fluorescence imaging signals in the ex vivo setting. Several groups are working on the real-time detection of the actual amount and concentration of the fluorescent agent that accumulates in tissues. By scanning part of the tissue or by taking point measurements, the concentration can be determined, leading to exact quantification [19, 29]. Another method to objectify and automate quantification is by machine learning. Here, the software can be trained to identify the fluorescence cut-off value for true-positive fluorescence and true-negative fluorescence. With a learning set, these values can be validated and applied to all patients injected with the same agent and dose [30]. For now, these methods are not commercially available, and further research is required to validate their applicability, but semi-quantification of the fluorescence signal is already possible without these novel devices using methods described below.
Quality control procedures
FGS is intrinsically linked to the sensitivity of the imaging device used. Currently, various imaging systems, ranging from large open-field cameras to minimally-invasive endoscopic cameras, are available for NIRF excitation and emission signal detection during surgery and ex vivo. Consequently, results from different imaging systems are hard to compare. This is one of the main reasons that the FDA primarily reviews combination products, instead of an imaging agent and device separately [31]. This is in contrast to PET agents and scanners, where the implementation of quality control (QC) procedures have led to an established method to verify consistency, linearity, and safety functions of PET scanners. For PET imaging, the National Electrical Manufacturers Association (NEMA) has formulated performance standards, to which manufacturers need to adhere [32]. For fluorescence imaging devices, this is still far from standard practice, with only safety standards currently available. Incorporating documentation on performance testing can help to identify relevant characteristics (e.g., spatial resolution, uniformity, sensitivity, dynamic range), provide guidelines for testing (e.g., phantom material property range/geometry, methods for calculating metrics), and describe viable test methods for the validity of performance characteristics [31].
General aspects of fluorescence data analysis
Ideally, all acquired FGS data should be analyzed for the correlation between imaging results and pathology using a quantitative and qualitative approach.
Targeted agents are usually present in the tissue of interest at nanomolar concentrations, which requires sensitive cameras with low detection thresholds. Analysis of this threshold for different imaging systems and agents is important when evaluating agents for their intended use. If one aims to detect micrometastases, the sensitivity of the camera and the specificity of the agent should both be extremely high. DSouza et al. performed a study to determine the detection limit of various fluorescent imaging systems using dye concentrations in a phantom and showed that devices with higher bit depths, variable electronic gain settings, and background-light correction during acquisition, had the highest sensitivities [33]. Previously, we have shown that small numbers of cancer cells can be detected in optimized ex vivo settings both preclinically (2.4×104 cells) and clinically (< 5 mm) [34].
Quantification parameters
Significant variations can occur when reporting on fluorescence signal intensities since the value remains dependent on the way the images are analyzed. Below we discuss various methods to quantify fluorescence imaging data.
Mean fluorescence intensity
The mean fluorescence intensity (MFI) is a measurement of the fluorescence signal in a region of interest (ROI) divided by the area within that ROI (either in pixels or cm2). The MFI is typically shown in arbitrary units of fluorescence (AU) or total number of photons detected by the device for each pixel, or per cm2. Arbitrary values are generally used for relative, ratiometric quantification to determine the fold difference or change between various samples that are analyzed in parallel. Devices that use a scaled algorithm for determining fluorescence signal also use AU.
The MFI can also be shown in relative fluorescence units (RFU), which is a relative unit of measurement compared to a reference measurement using the same ROI area. In PET imaging a defined background is determined to compare to the SUVmax value in order to determine the presence of increased uptake. As with PET imaging, it may be recommended to use the maximum fluorescence value, since this is independent from an ROI, less observer-dependent and more reproducible compared to the mean value. The primary disadvantage is that a maximum value is more susceptible to noise. Comparing the maximum fluorescence value to that of a set background (Table 1), may be used to correct for this noise.
Tumor-to-background ratio
When addressing the quality of an imaging agent to provide tumor-specific contrast, it has generally been related to a ratio such as tumor-to-background ratio (TBR), signal-to-noise ratio (SNR) or contrast-to-noise ratio (CNR). In the past, studies aimed for a TBR of >2.5, since it was thought that any lower rate was insufficient to identify cancerous tissue intraoperatively [2, 35]. However, an intraoperative TBR of >2.5 is relatively hard to achieve in a clinical setting with currently available agents and imaging systems, although at this TBR the tumor can be clearly distinguished from the surrounding tissue. While a higher signal in the tumor when compared to surrounding tissue is preferred, there are many other variables that contribute to an agent's ability to differentiate normal from diseased tissues. Therefore, it may not be appropriate to identify a specific number as a minimum value before one can determine there is "sufficient contrast". At a minimum, the difference in signal needs to be high enough for the surgeon to differentiate tumor from normal tissue—in our experience a TBR >3.0 in preclinical studies and >1.5 in clinical studies would be appropriate for further studies.
Another important note is that TBR is highly dependent on the dynamic range of the imaging devices used in addition to the variability in properties of the chosen background tissue. The background will greatly influence the TBR value, and currently no guidelines exist regarding an appropriate background for various cancer types. If unrealistically high values of TBR are set as a standard, it is likely that only surrounding tissues with virtually no fluorescence will be candidates for employing these techniques. However, to ensure clinical applicability of the technique, the background tissue is inherently in close proximity of the tumor even when this tissue displays some intensity of fluorescence. For example, in pancreatic cancer surgery, muscle would not be an appropriate background, whereas for head and neck cancer, muscle would be appropriate based on the surgical field of view (Table 1).
Signal-to-noise ratio (SNR)
The SNR is the quotient of the MFI measured in a ROI and the standard deviation (SD) of the signal intensity in a region outside the boundaries of the object being imaged (i.e., a region from which the tissue's fluorescence signal is zero) [36]. There are two forms of noise in images: random and structured. Random noise (or statistical noise) is directly related to the number of signals coming from the imaging agent. Structured noise refers to non-random variations in counting rates. The latter will adversely affect the interpretation and analysis of the images. Examples of structured noise are organ motion, and imaging instrument non-uniformities [37].
Contrast-to-noise ratio (CNR)
To ensure only contrast through targeted uptake is measured, and contrast through non-specific EPR is excluded, contrast can be quantified by calculating the average signal in the tumor and subtracting the average signal in the selected background tissue. This value can be divided by the standard deviation of the background to estimate the CNR [38]. This technique may be particularly helpful to assess off-target accumulation in non-cancerous tissues that express the biomarker of interest. CNR is especially useful in situations where the background and tumor signals fluctuate widely. In these cases, the TBR value could be the same as compared to a situation with a more constant signal profile. However, the tumor would be more consistently clearly visible in case of a constant pattern. In situations with more fluctuation, CNR would show a difference in value, providing a more representative value that assists in distinguishing true contrast from noise [38].
When detecting lesions in the body, a high SNR alone will not guarantee that sufficient contrast exists to make the lesion detectable. Therefore, SNR should be used to assess one single image. CNR on the other hand can be used to identify fluctuations within one patient over time as it compares a measure of signal fluctuations to noise. In summary, SNR is a good measure to assess data quality of a single image, and CNR provides knowledge regarding how easy or hard it is to detect signal fluctuations over time [36].
A topic of constant debate in the field of FGS is the reporting of test characteristics. Certain groups choose not to report sensitivities and specificities in early phase clinical trials, since the number of patients is insufficient for a powered calculation. Some groups use multiple separate specimens from each patient to generate a sufficient sample size for determining test characteristics. We believe that reporting on sensitivity and specificity in early trials is important in order to determine the potential of the fluorescence imaging agent for FGS. In larger clinical trials in later phases, the additional benefit of sensitivity and specificity should focus on improving or complementing the surgeon's assessment.
Suggestions for tissue to appoint as background for quantitative fluorescence imaging analysis.
Cancer type and location
Ideal background
Appropriate background
Breast Uninvolved breast tissue Adipose tissue
Head and neck Muscle Skin or mucosa
Colorectal Uninvolved bowel serosa Normal bowel mucosa
Pancreas Peritumoral inflammation Normal pancreatic tissue
Lung Uninvolved lung tissue Skin
Brain Uninvolved brain tissue Uninvolved brain tissue
Hepatocellular and CRLM Immature hepatocytes Uninvolved liver tissue
Prostate Uninvolved prostate tissue Connective tissue
Parathyroid Thyroid tissue Muscle
Demonstration of value in early phase clinical trials: Three critical elements
1. Intraoperative data collection
Real-time fluorescence tumor imaging should demonstrate sufficiently higher contrast enhancement in the tumor relative to surrounding normal structures in order to augment the current standard of care. During minimally-invasive and robotic surgery, this real-time detection of fluorescence is easily integrated as the current technology requires the surgeon to operate using a screen to visualize the surgical field. However, to properly interpret a positive fluorescence signal that will subsequently affect clinical decision-making, consensus should be reached regarding validation of fluorescent markers and imaging devices designed to differentiate tumor from peri-tumoral tissue. To date, an insufficient number of standardized studies have been performed to reach this type of consensus.
Developers of strategies for intraoperative imaging should recognize that the surgical approach varies significantly by tumor type, and that each approach has a unique workflow. The incorporation of intraoperative FGS into the surgical workflow will be individualized to the type of procedure being performed, and the type of cancer being resected. For example, in the case of ovarian cancer, brain cancer or peritoneal metastases during a cytoreduction and hyperthermic intraperitoneal chemotherapy procedure (HIPEC), the primary goal is a more complete debulking [39]. In these cancer types, it is known that extensive debulking leads to prolonged survival for patients [40]. Here, FGS has the potential to be beneficial in identification of subclinical disease, or occult tumor deposits [12]. For other tumor types, complete resection is the key to prolonged survival. In these situations, FGS will play a crucial role in assessing the resection bed for residual tumor after initial resection or to assess the margins of the specimen [6, 9, 13, 41]. Next steps in treatment could be informed by the presence of residual fluorescence, warranting either further resection or, for example, novel techniques such as applying PDT to the resection bed [42].
Intraoperatively, FGS is particularly important for: 1) Identification of tumor; 2) Assessment of resection margins, both before the resection for operative planning and after to assess the wound bed; and 3) Detection of tumor-positive lymph nodes, especially in locations that would suggest metastatic disease. In this case, for example, FGS could inform clinical decision making by aborting a surgery when there is no oncologic benefit.
Margin assessment in the OR
One of the biggest gaps in oncologic surgery remains the high rate of positive margins following surgical resections, which directly correlates with poor survival and locoregional recurrence [43-45]. Both the in vivo assessment of the resection bed and the ex vivo assessment of the specimen are critical to ensure negative margins. The current approach to margin assessment in most tumor types is circumferential analysis of the resected specimen using frozen sections [46]. Therefore, only a fraction of the tumor mass can be analyzed due to the limited sampling that is feasible with frozen sectioning. A tumor-specific fluorescent contrast agent can be leveraged to perform fluorescence mapping of the surgical specimen. Fluorescent 'hot spots' could be used to direct clinicians toward suspicious regions, and thereby reduce sampling error. The detection of a fluorescence signal using back-table benchtop devices could also result in reduction of time needed for specimen analysis, since sampling can be performed based on fluorescence-positive areas, as opposed to sampling all surfaces of a large tumor specimen (i.e., hepatic tumor resections).
Data representation from intraoperative imaging
During surgery, fluorescence imaging should be performed at multiple fixed time points as outlined in the clinical trial protocol and standard operation procedure (SOP). For example, one can identify three imaging time points to be used in most trials: First, while scanning the area of interest for the localization of the primary tumor and/or detection of metastases prior to excision. Second, once the tumor has been exposed while still in situ, with surrounding normal tissue in the field of view. And third, after resection of the primary tumor for assessment of the wound bed. During surgery, both endoscopic and open-field imaging systems can be used. In some operative cases, such as an abdominal laparoscopy that is converted to an open procedure, both systems can be used at different timepoints. Since the two devices will generate data that is not necessarily comparable, it is important to clearly state which device's data will be used in a clinical trial and document this in the SOP. Depending on the capabilities of the fluorescence camera, multiple images should be obtained in each setting; a bright field image, a black-and-white fluorescence image, a pseudo-colored fluorescence overlay image, and/or a heat-map whereby fluorescence signal intensity differences are displayed in different colors (Figure 2). Ex vivo imaging of fresh tissue should be presented in a similar manner. Quantitative data of intraoperative images should consist of a numeric value representing fluorescence signal. This can either be reported in MFI values or in a ratio such as TBR.
The development process of an optimal intraoperative imaging strategy should keep in mind the specific nature of the surgical workflow in order to minimize interruptions and facilitate the adoption of this technology. Early phase clinical trials are designed to demonstrate the safety, appropriate dose and tumor specificity of experimental agents. For these trials, the secondary outcomes primarily focus on the tumor-specific contrast that is generated between tumor tissue and background tissue using the agent-device combination. Regulatory standards ensure the workflow of these early phase trials maintain the standard of care, which makes it difficult to objectively assess the potential clinical value and patient benefit of FGS. For larger clinical trials, clinically relevant endpoints that necessitate experimental assessment will be needed to demonstrate superiority to the current standard of care. Examples of secondary endpoints include improved detection of tumor-positive margins, decreased morbidity, reduced local recurrence, or increased efficiency in the operating room [31]. These endpoints can be directly correlated with known statistics pertaining to survival, thereby demonstrating clinical benefit.
It is important to recognize that the success of these trials will be influenced by the parameters of the clinical imaging devices employed. Not all imaging devices are able to show a TBR in real-time, and the significant differences in sensitivity among the various devices will make it challenging to achieve consistency and compare results regarding the clinical utility of tumor-specific contrast agents. Another limitation that should be recognized is the inability to directly correlate intraoperative images with pathology results in real-time. Therefore, dependence on ex vivo imaging to confirm tumor status will remain a critical component of FGS validation, especially in early phase clinical trials where confirmation of tumor specificity is critical. To circumvent this limitation, ex vivo imaging can be done in the form of back-table fluorescence imaging in the operating room using either a clinical camera or a bench-top device developed for this purpose. These results can later be directly correlated to the pathological assessment [6-9, 12, 13, 27, 41].
2. Specimen mapping
An important stage in the validation of FGS is the correlation of the fluorescence imaging-based results with the pathologic findings, which is used to determine if the fluorescence signal is specifically localized to the tumor. It is recommended that the correlation be performed in a standardized and rigorous method as described in Figure 3. After analysis of the resected fresh tissue, the surgical specimen is processed into bread loaves (either before or after formalin-fixation) and later into blocks to be placed in cassettes (Figure 3). These cassettes are then imaged on a fluorescence scanner both before and after paraffin embedding. Finally, these cassettes are processed into microscopy slides where fluorescence can then be correlated with hematoxylin and eosin (H&E) histopathology. These steps are possible when the fluorescent capabilities of the probe are maintained after formalin fixation. Additional immunohistochemical correlation of the target of interest and H&E should be performed to determine co-localization of the target and fluorescence, which will be discussed later.
Suggested method of reporting intra-operative imaging results. This includes a bright field image (A), black-and-white fluorescence image (B), fluorescence overlay image (C), and fluorescence heat-map (D). In this case, an example of a tumor-positive lymph node during abdominal surgery is shown.
Detailed overview using a clinical example of the ex vivo mapping process of a surgical specimen to ensure exact correlation of the surgical specimen with pathologic assessment. During step 1, the fresh tissue specimen is imaged ex vivo to ensure images from all angles. After formalin fixation, the specimen is mapped and sliced into bread loaves in step 2. Fluorescence imaging is subsequently performed of the bread loaves separately. In step 4, cassettes are made that include one bread loaf each and are imaged either on a fluorescence scanner or in a closed-field imaging system. The cassettes are then paraffin-embedded and sectioned to produce microscopy slides. In step 5, these slides are used for pathologic assessment and fluorescence scanning.
Mapping process of the gross surgical specimen
To facilitate the processing of the specimen, a bright-field image of the gross surgical specimen can be acquired and used as a reference map as the specimen is sectioned and placed into cassettes. The origin of the cassette-specific sections can be drawn on a printed or digital image of the primary specimen and saved for later correlation at the time of histopathologic study. This methodology is commonly employed during pathological processing of large surgical specimens. Precise imaging of the gross specimen and close correlation with histopathologic sections increases the efficiency and accuracy of pathologic assessment and enables consistent and accurate interpretation of the technique's specificity. This method is anecdotally used during Mohs surgery and is also described in the standardized pathologic assessment of breast cancer specimens [47]. It is important to maintain the specimen orientation relative to the patient so that the slide-mounted section can be registered back to the primary specimen, and ultimately to the wound bed. This approach will allow the clinician to determine if fluorescence observed on either the resected specimen or in the wound bed is clinically relevant and a source of potential recurrence.
Data representation of ex vivo imaging
After removal from the patient, the fresh specimen is imaged at the back-table using a benchtop device or the surgical camera. Fresh tissue should be imaged when possible and fluorescence intensity should be expressed relative to the surface area of the specimen.
After imaging the fresh surgical specimen, the tissue should be formalin-fixed prior to being processed into bread loaves. Formalin-fixed tissue can still be used for qualitative and quantitative analysis of fluorescence imaging signal, in contrast to paraffin-embedded tissue, which is more suitable for qualitative data analysis. Cassetted, formalin-fixed tissues are ideal for identification of complex tumor-containing tissues since both the orientation and size are matched to the H&E-stained slide of that specific block after paraffin embedding. Quantitative analysis of formalin-fixed tissue can be performed in two ways. First, an absolute quantitative comparison of MFI from the raw data can be performed between tumor tissue and normal surrounding tissue, either per patient or per dose cohort, as demonstrated by an example in pancreatic cancer in Figure 4A. Alternatively, a semi-quantitative scoring method could be used to determine the percentage of fluorescent tissue, compared to the percentage of tumor tissue per tissue block (Figure 4B). The amount of tumor tissue can be assessed on the H&E slide from a particular block, while fluorescence can be measured either with a fluorescence scanner or a closed-field imaging device of a deparaffinized slide.
Qualitative representation of ex vivo imaging preferably includes images of the ex vivo specimen, a bread loaf slice and the corresponding cassette to ensure correlation, as also shown in Figure 3. In this context, the bright field image, a black-and-white fluorescence image, and fluorescence overlay image should be shown of each specimen, and ideally also a fluorescence heat-map image.
Quantitative analysis of ex vivo imaging. Quantitative analysis of formalin-fixed tissue can be performed in several ways. Two examples are shown here. (A) A quantitative comparison using the calculated MFI could be performed between tumor tissue and normal surrounding tissue, either per patient or per dose cohort. (B) A semi-quantitative scoring method could be used to determine the percentage of fluorescent tissue, compared to the percentage of tumor tissue per tissue block.
3. Target validation
After paraffin-embedding of the tissue, the fluorescence signal will be attenuated. This influences the quantification properties of the signal. This, on the other hand, does not influence two other key aspects of data analysis in FGS trials. In the pathologic assessment one should focus on (1) confirmation of tumor targeting using histology, and (2) confirmation of molecular targeting of the biomarkers to the tumor cell. Lastly, correlation of fluorescence intensity with the density of the target molecule can be performed (Figure 1, panel III). Other key factors associated with delivery of the agent can also be assessed in this stage including vascular density, the presence or absence of lymphatic vessels, and the amount of cell proliferation.
Confirmation of tumor cell targeting
As discussed above, this step allows for direct correlation between tissue fluorescence and tumor status on H&E. In early phase trials, this step is critical to ensure the agent is indeed targeting the tumor. Confirmation of tumor status on the H&E slides should be performed in close collaboration with a trained pathologist, who is preferably blinded to the fluorescence imaging results. With the use of a fluorescence scanner, the location of fluorescence can be detected with a µm resolution. Because the tumor is often composed of stromal elements, it will be necessary to distinguish tumor/cancer cell targeting and targeting of other structures within the tumor mass.
If the mapping process (as described above) is performed in a rigorous manner, the correlation generated at this step can be traced back to the images of the intact gross surgical specimen acquired during back-table imaging. It is even possible to apply this correlation back to the intraoperative findings; however, this is complicated by the necessary preservation of the specimen's orientation at each step in addition to the influence of ambient light on intraoperative fluorescence.
Confirmation of molecular targeting
In the case of a targeted agent, the confirmation of precise tumor targeting should be a required step of the data analysis. Here, co-localization of the target of interest and fluorescence signal shows that the agent truly targets the biomarker, as compared to fluorescence signal seen in the tumor as a result of the EPR effect. A (semi-)quantitative analysis can be performed to analyze the fluorescence intensity relative to the receptor density of a specific tissue section (Figure 1). Co-localization can be performed using serial tissue sections, where one slide is used for immunohistochemistry (IHC) to confirm the target biomarker and one is used for fluorescence scanning. Additional IHC may be performed to gain a better understanding of the behavior of the factors influencing the tissue target; for example, for markers that influence delivery of the agent such as vascular density, the presence of lymphatic vessels, and the amount of cell turnover. Therefore, this staining will uniquely be performed during early phase trials when this information is relevant to advancing the agent and further characterizing its potential as a fluorescent biomarker. In later phase trials, one could choose to perform additional staining if the imaging results of a patient are out of the range of what is expected but would not necessarily be performed routinely. Fluorescence microscopy may be introduced into future analyses in FGS clinical trials in order to determine the position of the imaging agent in the tumor, e.g., membrane-bound, internalized, or in stroma.
To ensure wide-spread use and FDA approval of FGS, the quality and standardization of reporting is paramount. Therefore, we present here recommendations for standardized reporting with the goal of establishing a set of minimum requirements for reporting FGS clinical trial results. In this approach, both qualitative and quantitative data play a major role. Three critical elements of early phase clinical trials can be identified and should be reported:
1) Intra-operative data collection: FGS has the potential to play a unique role in the identification of tumor tissue, assessment of resection margins, and detection of tumor-positive lymph nodes, especially in locations that would suggest metastatic disease. In early phase trials, qualitative data should consist of multiple images obtained in each setting, which include a bright field image, a black-and-white fluorescence image, a pseudo-colored fluorescence overlay image, and/or a heat-map. Quantitative data should consist of numerical values reporting fluorescence, preferably both raw MFIs and a ratio such as TBR.
2) Specimen mapping: This is critical to the validation of FGS to correlate fluorescence imaging-based results with the pathologic findings, preferably using fresh tissue. After imaging the fresh surgical specimen, the specimen should be formalin fixed. Formalin-fixed tissue can be used for qualitative and quantitative analysis of fluorescence signal, in contrast to paraffin-embedded tissue, which is more suitable for qualitative data analysis.
3) Target validation: Co-localization of the target of interest and fluorescence signal needs to demonstrate that the agent truly targets the biomarker. A semi-quantitative analysis can be performed to analyze the fluorescence intensity relative to the receptor density of a specific area.
In summary, if these guidelines are widely accepted, trial results could be comparable and collated to expedite future FDA approval.
AU: arbitrary units; CNR: contrast-to-noise ratio; EPR: enhanced permeability and retention; FDA: Food and Drug Administration; FGS: Fluorescence-guided surgery; H&E: hematoxylin and eosin; ICG: indocyanine green; IHC: immunohistochemistry; SUVmax: maximum standard uptake values; MFI: mean fluorescence intensity; NEMA: National Electrical Manufacturers Association; NIRF: near-infrared fluorescent; PDT: photodynamic therapy; PET: Positron emission tomography; QC: quality control; ROI: region of interest; RFU: relative fluorescence units; SNR: signal-to-noise ratio; SD: standard deviation; SOP: standard operation procedure; TBR: tumor-to-background ratio.
No conflicts to state.
1. Vahrmeijer AL, Hutteman M, van der Vorst JR, van de Velde CJ, Frangioni JV. Image-guided cancer surgery using near-infrared fluorescence. Nat Rev Clin Oncol. 2013;10:507-18
2. Jiang JX, Keating JJ, Jesus EM, Judy RP, Madajewski B, Venegas O. et al. Optimization of the enhanced permeability and retention effect for near-infrared imaging of solid tumors with indocyanine green. Am J Nucl Med Mol Imaging. 2015;5:390-400
3. Madajewski B, Judy BF, Mouchli A, Kapoor V, Holt D, Wang MD. et al. Intraoperative near-infrared imaging of surgical wounds after tumor resections can detect residual disease. Clin Cancer Res. 2012;18:5741-51
4. Zhang RR, Schroeder AB, Grudzinski JJ, Rosenthal EL, Warram JM, Pinchuk AN. et al. Beyond the margins: Real-time detection of cancer using targeted fluorophores. Nat Rev Clin Oncol. 2017;14:347-64
5. Rosenthal EL, Warram JM, Bland KI, Zinn KR. The status of contemporary image-guided modalities in oncologic surgery. Ann Surg. 2015;261:46-55
6. Rosenthal EL, Warram JM, de Boer E, Chung TK, Korb ML, Brandwein-Gensler M. et al. Safety and tumor specificity of cetuximab-irdye800 for surgical navigation in head and neck cancer. Clin Cancer Res. 2015;21:3658-66
7. Burggraaf J, Kamerling IM, Gordon PB, Schrier L, de Kam ML, Kales AJ. et al. Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-met. Nat Med. 2015;21:955-61
8. Hoogstins CE, Tummers QR, Gaarenstroom KN, de Kroon CD, Trimbos JB, Bosse T. et al. A novel tumor-specific agent for intraoperative near-infrared fluorescence imaging: A translational study in healthy volunteers and patients with ovarian cancer. Clin Cancer Res. 2016;22:2929-38
9. Boogerd LSF, Hoogstins CES, Schaap DP, Kusters M, Handgraaf HJM, van der Valk MJM. et al. Safety and effectiveness of sgm-101, a fluorescent antibody targeting carcinoembryonic antigen, for intraoperative detection of colorectal cancer: A dose-escalation pilot study. Lancet Gastroenterol Hepatol. 2018;3:181-91
10. Miller SE, Tummers WS, Teraphongphom N, van den Berg NS, Hasan A, Ertsey RD. et al. First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-irdye800. J Neurooncol. 2018;139:135-43
11. Tummers WS, Miller SE, Teraphongphom NT, Gomez A, Steinberg I, Huland DM. et al. Intraoperative pancreatic cancer detection using tumor-specific multimodality molecular imaging. Ann Surg Oncol. 2018;25:1880-8
12. van Dam GM, Themelis G, Crane LM, Harlaar NJ, Pleijhuis RG, Kelder W. et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: First in-human results. Nat Med. 2011;17:1315-9
13. Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG. et al. Tumor-specific uptake of fluorescent bevacizumab-irdye800cw microdosing in patients with primary breast cancer: A phase i feasibility study. Clin Cancer Res. 2017;23:2730-41
14. Shankar LK, Hoffman JM, Bacharach S, Graham MM, Karp J, Lammertsma AA. et al. Consensus recommendations for the use of 18f-fdg pet as an indicator of therapeutic response in patients in national cancer institute trials. J Nucl Med. 2006;47:1059-66
15. Barrington SF, Qian W, Somer EJ, Franceschetto A, Bagni B, Brun E. et al. Concordance between four european centres of pet reporting criteria designed for use in multicentre trials in hodgkin lymphoma. Eur J Nucl Med Mol Imaging. 2010;37:1824-33
16. Boellaard R, Krak NC, Hoekstra OS, Lammertsma AA. Effects of noise, image resolution, and roi definition on the accuracy of standard uptake values: A simulation study. J Nucl Med. 2004;45:1519-27
17. Antunovic L, Rodari M, Rossi P, Chiti A. Standardization and quantification in pet/ct imaging: Tracers beyond fdg. PET Clin. 2014;9:259-66
18. Kinahan PE, Fletcher JW. Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy. Semin Ultrasound CT MR. 2010;31:496-505
19. Kim A, Khurana M, Moriyama Y, Wilson BC. Quantification of in vivo fluorescence decoupled from the effects of tissue optical properties using fiber-optic spectroscopy measurements. J Biomed Opt. 2010;15:067006
20. Weersink R, Patterson MS, Diamond K, Silver S, Padgett N. Noninvasive measurement of fluorophore concentration in turbid media with a simple fluorescence /reflectance ratio technique. Appl Opt. 2001;40:6389-95
21. Pogue BW, Burke G. Fiber-optic bundle design for quantitative fluorescence measurement from tissue. Appl Opt. 1998;37:7429-36
22. Westerterp M, Pruim J, Oyen W, Hoekstra O, Paans A, Visser E. et al. Quantification of fdg pet studies using standardised uptake values in multi-centre trials: Effects of image reconstruction, resolution and roi definition parameters. Eur J Nucl Med Mol Imaging. 2007;34:392-404
23. Scheuermann JS, Saffer JR, Karp JS, Levering AM, Siegel BA. Qualification of pet scanners for use in multicenter cancer clinical trials: The american college of radiology imaging network experience. J Nucl Med. 2009;50:1187-93
24. Wu J, Feld MS, Rava RP. Analytical model for extracting intrinsic fluorescence in turbid media. Appl Opt. 1993;32:3585-95
25. Patterson MS, Pogue BW. Mathematical model for time-resolved and frequency-domain fluorescence spectroscopy in biological tissues. Appl Opt. 1994;33:1963-74
26. Huang Z, Shi S, Qiu H, Li D, Zou J, Hu S. Fluorescence-guided resection of brain tumor: Review of the significance of intraoperative quantification of protoporphyrin ix fluorescence. Neurophotonics. 2017;4:011011
27. Miller SE, Tummers WS, Teraphongphom N, van den Berg NS, Hasan A, Ertsey RD. et al. First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-irdye800. J Neurooncol. 2018
28. Tahari AK, Chien D, Azadi JR, Wahl RL. Optimum lean body formulation for correction of standardized uptake value in pet imaging. J Nucl Med. 2014;55:1481-4
29. Valdes PA, Angelo JP, Choi HS, Gioux S. Qf-ssop: Real-time optical property corrected fluorescence imaging. Biomed Opt Express. 2017;8:3597-605
30. Choi H. Deep learning in nuclear medicine and molecular imaging: Current perspectives and future directions. Nucl Med Mol Imaging. 2018;52:109-18
31. Tummers WS, Warram JM, Tipirneni KE, Fengler J, Jacobs P, Shankar L. et al. Regulatory aspects of optical methods and exogenous targets for cancer detection. Cancer Res. 2017;77:2197-206
32. Daube-Witherspoon ME, Karp JS, Casey ME, DiFilippo FP, Hines H, Muehllehner G. et al. Pet performance measurements using the nema nu 2-2001 standard. J Nucl Med. 2002;43:1398-409
33. Souza AV, Lin H, Henderson ER, Samkoe KS, Pogue BW. Review of fluorescence guided surgery systems: Identification of key performance capabilities beyond indocyanine green imaging. J Biomed Opt. 2016;21:80901
34. Prince AC, Jani A, Korb M, Tipirneni KE, Kasten BB, Rosenthal EL. et al. Characterizing the detection threshold for optical imaging in surgical oncology. J Surg Oncol. 2017;116:898-906
35. Zhang C, Liu T, Su Y, Luo S, Zhu Y, Tan X. et al. A near-infrared fluorescent heptamethine indocyanine dye with preferential tumor accumulation for in vivo imaging. Biomaterials. 2010;31:6612-7
36. Welvaert M, Rosseel Y. On the definition of signal-to-noise ratio and contrast-to-noise ratio for fmri data. PLoS One. 2013;8:e77089
37. Weissleder R, Ross B, Rehemtulla A, Gambhir SS. Molecular imaging: Principles and practice. 1st ed. Raleigh, USA: People's Medical Publishing House. 2010
38. Tichauer KM, Holt RW, Samkoe KS, El-Ghussein F, Gunn JR, Jermyn M. et al. Computed tomography-guided time-domain diffuse fluorescence tomography in small animals for localization of cancer biomarkers. J Vis Exp. 2012;65(e):4050
39. Tipirneni KE, Warram JM, Moore LS, Prince AC, de Boer E, Jani AH. et al. Oncologic procedures amenable to fluorescence-guided surgery. Ann Surg. 2017;266:36-47
40. Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: A prospective study in 52 consecutive patients. J Neurosurg. 2000;93:1003-13
41. Tummers WS, Miller SE, Teraphongphom NT, Gomez A, Steinberg I, Huland DM. et al. Intraoperative pancreatic cancer detection using tumor-specific multimodality molecular imaging. Ann Surg Oncol. 2018
42. Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer. 2003;3:380-7
43. Sadot E, Groot Koerkamp B, Leal JN, Shia J, Gonen M, Allen PJ. et al. Resection margin and survival in 2368 patients undergoing hepatic resection for metastatic colorectal cancer: Surgical technique or biologic surrogate?. Ann Surg. 2015;262:476-85 discussion 83-5
44. Pawlik TM, Scoggins CR, Zorzi D, Abdalla EK, Andres A, Eng C. et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715-22 discussion 22-4
45. O'Kelly Priddy CM, Forte VA, Lang JE. The importance of surgical margins in breast cancer. J Surg Oncol. 2016;113:256-63
46. Black C, Marotti J, Zarovnaya E, Paydarfar J. Critical evaluation of frozen section margins in head and neck cancer resections. Cancer. 2006;107:2792-800
47. Provenzano E, Bossuyt V, Viale G, Cameron D, Badve S, Denkert C. et al. Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: Recommendations from an international working group. Mod Pathol. 2015;28:1185-201
48. Gao RW, Teraphongphom NT, van den Berg NS, Martin BA, Oberhelman NJ, Divi V. et al. Determination of tumor margins with surgical specimen mapping using near-infrared fluorescence. Cancer Res. 2018
Author contact
Corresponding author: E.L. Rosenthal, MD. Professor of Otolaryngology and Radiology, Ann & John Doerr Medical Director, Stanford Cancer Center, Stanford, CA. Tel: 650 723 4250; Fax: 650 723 2225; E-mail:elredu
Received 2018-5-21
Accepted 2018-8-22
©2022 Ivyspring International Publisher. Terms of use


UK Indymedia | Why is there so much Violence in Colombia?
Why is there so much Violence in Colombia?
Too often, the ongoing conflict in Colombia is naturalized in mainstream media coverage as though it were a timeless, inherent characteristic of the country and its people.
London branch meetings of the Colombia Solidarity Campaign take place at 7pm every third Tuesday of the month at The Apple Tree pub, 45 Mount Pleasant, WC1X 0AE (Russell Square tube station).


text:
The Stratton Story is een Amerikaanse film uit 1949 onder regie van Sam Wood. De film vertelt het verhaal van honkballer Monty Stratton. Destijds werd het in Nederland uitgebracht onder de titel Als Mannen Willen.

Verhaal

Het verhaal van de uit Texas afkomstige Monty Stratton, die zich aansluit bij het honkbalteam Wagner Wild Cats. In zijn vrije tijd biedt hij zijn familie een helpende hand op de familieboerderij. De voormalige achtervanger Barney Wile merkt zijn sporttalenten op en vertelt hem dat hij, mits hij de goede training krijgt, een van de grootste honkbalspelers ter wereld kan worden. Gedurende de winter wordt Monty getraind door Barney en hij regelt vervolgens een ontmoeting met Jimmy Dykes, de manager van de Chicago White Sox.

Jimmy is onder de indruk van Monty's snelheid en nauwkeurigheid, maar twijfelt nog of hij voor het team mag spelen. Hij geeft hem een kans en biedt hem uiteindelijk een plaats aan in het team. Monty wordt overweldigd met het leven in een grote stad, maar laat zich door teamspeler Eddie Dibson overtuigen mee te gaan naar een dubbeldate. Hij wordt gekoppeld aan Ethel, een aantrekkelijke vrouw op wie Eddie ook een oogje krijgt. Hij gooit zijn charmes in de strijd om Monty's date te imponeren, maar zij geeft de voorkeur aan haar date.

Ondertussen gaat het goed met zijn carrière. Na een seizoen op de banken als reservespeler te hebben gezeten, krijgt Monty eindelijk de kans zichzelf te bewijzen. Hij wordt echter ingemaakt door zijn tegenstanders, de New York Yankees. Ethel wil dolgraag met hem trouwen, maar hij wil eerst een aantal hoogtepunten halen bij het honkballen voordat hij settelt. Hij wint een aantal wedstrijden in Omaha en wordt beschouwd als een van de beste spelers van de White Sox. Niet veel later trouwt hij met Ethel. Over de jaren heen wint hij wedstrijden aan de lopende band en zet enkele records neer. Ondertussen bevalt zijn vrouw van een zoontje, die naar zijn vader wordt vernoemd.

Ondanks zijn succes als honkbalspeler is Ethel erg bezorgd om haar man. De sport eist alle tijd van Monty op, waardoor hij nauwelijks tijd met zijn vrouw doorbrengt. Een aantal maanden gaan voorbij als hij op een dag per ongeluk de trekker van een geweer laat afgaan en zichzelf in zijn been schiet. Als Ethel hem aantreft is het al te laat; zijn been zal worden geamputeerd. Monty verliest zijn levenslust en doet maandenlang niets anders dan bitter voor zich uit kijken. Ethel weet niet wat ze moet doen en besluit haar man te steunen. Wanneer hij zijn zoon zijn eerste stappen ziet zetten, realiseert hij zich dat hij lang genoeg zelfmedelijden heeft gehad.

Monty leert te lopen met een kunstbeen en ontdekt dat zijn vrouw zal bevallen van nog een kind. Hierna overtuigt hij zijn trainer hem weer een plek te geven in het team. Zijn teamleden weten niet goed hoe ze hem moeten behandelen en kunnen hun ogen niet geloven als Monty met veel moeite een wedstrijd wint. Gedurende de rest van zijn carrière behaalt Monty het ene succes na het andere, ondanks zijn afwijking.

Rolverdeling

|-
||| Monty Stratton
|-
||| Ethel
|-
||| Barney White
|-
||| Ma Stratton
|-
||| Eddie Dibson
|-
||| Ted Lyons
|-
||| Josh Higgins
|-
||| Dot
|-
||| Luke Appling
|-
||| Earnie
|}

Achtergrond
In februari 1948 werd aangekondigd dat er een biografische film over de honkbalspeler gemaakt zou worden, met Roy Rowland als regisseur. Al in december 1947 werd vermoed dat Gregory Peck de hoofdrol zou spelen, maar het is niet bekend of hij de rol ook daadwerkelijk aangeboden heeft gekregen. In maart 1948 kreeg Van Johnson de hoofdrol, maar hij trok zich al snel terug. Hij was in 1943 namelijk betrokken bij een ernstige auto-ongeluk en werd door zijn dokter afgeraden mee te doen aan een film die fysiek veel van hem vereiste. Vervolgens werd James Stewart gevraagd, de acteur waar Stratton al sinds het begin de voorkeur aan gaf.

Donna Reed werd lang overwogen voor de vrouwelijke hoofdrol. Toen Stewart een rol kreeg, besloten de makers haar niet te vragen. De actrice werkte namelijk eerder met hem aan It's a Wonderful Life (1946) en hoewel de film de geschiedenisboeken in ging, was het destijds geen succes. De makers vreesden ervoor dat ook deze film zou falen als ze opnieuw naast elkaar te zien waren. Stewart nam de rol zeer serieus en bracht maandenlang zijn tijd met Stratton door. Ook probeerde hij in topvorm te komen om geloofwaardig over te komen als sporter.

Na de uitbrengst werd de film een groot succes en tegenwoordig wordt het beschouwd als een van de beste biografische films over sporters. Het won een Oscar en twee Photoplay Awards.

Externe link

Stratton Story, The
Stratton Story, The
Stratton Story, The
Stratton Story, The
Stratton Story, The
Stratton Story, The
Stratton Story, The
Stratton Story, The

redpajama_set_name: RedPajamaWikipedia


AVENGERS ENDGAME - Crew Jacket - MCU Original crew gift from Marvel. Size is XXL fits like a XL. The jacket is NEW never worn. What you see in the photos is the jacket you get. No INTL shipping.
Promotional jacket for the movie 'Long Shot' given out at the SXSW World Premiere. In great condition, never worn. Size medium, has loose fit.
It has been in storage ever since. Recently rediscovered! Classic, lightweight lined windbreaker-type jacket with snap button front closures, optional drawstring bottom and 2 side pockets. Features iconic trumpet logo decal on front with the the phrase "Who's the coolest guy in the world?".
Up for sale is this Rare Adidas The Waterboy Jacket. Adidas logo has cracking as seen.
LAME DUCKS, Movie Crew Jacket, RARE find! XL Good Condition!
XL Good Condition! • Green Wool Body. • Satin inside with Chest pocket. • Perfect Embroidery on back.
Great item that was not for sale just available to the crew.
The jacket is in mint condition, never worn. I am 5'8 and 150lbs and it fits perfectly.
Star Trek Deep Space Nine Cast and Crew Jacket...Not Sold in Stores.
Star Trek Deep Space Nine Cast and Crew Jacket...Not Sold in Stores.. Shipped with USPS Priority Mail.
Grey Leather with Grey Wool, GREAT CONDITION! • Inside is quilted nylon, Black. • In storage box - worn very little if any!
Diagnosis Murder. Jacket has two small tears- one near the cuff and one near the back of the armpit. Fleece collar and lining are in excellent shape for its age! Back reads Condition is Pre-owned.
New ListingVintage 1991 "Cool World" Crew Jacket, Large, very good condition.
Vintage 1991 "Cool World" Crew Jacket, Large, very good condition. From the Ralph Bakshi animation/live action cult film starring Kim Basinger and a very young Brad Pitt. Never worn, very good condition, and very WARM.
There are two hand pockets on the front. The lettering on the right sleeve reads: DOLBY ATMOS.
Great Condition, not worn, in storage!
Manufactured by ID Wear. 60% acrylic, 40% polyester. Made in Canada.
Full front zipper with Velcro storm flap. Two front slash pockets. Has inside pocket. Waist lays loose and does not have elastic. Screen printed graphics. In very good condition with light normal wash wear.
This is from the 74th Academy Awards which took place in 2002. The 74th Academy Awards logo is embroidered on the right sleeve. This is a jacket that was only available to those who worked the Academy Awards show otherwise known as the Oscars.
This is from the 83rd Academy Awards which took place in 2010. The 83rd logo is embroidered on the upper front left. This is a jacket that was only available to those who worked the Academy Awards show otherwise known as the Oscars.
BRUCE ALMIGHTY Crew Jacket with hood. Never worn! •This jacket is reversible! •Logo is low key on the bottom right of cuff! SECOND PHOTO IS OF THE JACKET INSIDE OUT!
Lethal Weapon TV Series Cast & Crew Season One Jacket Rare Exclusive Collector's. Shipped with USPS First Class Package. Sold as is! No refunds!
Never worn, like new 100% authentic THE BUCKET LIST 2008 movie NIKE PARKA JACKET. Features multiple inside pockets for storing your cell phone, headphones and cash as well as a plethora of pockets on the outside that both zip and button for added security.
Bought this at a visit to Universal studios around 15 years ago. Been in my closet ever since, I may have worn it a total of 2 hours. The size is 50. It could probably use a cleaning just to soften the leather up a bit. Otherwise in very good condition. Let me know if you need any more photos. Message me with questions.
This jacket was a promotional item made exclusively for HBO. It has a zip-out liner which also has openings in the upper part of both sides to allow access to the hidden breast pockets. It has 5 buttons up the front and there is an extra one in the left-side hidden breast pocket.
Catwoman embroidered on front, Catwoman Picture embroidered on back.
LAID FLAT ACROSS THE CHEST FROM SIDE TO SIDE 24". This Jacket is in Mint NWOT condition.
John Waters "Serial Mom" black denim jacket. "Serial Mom" embroidered logo above pocket. Metal buttons and patch pockets. International Denim Authentic Jeanwear. Owned by Production Designer Vincent Peranio.
FEATURES "SCHOOL OF ROCK" MOVIE LOGO ON FRONT LEFT POCKET AND LARGE LOGO ON BACK, SIZE XL ADULT, JACKET BY PORT AUTHORITY OF U.S. DESIGN. Get Images that. Make Supersized Seem Small.
This jacket has never been worn. Duck Detroit. FILM CREW JACKET.
THIS IS A GREAT PIECE OF BLOCKBUSTER VIDEO HISTORY. VERY LIMITED AMOUNT OF THESE WERE GIVEN OUT. LARGE AMOUNT OF BOWIE, STONES, AND TONS OF OTHERS. JUST CHECK BACK OFTEN AS I DIG THEM OUT AND GET THEM LISTED.
Pit to pit: 25". Shoulder to shoulder: 21".
Barely worn. Very small drip stain on right shoulder (shown in photo). Just a wonderful leather jacket! Patches on each sleeve.
Rare, unusual and 100% authentic denim crew jacket from the 1988 film Big Top Pee-Wee. I'm the original owner. This jacket is highlighted by brilliantly colored embroidery of the film's logo in a "circus font.".
Amazing, mint condition for age. Don't think it was ever worn. Men's Large. Own a piece of Hollywood today!
Very good condition with a bit of wear around the patch. Leather patch located on the upper lefthand front of the jacket.
It's in excellent condition like new for it's age. Very warm jacket.
This is a Mission Impossible III Jacket. The size marked is L.
Satin Dugout Jacket. Ricky "Wild Thing" V aughn.
The size is listed as a Ladies Large. Great Condition. NOW FOR THE BORING STUFF! I WILL HAPPILY COMBINE MULTIPLE WINS.
Vintage 1991 "Cool World" Crew Jacket, Large, very good condition.


Police are supporting the return of Wakefield residents evacuated due to the Nelson fires but say that residential areas of Wakefield will remain closed to everyone except residents until 7am tomorrow morning.
State Highway 6 will also have reduced speed limits through the Wakefield township area until at least 7am tomorrow.
To help facilitate the return of residents police are asking people who don't have essential reasons for travelling through this part of SH6 to stay away.
Police and the NZDF will maintain a "high visibility presence overnight in the Wakefield area at key locations" according to Acting Tasman District Commander Zane Hooper.
Meanwhile, the civil defence emergency- and risk of re-evacuation- prevails.
A national media release will be issued and the Civil Defence website will be updated.
On hearing the evacuate signals, police are asking residents to leave the area in an orderly and timely manner.
Police have stated that any decision to evacuate will allow residents sufficient time to gather their pets, pre-packed personal items before leaving the area.
The Ministry of Social Development (MSD) helpline is available from 7am to 8pm, Monday to Friday.
Group General Manager Client Service Delivery, Kay Read says people affected by the fires don't have to be on a benefit to get help from MSD.
"If you're experiencing hardship as a result of the fires, we're here to help you and we want to hear from you."


The Polson Chamber of Commerce was founded on August 31, 1909 with the intent to serve, support and strengthen our members by enhancing the business climate, promoting our area, and fostering a sense of community. Today, the chamber continues that goal by offering platforms for networking, community outreach, and development. The chamber has two monthly events open to the public, the General Meeting Luncheon and S.P.L.A.S.H. The luncheons take place on the first Wednesday of every month, from noon to one o'clock. S.P.L.A.S.H., Support Polson Late Afternoon Social Hour, takes place on the third Thursday of every month Locations for these events vary, please check our events calendar for details. The chamber also puts on the Fourth of July parade and fireworks, the Annual Chamber Banquet celebrating our member, and the Chamber Blast fundraiser. The Polson Chamber of Commerce welcomes all businesses and community members to join.
Polson lies in a natural amphitheater at the south end of Flathead Lake in Northwest Montana, and is located on the Flathead Indian Reservation. This charming lake shore community is the trading center for one of most fertile farming areas in Montana. This prime cherry growing region is home to dozens of orchards, which Polson celebrates with its annual Cherry Festival. Polson becomes a popular attraction in the summertime, when temperatures range from 80 to 95 degrees.
The broad, sweeping Mission Valley, south of Polson, is bordered by the rugged, snow-capped Mission Mountains. At the foot of the mountains is Flathead Lake. Flathead Lake is the largest natural freshwater lake in the United States, west of the Mississippi River. Studies at the Flathead Biological Station show that water quality in Flathead Lake is among the best in the world. The Flathead River flows through Polson and features the Seli'š Ksanka Qlispe', formerly Kerr Dam. The dam is located at the outlet of Flathead Lake in Polson.
Just south of Polson, visitors can see large herds of bison, elk, deer, antelope and barn sheep at the National Bison Range at Moiese. Bird watchers will enjoy the Ninepipes and Pablo Wildlife Refuges. Visit one of our museums, The Miracle of America, the Polson-Flathead Historical Museum, or the Peoples Center in Pablo. All offer many displays and historic memorabilia. Polson also has several city parks situated along the lake and the beautiful Polson Golf Course.


The next concert from the Tippecanoe Chamber Music Society is Sunday afternoon, April 3rd, and features selections by Johann Sebastian Bach. On the program, Back to Bach, is the Cantata No 196, ; the D minor Harpsichord Concerto; the G major Trio Sonata; and the E major Violin Sonata. Executive Director Margot Marlatt says it was fun to put the program together, and that it was an easy decision to feature an all Bach program.
The Bach Chorale Singers perform this Sunday afternoon, February 21st, at St. John's Episcopal Church. On the program are two early cantatas by Johann Sebastian Bach: Weinen, Klagen, Sorgen, Zagen (Weeping, lamenting, worrying, fearing), BWV 12; and Christ lag in Todes Banden (Christ lay in death's bonds), BWV 4.


Title was 'Anais da Sociedade Entomol�gica Brasileira' until 2000.
Title was 'Revista Neurol�gica Argentina' until 2008.
Title changed to 'Neurology Asia' since 2004.
Title was 'Neurological Journal of South East Asia' until 2003.
Changed title to 'Neurotherapeutics' in 2006.
Only certain sections are free after 6 months.
Title changed to 'Journal of the American Dental Society of Anesthesiology' since 1958.
Only articles of the year 2006 are free.
Title changed to 'International Journal of Sports Physical Therapy' since 2011.
Title changed to 'Nova Scotia Medical Journal' since 1988.
Title was 'Nova Scotia Medical Bulletin' until 1987.


text:
World's Wackiest Holiday Traditions
Check out our top 4 picks for the world's wackiest holiday traditions.
By: Valerie Conners
Holidays and Celebrations Travel's Best
Hanging stockings by the fire, waiting for jolly old St. Nick to deliver presents, drinking eggnog and eating turkey, waiting for the New Year's ball to drop in Times Square -- these traditions are such a big part of our American holiday season, we barely bat an eye at them. But our traditions are far from the norm in other countries. From a goat-like monster to a benevolent old witch, and even the skull of a horse, some holiday traditions across the globe may cause you to raise an eyebrow. Check out our top 4 picks for the world's wackiest holiday traditions.
Photo by: Giulio, flickr
Giulio, flickr
Naughty boys and girls in Austria, Hungary, Croatia and Slovenia would be wise to perfect their hiding places each holiday season, or they'll be tossed in the sack of Krampus, St. Nick's nasty counterpart. As legend has it, the mythical Krampus keeps St. Nick company during the Christmas season. But while St. Nick dishes out the holiday cheer, Krampus has other plans; he's warning ill-behaved children to shape up.
When a particularly rotten kid crosses his path, Krampus shoves him in his sack to be taken back to his lair and, in a rather twisted twist, eaten. Looking a bit like an evil Satyr or monster goat, complete with horns and mangled fang-like teeth, Krampus appears in towns on December 5th, when locals don costumes and wander streets, terrifying the children -- and a few adults, we'd imagine -- who dare cross his path.
Mari Lwyd
Photo by: Paul Seligman, flickr
Paul Seligman, flickr
When your doorbell rings during the holiday season in Wales, don't expect to see a gaggle of carolers; rather, you might come face-to-skull with the head of the Mari Lwyd, or Grey Mare, and a small gang of attendees who will, in fact, be singing. The Mari Lwyd is a rendering of a horse and typically consists of a wood or cardboard horse skull, attached to a pole and carried by an individual draped in a sheet and accompanied by a small crowd of revelers.
The Mari Lwyd is brought around on or near the New Year by an ofttimes rowdy group who challenge homeowners to singing contests, and hope to be rewarded with entry to their homes and celebratory food and drink. The tradition is thought to stem from ancient Celtic rites, and is believed to bring luck to all the participants.
KFC Holiday Meal
KFC holiday meal in Japan
Photo by: rjzii, flickr
rjzii, flickr
Japanese gear up for the Christmas holiday -- which, it should be noted, is not officially celebrated in Japan -- up to 2 months in advance with an unexpected action: making reservations at their local KFC. Yes, that's right. KFC. The marketing geniuses at the corporation have managed to position its packaged fried chicken meals as a great American holiday tradition, stoking a fevered rush for the meals on Christmas Eve in Japan.
The demand for fried chicken is so high at this time, that the company suggests reserving a meal at least 2 months prior to the holiday's arrival. The standard Christmas meal here typically features fried chicken, a salad and chocolate cake. If you plan to join the fray, be prepared to settle in for a wait; lines can wrap out the fast-food joints' doors and down the block.
Photo by: Eleonara Gianinetto, flickr
Eleonara Gianinetto, flickr
Santa Claus (not to mention Mrs. Claus!) has competition across the Atlantic, in Italy, where the kindly old woman known as La Befana delivers presents to children every January 5th, the eve of the Epiphany, when it's believed the 3 Wise Men arrived at the manger of Jesus Christ delivering gifts.
La Befana is a gentle character, bestowed with magical powers, who appears every bit a witch, down to her long crooked nose and broomstick -- which she apparently uses both for transportation and to tidy messy homes. Eh, why not? Much like St. Nick, La Befana delivers Christmas presents to good boys and girls, and lumps of coal to the naughty. Though now tied to Christmas, the tradition of La Befana is thought to date as far back as the ancient Romans' pagan festival, Saturnalia, when people would go to a temple to have their fortunes read by an old woman.
Tuscany Should Be Your Next Adventure Travel Destination
Under the Tuscan Sun has given us a certain vision of idyllic Tuscany. But beyond its pretty looks and tasty food, there's outdoor adventure for everyone.
Meet the Yule Lads, Iceland's Terrifying Christmas Trolls
This cast of seasonal characters (and their mother, and a man-eating cat) make Krampus look like the Elf on the Shelf.
World's Best New Year's Eve Parties
Head to one of the world's finest New Year's Eve celebrations.
Europe's Best Christmas Festivals
Get in the holiday spirit at these great European Christmas markets.
Why This Mexican Town You Probably Haven't Heard of Is Worth a Visit for Day of the Dead
Instead of experiencing the holiday in Mexico City, go a little further off the beaten path for more intimate Noche and Dia de Muertos celebrations in Erongaricuaro.
Suite Deals for Travelers
Grab your pals, and make staying in a luxury suite an affordable experience.
Most Festive Christmas Cities
'Tis the season to plan a Christmas vacation with the family.
Christmas Festivals Around the World
Learn about Christmas celebrations around the world.
The following list of the New Seven Wonders is presented without ranking, and aims to represent global heritage. Keep in mind: Price and stock could change after publish date, and we may make money from these links.
Designer-Inspired Hotels
Stay at a luxurious hotel inspired by famous fashion designer.

redpajama_set_name: RedPajamaCommonCrawl


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Helma Klooss
Middendorp's Another Kind of Blue Creates a Complex Mosaic of Sight and Sound in Wave
by Helma Klooss
Rijswijkse schouwburg
Generaal Spoorlaan 10
Helma Klooss is a Netherlands-based dance writer and festival organizer. More about her dance festivals can be found at www.danskaravaan.nl, www.danskaravaan-educatief.nl and www.stranddans.nl
Choreographer David Middendorp a 2014 finalist on the television show America's Got Talent, created Wave, a new program in which he further investigated how dance and technology go together. Wave asks what the impact of technology is on society and whether mathematics and physics can be used to explore the emotional side of life—After all, we use waves every day to communicate and connect.
The program consisted of five works that were made in collaboration with the company's dancers. In between each piece, Middendorp and his dancers commented on the film elements of the works.
The program on December 4, 2021, began with the work "Frequency 1". In it, two dancers in silver-blue jumpsuits and side by side, made Chladli patterns (named after German physicist/musician Ernst Chladni) in the sand, with synchronous elegant twists. These Chladni patterns arise when a surface of fine sand is vibrated. The sand collects in the places where the surface does not move and disappears where the sand moves. Beautiful mosaics are the result. Bach's solo cello concerto accompanied the dancers. The dancers were filmed from above. The film, projected as a background, showed the dancers from a different perspective, surrounded by the mosaics. It was fascinating how the phenomenon from nature unfolded so beautifully before us.
Next, dancer Richel Wieles, dressed in a very special suit, along with 12 drones, created an exciting game of question and answer in the work "Airman."
To musician Brian Fennell's (a.k.a Syml) romantic song "Fear of the water," Wieles performed a powerful dance with large arm movements and gestures. His dancing created a mysterious atmosphere. The luminous drones flying above him seemed to move independently, which had an alienating effect. They were controlled by silver-grey balls on his costume and were part of a motion capture system. By means of reflection, they corresponded with special cameras so that the computer recorded the movements of the dancer in a 3D model that directed the drones.
Next, the duet "15 Minute Universe" was danced to a beautiful composition by Dutch composer Simeon ten Holt that was played live by the harpist Astrid Haring. Against a starry sky projection as a backdrop, we followed dancers Richel Wieles and Gijs Hanegraaf in slow impressive movements. Projected images of the sea, the high tide line, and undulating water were seen on the backdrop as well as on the floor. Moments later, the dancers moved in fast rotations caused by a small board with wheels under them. The projected background images were like that of a fairytale.
While "15 Minute Universe" proved magical, I would have loved to see this ballet danced by a male and female dancer couple because it would have created more variation and tension in their bodies.
At times hand gestures can be clearer than words. A clenched fist can show anger and enthusiastic waving of them can indicate we are happy. In a sense, they are like a dance.
The ballet "Hands ON Stage" sought to tap into that form of communication. It began with a duet of two women against a projected backdrop of magnified hands. They were joined by four more dancers and the ensemble performed to music by Bob Dylan and Asaf Avidan creating a lovely and elegant piece.
It was a wise choice to put the six dancers together because the technique used in the previous ballets on the program seemed to limit the choreographic possibilities. The dancers often use the same movements.
The program closed with "Frequency 2," the follow-up to the opening work "Frequency 1," only this time with three female dancers. Between them was the heavy motor of a sand machine. It is ingenious how Middendorp created a far more complex mosaic via the use of projections and with their powerful dance in the sand, how the trio of women avoided the spinning sand motor.
Middendorp is unique among the choreographers in the Netherlands and beyond. It is nice to see how his performances have developed in his career and what great success he has had with them.
Another Kind of Blue in "Airman"
Photo © & courtesy of Kim Vos
Another Kind of Blue in "15 Minute Universe"
Another Kind of Blue in "Frequency 1"
Another Kind of Blue in "Hands ON Stage"


Obama lands in Africa amid Mandela gloom – The Point Newspaper, Banjul, The Gambia | Peter "Just Loves Flying"
via Obama lands in Africa amid Mandela gloom – The Point Newspaper, Banjul, The Gambia.
US President Barack Obama landed in Senegal on Wednesday to begin a long awaited first major tour of Africa with the world preparing to bid a reluctant farewell to Nelson Mandela.
The possibility that the critically ill anti-apartheid icon could fade away within days has sparked uncertainty about Obama's itinerary.


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Wardlaw-Hartridge's Kuo is Home News Tribune 2018 Girls Golfer of the Year
Wardlaw-Hartridge's Kuo is Home News Tribune 2018 Girls Golfer of the Year Wardlaw-Hartridge's Kuo is Home News Tribune 2018 Girls Golfer of the Year Check out this story on mycentraljersey.com: https://mycj.co/2JEvRlA
Greg Tufaro, Courier News and Home News Tribune Published 8:34 a.m. ET June 12, 2018 | Updated 8:47 a.m. ET June 12, 2018
Wardlaw-Hartridge's Sydney Kuo is Home News Tribune 2018 Girls Golfer of the Year(Photo: ~submitted photo)
An injury that ended her promising career in one sport led Sydney Kuo to embrace a new athletic endeavor at which she has proved to be most successful.
The Wardlaw-Hartridge sophomore, who picked up golf less than four years ago after chronic foot pain forced her to abandon tennis, starred on the links for the Rams, capturing the Greater Middlesex Conference Tournament championship and placing 17th at the Prestigious Tournament of Champions.
READ:Kuo wins 2018 GMC girls golf tournament
Kuo is the 2018 Home News Tribune Girls Golfer of the Year, claiming the honor for the second consecutive season.
"This year, number's wise, she was much more consistent," Wardlaw-Hartridge coach Jim Howard said, noting Kuo trimmed two strokes off her average.
"She's multi-talented. She does so many different things. I told her she has to starting thinking about cutting back if she really wants to start playing golf. She's very determined. She's a really smart person who knows how to go about doing things."
In addition to excelling in the classroom, Kuo is a gifted pianist, artist and singer. Playing golf at the next level, however, appears to be her passion.
"Of all the extracurriculars, golf is the one I have the most interest in," Kuo said. "My hopes are to play at a Division I, maybe Division II college."
READ:Kuo is 2017 Home News Tribune Girls Golfer of the Year
Kuo is the top player on the boys golf team at Wardlaw-Hartridge, which does not field a girls team. She garnered All-Blue Division honors for the Rams, who finished with an 11-1 record, the lone loss coming with Logan D'Amore, another of the squad's top golfers, out of the lineup.
Kuo and talented teammate Mia Sutton, the other girl on the squad, will be joined next season by another female, an incoming eighth grader from Piscataway who is expected to challenge for the conference tournament title.
Motivated by the outcome of last year's league tournament, which Kuo lost on a match of cards after she and two other competitors finished in a tie after 18 holes, Kuo finished two strokes ahead of runner-up Sutton in this year's event.
"She didn't always show it," Howard said, "but that was a big motivation for her. She was really disappointed that she lost last year. That's something she was really working for."
Kuo's father introduced her to golf when playing tennis became unbearable due to her foot injury. She attended a golf camp at the West Nine in Plainfield and fell in love with the sport.
"Ever since I was a little kid, I used to play tennis," Kuo explained. "I was playing competitively in tournaments. After a while, I started to have chronic foot pain. It was hard to run around the court. My dad and I always thought I should have a sport to do. Why not golf?"
Kuo said she enjoys being a member of the Wardlaw-Hartridge squad but also appreciates the individual component of golf, where a player is competing against his or herself and the course.
"I think I do like relying on myself," Kuo explained, noting she can "be proud of myself or blame myself whenever I have a really good round."
Howard said were it not for a bad hole or two at both the Tournament of Champions and the Prep Tournament, where Kuo finished second, his star golfer would have placed higher in both events. Kuo attributed the difficulty in the former tournament to her stamina.
"I think that day, on the front nine, I played very well," she said. "As I kept going, the heat was crazy. That wore me down, as well as having a little bit of pressure. I got a little tired and started to lose my form. That hurt me a little bit. Other than that, I think I played very well that day."
Kuo said she will use that performance as motivation during the offseason to improve her game.
2018 All-GMC Girls Golf
Alexandra Caro, East Brunswick; Vritti Vazirani, J.P. Stevens; Rashi Sawant, South Brunswick; Roshni Shenoy, J.P. Stevens; Vidisha Jha, J.P. Stevens; Katie Nugent, Metuchen; Hailey Schaffer, East Brunswick; Maanasi Kondai, South Brunswic; Kayla McMahon, Sayreville. Sportsmanship: Sayreville. Coach of the Year: Mark Motusesky, East Brunswick.
Boys Basketball: Home News Tribune/GMC Top 10
Boys Basketball: Courier News Top 10


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3 boys arrested for attack on mentally challenged man
A man named Mark was punched in the face by a teenager on the streets of Phladelphia
Connie Andrews | 08 Июня, 2017, 00:48
The video has been viewed millions of times on Facebook since it was posted on Monday.
An alleged associate of the victim, Gerald Andrews Sr., reportedly shared the 30-second graphic visual to his Facebook last week, which features the individual, whom Andrews noted as "Mark", being approached by five young men outside of a business in the Germantown section of the east coast city.
"This guy is a friend of mine who happens to be mentally challenged", Andrews said.
According to Andrews, the victim is named Mark Smith, 38, and is one of his coworkers. "He's a good guy", he said.
A video that shows a man getting punched in the face by two juveniles is calling on police to bring justice to the situation.
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"He keeps that smile on his face".
After viewing the video, Philadelphia police asked the public to help them identify the juvenile boys.
Philadelphia Police Captain Malachi Jones says police had been looking for similarities in this incident and another incident in which a school principal was struck with a brick, just days after the other assault was caught on video. "It's a senseless act of violence". Another 15-year-old boy who delivered the second punch was apprehended Tuesday night, sources tell Action News "To them, they might have thought this was clever, but my message to them and kids in general is to do more constructive things with your time".
Three of the boys were arrested at school Tuesday and released into the custody of their parents.
No word yet on charges in the case.
The video has been viewed millions of times on Facebook since it was posted on Monday.An alleged associate of the victim, Gerald Andrews Sr., reportedly shared the 30-second graphic visual to his Face...
http:///2017/06/3-boys-arrested-for-attack-on-mentally-challenged-man/
Report Says Dalton Sears, Fort Oglethorpe Kmart On Closing List
The parent company of Sears and Kmart has reportedly chose to shut down 72 more stores this year. Revenue for the retailer was down by about a billion dollars in the first quarter of this year.
White House aide says Russia probe 'detracts' from agenda
"He's become more famous than me", the President joked before beckoning Comey over and giving him a warm handshake. His appearance will mark Comey's first public comments since he was abruptly fired by the president last month.
Virender Sehwag forwards two-line resume, BCCI demands a elaborate version
We had to ask him to send his CV too along with his application. "It will the first time he will be appearing for an interview". Amongst all the prominent names that applied for the job, former Australian cricketer Shane Warne was not one of them.
Former FBI Director James Comey to testify in Senate June 8
People close to Comey have said he wants to clear his name through public testimony. Comey and Trump's working relationship wasn't all bad.
How to watch Mark Zuckerberg's Harvard commencement speech
The CEO says that in history, the millennials are one of the most charitable generations. Last week, Zuckerberg posted a video of his reaction when he got into Harvard .
Many will agree these students crossed a line and forfeited the right to engage in unfettered debate, at least at Harvard . But with this action, Harvard is sending a message with a classic free-speech chill: You can say anything - but not here.
Airstrikes on Islamic State-held Syrian city kill 12
Turkey views the YPG as a terrorist group aligned with the PKK which has fought a bloody campaign in southeast Turkey since 1984. Almost 200,000 people and 5,000 militants live in the city, according to the organization Raqqa is Being Slaughtered Silently.
Huddersfield wins soccer's richest game, promoted to EPL
Gab Marcotti provides insight into Huddersfield Town manager David Wagner as the Terriers move up to the Premier League . Speaking to Sky Sports , he said: "By the way, Ian Holloway , all the best for next season".
President Xi leaves for Kazakhstan visit, SCO summit The SCO was founded in 2001 in Shanghai by the leaders of China, Kazakhstan, Kyrgyzstan, Russia, Tajikistan, and Uzbekistan. Srinivas said there could also be a couple of bilateral meetings with the leaders of the SCO member countries.
Florida Medical Marijuana Legislation Still Stagnating in Legislature If legislators can't reach an accord, Florida's public schools could be in danger of losing billions for the upcoming school year. First taking on economic development and educational funding, the topic of medical marijuana isn't now on theirscheduled agenda.
Gurugram gangrape: ACP reveals new details, arrested man confesses The police also reportedly did not register an FIR of gangrape initially but included the charge five days after the incident. The three accused allegedly started molesting the victim to which she resisted and the men threw the baby out of rickshaw.
Ex-Newcastle player Tiote dies after collapsing in training He was also part of the Ivory Coast squad who delivered the 2015 Africa Cup of Nations after a 23-year drought. Tiote's talent was spotted by Anderlecht officials, who signed him in 2005 on a three-year contract.
French Open Day 9: Murray and Halep hit top gear Former French Open champion Stan Wawrinka and two runners-up will complete their fourth-round matches on Monday at Roland Garros . Their head-to-head record stands at 2-2, with Garcia winning the pair's only previous meeting on clay in Madrid two years ago.
Gunman in Manila hotel attack dead from self-inflicted gunshot, police report The suspect fled the scene of the attack after robbing the casino, setting tables on fire as he went, dela Rosa added. He had stuffed chips totalling 113 million pesos ($2 million) in a backpack, but it was later recovered by police.
New smart speaker expected as Apple kicks off conference Amazon just announced its AI assistant Alexa will now be able to recognize commands to set reminders and named timers. - iPhone 8. Amazon has updated its smart speaker so that it's fully functional in the build-up to the General Election.
Thad Matta out as basketball coach at Ohio State The Buckeyes said a national search for a new coach would begin right away. When asked if he was finished coaching, Matta said, "Never say never.


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I don't know if this is just me, or whether we are all the same, but when friends or family are due to visit, I clean in places I hardly knew existed. Who is going to run their finger along the top of a wardrobe, or check for rolls of dust under a chest of drawers ? But somehow I feel impelled to clean there, just in case. The rest of the time I can live happily surrounded by dust, as I am out in the garden anyway !
So, when my partner and I were idly chatting a couple of weeks ago about the garden, one of us - probably him - mentioned the NGS (Yellow book), and suggested that we apply to open our garden for them next year. We had had a couple of glasses of wine. It seemed like a good idea.
We opened our garden for the NGS (National garden Scheme) in 2010 and thoroughly enjoyed the experience although the thought of it was quite scary initially. We intended to open again the following year but the terrible winter totally decimated the garden, killing lots of large exotics like tree ferns and palms and also the extensive hebe hedging. The low temperatures caused such devastation that we had to pull out of opening and replant. It has taken this long for new planting to establish itself.
Opening your garden for the NGS is a fantastic opportunity to make lots of money for charity and to chat with lots of passionate gardeners and swap ideas. Before we opened I had expected those visitors to be very knowledgable and very critical, if I am honest. Turns out that the former was true and the latter was false! Everyone was very forgiving and friendly, willing to share knowledge and ideas and to overlook the flaws in the garden.
So, that decision taken after a couple of glasses of wine became a reality, and we quickly received notification that Helen, our local organiser would be paying us a visit. Boy, did that goad us into action! We gardened through torrential rain, searing sun and darkness to get the metaphorical dust off the top of the wardrobe . We bought new plants to fill in gaps, and cut back unruly ones. We did unheard of things like raking the gravel and weeding between the raspberry canes. We waded into the ponds to remove excess weeds and cut back the marginals. 'Headless chickens' wouldn't begin to describe us, we worked every hour to get that garden to look as good as we possibly could. When we looked around it we saw only the flaws, the work undone, the rough edges. We asked ourselves why we were bothering to apply when we would surely be turned down.
Helen, our local organiser duly came, one warm sunny morning last week, and we showed her around the garden. She was lovely and very positive, and not critical in the slightest. And she told us, as we enjoyed tea and carrot cake sitting in the garden, that we are IN! Fantastic news ! And, to be fair, she actually told us BEFORE the carrot cake was in view, so it was a fair decision and not cake-based at all !
Euphoria presided at our house for all of a day. We drank more wine, we had a meal with friends, we drank some fizz... then reality set in !
Instead of spending a little time resting on our tiny laurels, one of us said "So, what improvements do we need to make before next year ?" and then we made a list. A very long list !
So now we are back out in the garden, planting, pruning, weeding and planning until late in the evening ... working towards our opening day next summer.


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