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Background Shoulder pathology can occur concurrently with a distal radius fracture (DRF) but few studies have examined this population. Purpose The purpose of this study was to expand the understanding of the impact of shoulder pathology on individuals with DRF. Study Design: Mixed Methods Design. Methods A total of 45 participants with a DRF were categorized into a DRF only (n = 29) and shoulder pathology concurrent with DRF (SPCDRF) (n = 16) groups. Quantitative data gathered included demographics, Quick Disabilities of the Arm, Shoulder, and Hand, Tampa Scale of Kinesiophobia-11, Visual Analog Scale, and Compensatory Mechanism Checklist. Qualitative interviews were performed with 7 participants in the SPCDRF group. Within group correlations were analyzed via the Spearman Rank. The Mann Whitney U test was used to compare the two groups. Qualitative analysis was performed to describe the experience of participants in the SPCDRF group. A mixed methods analysis compared quantitative and qualitative data. Results Sixteen participants (35.6%) in the sample presented with shoulder pathology; 6 participants (37.5%) presented at initial evaluation due to the fall; 10 participants (62.5%) developed shoulder pathology due to compensation or disuse. Average number of days to develop shoulder pathology after the DRF was 43 days. SPCDRF participants had significantly greater pain levels (p = .02) and more activity avoidance (p = .03) than the DRF only group. Four qualitative themes emerged: It's difficult to perform occupations and changes had to be made; There is fear and uncertainty; The impact of pain; Tried to be normal but could not Mixed methods analysis found that qualitative data further illuminated quantitative findings. Conclusions Individuals with shoulder pathology concurrent with a DRF may present with higher pain levels and avoid activity more. In addition, they may describe fearfulness in using their injured upper extremity especially if they have high levels of pain. Study Design Mixed Methods Design.

This first-in-kind, perfused, and amputated human limb model allows for the collection of human data in preclinical selection of lead fluorescent agents. The model facilitates more accurate selection and testing of fluorophores with human-specific physiology, such as differential uptake and signal in fat between animal and human models with zero risk to human patients. Preclinical testing using this approach may also allow for the determination of tissue toxicity, clearance time of fluorophores, and the production of harmful metabolites.This study was conducted to determine the fluorescence intensity values and tissue specificity of a preclinical, nerve tissue targeted fluorophore, as well as the capacity of this first-in-kind model to be used for lead fluorescent agent selection in the future.Freshly amputated human limbs were perfused for 30 min prior toThis model demonstrates an opportunity for preclinical testing, evaluation, and selection of fluorophores for use in clinical trials as well as an opportunity to study peripheral pathologies in a controlled environment.

Background Re-excision rates following breast conserving surgery (BCS) remain as high as ~ 35%, with positive margins detected during follow-up histopathology. Additional breast cancer resection surgery is not only taxing on the patient and health care system, but also delays adjuvant therapies, increasing morbidity and reducing the likelihood of a positive outcome. The ability to precisely resect and visualize tumor margins in real time within the surgical theater would greatly benefit patients, surgeons and the health care system. Current tumor margin assessment technologies utilized during BCS involve relatively lengthy and labor-intensive protocols, which impede the surgical work flow. Methods In previous work, we have developed and validated a fluorescence imaging method termed dual probe difference specimen imaging (DDSI) to accurately detect benign and malignant tissue with direct correlation to the targeted biomarker expression levels intraoperatively. The DDSI method is currently on par with touch prep cytology in execution time (~ 15-min). In this study, the main goal was to shorten the DDSI protocol by decreasing tissue blocking and washing times to optimize the DDSI protocol to Results We evaluated the utility of the shortened DDSI staining methodology using xenografts grown from cell lines with varied epidermal growth factor receptor (EGFR) expression levels, comparing accuracy through receiver operator characteristic (ROC) curve analyses across varied tissue blocking and washing times. An optimized 8-min DDSI methodology was developed for future clinical translation. Conclusions Successful completion of this work resulted in substantial shortening of the DDSI methodology for use in the operating room, that provided robust, highly receptor specific, sensitive diagnostic capabilities between benign and malignant tissues.

Nuclear instruments & methods in physics research / A 1040, 167099 (2022). doi:10.1016/j.nima.2022.167099, Published by North-Holland Publ. Co., Amsterdam

The current five-year survival rate of less than 5% for pancreatic ductal adenocarcinoma (PDAC) is compounded by late diagnosis, a lack of PDAC-specific intraoperative guidance to ensure complete resection, and the ineffectiveness of current therapies. Previously, utilizing compound 1, a fluorophore with inherent PDAC selectivity, PDAC was visualized both in vivo and ex vivo in a murine model. In the current study, human PDAC tissue is targeted. Compound 1 selectively stains ducts of the adenocarcinoma versus the surrounding stroma, enabling the imaging of PDAC in frozen tissue sections with high contrast. To enhance the potential of 1 for intraoperative applications, the ex vivo staining protocol was optimized for rapid margin assessment, with a final staining time of ~15 min. To measure diagnostic performance, the area under a receiver operating characteristic (ROC) curve was measured for the identification of ductal adenocarcinoma vs. stroma. The bright fluorescence contrast enabled quantitative determination of PDAC (or precancerous PanIN lesions) versus healthy pancreas tissue in human tissue array samples.

Review of scientific instruments 93(6), 063303 (2022). doi:10.1063/5.0094859, Published by American Institute of Physics, [Erscheinungsort nicht ermittelbar]

Iatrogenic nerve injury significantly affects surgical outcomes. Although intraoperative neuromonitoring is utilized, nerve identification remains challenging and the success of nerve sparing is strongly correlated with surgeon experience levels. Fluorescence guided surgery (FGS) offers a potential solution for improved nerve sparing by providing direct visualization of nerve tissue intraoperatively. However, novel probes for FGS face a long regulatory pathway to achieve clinical translation. Herein, we report on the development of a clinically-viable, gel-based formulation that enables direct administration of nerve-specific probes for nerve sparing FGS applications, facilitating clinical translation via the exploratory investigational new drug (eIND) guidance. The developed formulation possesses unique gelling characteristics, allowing it to be easily spread as a liquid followed by rapid gelling for subsequent tissue hold. Optimization of the direct administration protocol with our gel-based formulation enabled a total staining time of 1-2 minutes for compatibility with surgical procedures and successful clinical translation.

Tinnitus is defined as the perception of sound in the absence of external acoustic stimuli. Frequent comorbidities or associated factors are depression, anxiety, concentration problems, insomnia, resignation, helplessness, headache, bruxism, or social isolation, just to name a few. Although many therapeutic approaches have already been tested with varying success, there still is no cure available for tinnitus. The search for an effective treatment has been hampered by the fact that the mechanisms of tinnitus development are still not fully understood, although several models are available and discussed in this review. Our review will give a brief overview about preclinical models, presenting the heterogeneity of tinnitus sub-types depending on the different inner ear and brain structures involved in tinnitus etiology and pathogenesis. Based on these models we introduce the different target structures and transmitter systems implicated in tinnitus development and provide an extensive overview on preclinical drug-based therapeutic approaches that have been explored in various animal models. As the special extract from Ginkgo biloba leaves EGb 761® has been the most widely tested drug in both non-clinical tinnitus models as well as in clinical trials, a special focus will be given to EGb 761®. The efficacy of terpene lactones, flavone glycosides and proanthocyanidines with their distinct contribution to the overall efficacy profile of the multi-constituent drug EGb 761® will be discussed.

Fluorescence-guided surgery (FGS) to aid in the precise visualization of vital nerve structures in real-time intraoperatively could greatly improve patient outcomes. We took a medicinal chemistry approach that facilitated the design of our first-in-class NIR nerve-binding small molecule fluorophore libraries with excitation and emission profiles compatible with the “700-” and “800-” nm fluorescence imaging channels in the clinical grade FGS systems. Molecular engineering of the lead candidates allowed for the development of water-soluble nerve-specific contrast agents with improved safety profile that has great potential for clinical translation in the near future.

Nerve damage plagues surgical outcomes, significantly affecting post-surgical quality of life. Intraoperative nerve detection is difficult since neuroanatomy is varilable between patients, and nerves are typically protected deep within the tissue. Fluorescence-guided surgery (FGS) offers a potential means for enhanced intraoperative nerve identification and preservation. We have developed the first near infrared (NIR) nerve-specific fluorophores for use during FGS. Lead optimization has yielded water soluble derivatives with excellent safety and pharmacology parameters. Work is underway to plan and execute preclinical toxicity testing to enable first-in-human clincial trials.

Fluorescent contrast agents targeted to cancer biomarkers are increasingly being explored for cancer detection, surgical guidance, and response monitoring. Efforts have been underway to topically apply such biomarker-targeted agents to freshly excised specimen for detecting cancer cell receptors on the surface as a method for intraoperative surgical margin assessment, including dual-probe staining methods introduce a second ‘non-specific’ optical agent as a control to help compensate for heterogeneous uptake and normalize the imaging field. Still, such specimen staining protocols introduce multifaceted complexity with unknown variables, such as tissue-specific diffusion, cell-specific binding and disassociation rates, and other factors, affecting the interpreted cancer-biomarker distribution across the specimen surface. The ability to recover three-dimensional dual-probe biodistributions throughout whole-specimens could offer a ground-truth validation method for examining topical staining uptake behaviors. Herein, we report on a novel method for characterizing dual-probe accumulation with 3D depth-profiles observed from a dual-probe fresh-specimen staining experiment.

In the past several decades, a number of novel fluorescence image-guided surgery (FGS) contrast agents have been under development, with many in clinical translation and undergoing clinical trials. In this review, we have identified and summarized the contrast agents currently undergoing clinical translation. In total, 39 novel FGS contrast agents are being studied in 85 clinical trials. Four FGS contrast agents are currently being studied in phase III clinical trials and are poised to reach FDA approval within the next two to three years. Among all novel FGS contrast agents, a wide variety of probe types, targeting mechanisms, and fluorescence properties exists. Clinically available FGS imaging systems have been developed for FDA approved FGS contrast agents, and thus further clinical development is required to yield FGS imaging systems tuned for the variety of contrast agents in the clinical pipeline. Additionally, study of current FGS contrast agents for additional disease types and development of anatomy specific contrast agents is required to provide surgeons FGS tools for all surgical specialties and associated comorbidities. The work reviewed here represents a significant effort from many groups and further development of this promising technology will have an enormous impact on surgical outcomes across all specialties.

Accidental nerve damage or transection of vital nerve structures remains an unfortunate reality that is often associated with surgery. Despite the existence of nerve-sparing techniques, the success of such procedures is not only complicated by anatomical variance across patients but is also highly dependent on a surgeon’s first-hand experience that is acquired over numerous procedures through trial and error, often with highly variable success rates. Fluorescent small molecules, such as rhodamines and fluoresceins have proven incredibly useful for biological imaging in the life sciences, and they appeared to have potential in illuminating vital nerve structures during surgical procedures. In order to make use of the current clinically relevant imaging systems and to provide surgeons with fluorescent contrast largely free from the interference of hemoglobin and water, it was first necessary to spectrally tune known fluorescent scaffolds towards near infrared (NIR) wavelengths. To determine whether the well-documented Si-substitution strategy could be applied towards developing a NIR fluorophore that retained nerve-specific properties of candidate molecules, an in vivo comparison was made between two compounds previously shown to highlight nervous structures – TMR and Rhodamine B – and their Si-substituted derivatives.

Journal of Instrumentation 15(12), T12012 - T12012 (2020). doi:10.1088/1748-0221/15/12/T12012, Published by Inst. of Physics, London

Nerves are extremely difficult to identify and are often accidently damaged during surgery, leaving patients with lasting pain and numbness. Herein, a novel near-infrared (NIR) nerve-specific fluorophore, LGW01–08, was utilized for enhanced nerve identification using fluorescence guided surgery (FGS), formulated using clinical translatable strategies. Formulated LGW01–08 was examined for toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) parameters in preparation for future clinical translation. Optimal LGW01–08 imaging doses were identified in each formulation resulting in a 10x difference between the toxicity to imaging dose window. Laparoscopic swine surgery completed using the da Vinci surgical robot (Intuitive Surgical) demonstrated the efficacy of formulated LGW01–08 for enhanced nerve identification. NIR fluorescence imaging enabled clear identification of nerves buried beneath ~3 mm of tissue that were unidentifiable by white light imaging. These studies provide a strong basis for future clinical translation of NIR nerve-specific fluorophores for utility during FGS to improve patient outcomes.

Rationale Positive margin status due to incomplete removal of tumor tissue during breast conserving surgery (BCS) is a prevalent diagnosis usually requiring a second surgical procedure. These follow-up procedures increase the risk of morbidity and delay the use of adjuvant therapy; thus, significant efforts are underway to develop new intraoperative strategies for margin assessment to eliminate re-excision procedures. One strategy under development uses topical application of dual probe staining and a fluorescence imaging strategy termed dual probe difference specimen imaging (DDSI). DDSI uses a receptor-targeted fluorescent probe and an untargeted, spectrally-distinct fluorescent companion imaging agent topically applied to fresh resected specimens, where the fluorescence from each probe is imaged and a normalized difference image is computed to identify tumor-target distribution in the specimen margins. While previous reports suggested this approach is a promising new tool for surgical guidance, advancing the approach into the clinic requires methodical protocol optimization and further validation. Methods In the present study, we used breast cancer xenografts and receiver operator characteristic (ROC) curve analysis to evaluate a wide range of staining and imaging parameters, and completed a prospective validation study on multiple tumor phenotypes with different target expression. Imaging fluorophore-probe pair, concentration, and incubation times were systematically optimized using n=6 tissue specimen replicates per staining condition. Resulting tumor vs. normal adipose tissue diagnostic performance were reported and staining patterns were validated via receptor specific immunohistochemistry colocalization. Optimal staining conditions were tested in receptor positive and receptor negative cohorts to confirm specificity. Results The optimal staining conditions were found to be a one minute stain in a 200 nM probe solution (area under the curve (AUC) = 0.97), where the choice of fluorescent label combination did not significantly affect the diagnostic performance. Using an optimal threshold value determined from ROC curve analysis on a training data set, a prospective study on xenografts resulted in an AUC=0.95 for receptor positive tumors and an AUC = 0.50 for receptor negative (control) tumors, confirming the diagnostic performance of this novel imaging technique. Conclusions DDSI provides a robust, molecularly specific imaging methodology for identifying tumor tissue over benign mammary adipose tissue. Using a dual probe imaging strategy, nonspecific accumulation of targeted probe was corrected for and tumor vs. normal tissue diagnostic potential was improved, circumventing difficulties with ex vivo tissue specimen staining and allowing for rapid clinical translation of this promising technology for tumor margin detection during BCS procedures.

Molecular probes that selectively highlight pancreatic cancer (PC) tissue have the potential to improve pancreatic ductal adenocarcinoma (PDAC) margin assessment through the selective highlighting of individual PC cells. Herein, we report a simple and unique family of systematically modified red and near-infrared fluorescent probes that exhibit a field-effect-derived redshift. Two of thirteen probes distributed to the normal mouse pancreas following systemic administration. One selectively accumulated in genetically modified mouse models of PDAC. The probe exhibited intracellular accumulation and enabled visualization of four levels of the structure, including the whole organ, resected tissue, individual cells, and subcellular organelles. In contrast to the small-molecule probes reported previously, it possesses an inherent affinity toward PDAC cells and thus does not require conjugation to any targeting agent. The fluorescent probe can thus promote new strategies not only for precision image-guided surgery, but also for PC detection, monitoring of therapeutic outcomes, and basic research.

Nerve-binding fluorophores with near-infrared (NIR; 650 to 900 nm) emission could reduce iatrogenic nerve injury rates by providing surgeons precise, real-time visualization of the peripheral nervous system. Unfortunately, current systemically administered nerve contrast agents predominantly emit at visible wavelengths and show nonspecific uptake in surrounding tissues such as adipose, muscle, and facia, thus limiting detection to surgically exposed surface-level nerves. Here, a focused NIR fluorophore library was synthesized and screened through multi-tiered optical and pharmacological assays to identify nerve-binding fluorophore candidates for clinical translation. NIR nerve probes enabled micrometer-scale nerve visualization at the greatest reported tissue depths (~2 to 3 mm), a feat unachievable with previous visibly emissive contrast agents. Laparoscopic fluorescent surgical navigation delineated deep lumbar and iliac nerves in swine, most of which were invisible in conventional white-light endoscopy. Critically, NIR oxazines generated contrast against all key surgical tissue classes (muscle, adipose, vasculature, and fascia) with nerve signal-to-background ratios ranging from ~2 (2- to 3-mm depth) to 25 (exposed nerve). Clinical translation of NIR nerve-specific agents will substantially reduce comorbidities associated with surgical nerve damage.

Identification of tumor margins in the operating room in real time is a critical challenge for surgical procedures that serve as cancer cure. Breast conserving surgery (BCS) is particularly affected by this problem, with current re-excision rates above 25%. Due to a lack of clinically available methodologies for detection of involved or close tumor margins, much effort is focused on developing intraoperative margin assessment modalities that can aid in addressing this unmet clinical need. BCS provides a unique opportunity to design contrast-based technologies that are able to assess tumor margins independent from the patient, providing a rapid pathway from bench to bedside at a much lower cost. Since resected tissue is removed from the patient's blood supply, non-specific contrast agent uptake becomes a challenge due to the lack of clearance. Therefore, a dual probe, ratiometric fluorescence imaging approach was taken in an effort to reduce non-specific signal, and provide a modality that could demonstrate rapid, robust margin assessment on resected patient samples. Termed, dual-stain difference specimen imaging (DDSI), DDSI includes the use of spectrally unique, and fluorescently labeled target-specific, as well as non-specific biomarkers. In the present study, we have applied epidermal growth factor receptor (EGFR) targeted DDSI to tumor xenografts with variable EGFR expression levels using a previously optimized staining protocol, allowing for a quantitative assessment of the predictive power of the technique under biologically relevant conditions. Due to the presence of necrosis in the model tumors, ring analysis was employed to characterize diagnostic accuracy as measured by receiver operator characteristic (ROC) curve analysis. Our findings demonstrate the robust nature of the DDSI technique even in the presence of variable biomarker expression and spatial patterns. These results support the continued development of this technology as a robust diagnostic tool for tumor margin assessment in resected specimens during BCS.

Journal of physics / Conference series Conference series [...] 1350, 012186 (2019). doi:10.1088/1742-6596/1350/1/012186, Published by IOP Publ.39969, Bristol

Nerve damage during surgery is a common morbidity experienced by patients that leaves them with chronic pain and/or loss of function. Currently, no clinically approved imaging technique exists to enhance nerve visualization in the operating room. Fluorescence image-guided surgery has gained in popularity and clinical acceptance over the past decade with a handful of imaging systems approved for clinical use. However, contrast agent development to complement these fluorescence-imaging systems has lagged behind with all currently approved fluorescent agents providing untargeted blood pool information. Nerve-specific fluorophores are known, however translations of these agents to the clinic has been complicated by their lipophilic nature, which necessitates specialized formulation strategies for successful systemic administration. To date the known nerve-specific fluorophores have only been demonstrated preclinically due to the necessity of a dimethyl sulfoxide containing formulation for solubilization. In the current study, a polymeric micellar (PM) formulation strategy was developed for a representative nerve-specific fluorophore from the distyrylbenzene family, BMB. The PM formulation strategy was able to solubilize BMB and demonstrated improved nerve-specific accumulation and fluorescence intensity when the same fluorophore dose was administered to mice utilizing the previous formulation strategy. The success of the PM formulation strategy will be important for moving toward clinical translation of these novel nerve-specific probes as it is nontoxic and biodegradable and has the potential to decrease the necessary dose for imaging while also improving the safety profile.

PurposeRapid, intra-operative identification of tumor tissue in the margins of excised specimens has become an important focus in the pursuit of reducing re-excision rates, especially for breast conserving surgery. Dual-probe difference specimen imaging (DDSI) is an emerging approach that uses the difference in uptake/clearance kinetics between a pair of fluorescently-labeled stains, one targeted to a biomarker-of-interest and the other an untargeted isotype, to reveal receptor-specific images of the specimen. Previous studies using antibodies labeled with either enhanced Raman particles or organic fluorophores have shown promising tumor vs. normal diagnostic performance. Yet, the unique properties of quantum dot-labeled antibody complexes (QDACs), which provide spectrally-distinct fluorescence emission from a common excitation source, make them ideal candidates for this application. Herein, we evaluate the diagnostic performance of QDAC-based DDSI in excised xenografts.ProceduresExcised fresh specimens of normal tissue and human tumor xenografts with elevated expression of HER2 were stained with a HER2-targeted QDAC and an untargeted QDAC isotype. Stained specimens were imaged on a custom hyperspectral imaging system capable of spectrally separating the quantum dot signatures, and images processed using the DDSI approach. The diagnostic performance of this technique under different incubation temperatures and probe concentrations was evaluated using receiver-operator characteristic analysis.ResultsHER2-targeted QDAC-DDSI was able to distinguish HER2(+) tumors from normal tissue with reasonably high diagnostic performance; however, this performance was sensitive to temperature during the staining procedure. Area under the curve values were 0.61 when staining at room temperature but increased to over 0.81 when staining at 37 °C. Diagnostic performance was not affected by increasing stain concentration.ConclusionsThis study is the first to report dual-probe difference imaging of specimens using QDACs and hyperspectral imaging. Our results show promising diagnostic performance under certain conditions, and compel further optimization and evaluation of this intra-operative margin assessment technique.

Complete removal of malignant tissue during primary breast cancer resection is a critical prognostic indicator of local recurrence and overall patient survival, making intraoperative tumor margin assessment essential. Positive margin status following breast-conserving surgery (BCS) is a common difficulty reported in 20-60% of patients, with re-excision rates >55%. Re-excision increases the risk of morbidity and delays the use of adjuvant therapy, thus significant efforts are underway to develop successful intraoperative margin assessment strategies to eliminate repeat surgery. One novel strategy uses topical application of dual probe staining and a fluorescence imaging strategy termed dual probe difference specimen imaging (DDSI) where a receptor-targeted fluorescent probe and an untargeted, spectrally-distinct fluorescent probe are topically applied to the fresh resected specimen. While conceptually simple, resected specimen staining is dominated by non-specific uptake of fluorescent probes in normal tissue, requiring the use of a dual probe strategy for accuracy. DDSI permits fluorescence images from both the targeted and untargeted probes to be used to calculate a normalized difference image, facilitating quantitative identification of targeted probe tumor distribution in the specimen. While previous reports suggested this approach is a promising new tool for surgical guidance, advancing the approach into the clinic requires methodical protocol optimization and validation. Current work is focused on development of targeted and untargeted small molecule affinity tags, facilitating access to intracellular breast cancer biomarkers and quantitative assessment of DDSI signal in the context of varied biomarker expression level.

Nerve damage plagues surgical outcomes, significantly affecting post-surgical quality of life. Surprisingly, no method exists to enhance direct nerve visualization in the operating room, and nerve detection is completed through a combination of palpation and visualization when possible. Fluorescence image-guided surgery offers a potential means of enhanced nerve identification and preservation, however a clinically approved nerve-specific contrast agent does not yet exist. Several classes of nerve-specific fluorophores have recently been demonstrated including the distyrylbenzenes (DSB), select oxazines (oxazine 4 perchlorate), and certain cyanines (3,3’-diethylthiatricarbocyanine iodine), which could provide intraoperative guidance. The nerve-sparing radical prostatectomy is a surgical procedure that could benefit from fluorescence image-guided nerve identification. Although the nerve-sparing surgical technique was developed over 30 years ago, nerve damage following radical prostatectomy is reported in some form in up to 60% of patients one to two years post-surgery. To facilitate clinical translation of fluorescence image guided surgery to the nerve sparing prostatectomy, a direct administration methodology was developed that allows selective nerve highlighting with a significantly lower fluorophore dose than systemic administration, where large animal studies have confirmed the technique’s translatability. Tissue penetration will be critical for clinical feasibility of the direct administration methodology and novel formulation strategies have been explored to enhance tissue penetration for identifying buried nerves. In addition, several biomolecular targets of Oxazine 4, a promising candidate for nerve-specific fluorophore development into a near-infrared (NIR) agent, have been identified, providing insight into the mechanism of nerve-specificity. Fluorophore development has made progress towards the goal of creating a NIR nerve-specific fluorophore and determining the structure-activity relationship responsible for nerve binding.

After a successful production of isotopes of element 116 in the reaction 48Ca + 248Cm, the reaction 54Cr + 248Cm → 302120* was investigated at the velocity filter SHIP at GSI, Darmstadt, aiming to search for isotopes of element 120. One chain of events was observed, which is not created by chance with high probability. Parts of the chain agree with model predictions and measured data from a decay chain which could start at the isotope 299120. In a complementary study, model dependent shell-correction energies and related heights of fission barriers were deduced from measured Qα values. The results are compared with predictions of macroscopic-microscopic models. The consequences for calculations of crosssections are discussed.

The chosen design concepts and technical approaches as described in the Heavy Ion Driver Ignition Facility (HIDIF) study are compared with the present status of accelerator technologies and the experiences gained in the operation of the heavy ion accelerator facilities at GSI. Novel advanced technologies, as developed e.g. for the FAIR Project, may be used for a more compact and realistic driver layout. Major differences between a single shot and a high repetition rate facility will be discussed.

Intraoperative margin assessment is imperative to cancer cure but is a continued challenge to successful surgery. Breast conserving surgery is a relevant example, where a cosmetically improved outcome is gained over mastectomy, but re-excision is required in >25% of cases due to positive or closely involved margins. Clinical translation of margin assessment modalities that must directly contact the patient or required administered contrast agents are time consuming and costly to move from bench to bedside. Tumor resections provide a unique surgical opportunity to deploy margin assessment technologies including contrast agents on the resected tissues, substantially shortening the path to the clinic. However, staining of resected tissues is plagued by nonspecific uptake. A ratiometric imaging approach where matched targeted and untargeted probes are used for staining has demonstrated substantially improved biomarker quantification over staining with conventional targeted contrast agents alone. Our group has developed an antibody-based ratiometric imaging technology using fluorescently labeled, spectrally distinct targeted and untargeted antibody probes termed dual-stain difference specimen imaging (DDSI). Herein, the targeted biomarker expression level and pattern are evaluated for their effects on DDSI diagnostic potential. Epidermal growth factor receptor expression level was correlated to DDSI diagnostic potential, which was found to be robust to spatial pattern expression variation. These results highlight the utility of DDSI for accurate margin assessment of freshly resected tumor specimens.