Rules of engagement: Promoting academic-industry partnership in the era of digital pathology and artificial intelligence.

Academic industry partnership (AIP) represents an important alliance between academic researchers and industry that helps translate technology and complete the innovation cycle within academic health systems. Despite diverging missions and skillsets the culture for academia and industry is changing in response to the current digital era which is spawning greater collaboration between physicians and businesses in this marketplace. In the field of pathology, this is further driven by the fact that traditional funding sources cannot keep pace with the innovation needed in digital pathology and artificial intelligence. This concept article from the Digital Pathology Association (DPA) describes the rules of engagement for pathology innovators in academia and for their corporate partners to help establish best practices in this critical area. Stakeholders include pathologists, basic and translational researchers, university technology transfer and sponsored research offices, as well as industry relations officers. The article discusses the benefits and pitfalls of an AIP, reviews different partnership models, examines the role of pathologists in the innovation cycle, explains various agreements that may need to be signed, covers conflict of interest and intellectual property issues, and offers recommendations for ensuring successful partnerships.

Automated gigapixel circumferential surface microscopy of the prostate.

Positive surgical margins, or cancer cells found at the boundary of an excised tumor mass, are a significant problem in the management of many cancers resulting in worsened patient outcomes. The problem is exacerbated in organ sites such as the prostate, where unnecessarily wide local excisions can result in significant deterioration of post-operative quality of life due to collateral damage to neighboring structures. Yet, at the same time, incomplete tumor removal results in worsened prognosis and need for additional interventions. Here, we report the design and development of a rapid and completely automated system for intraoperative gigapixel ex vivo microscopy of the circumferential surgical prostate margin within intra-operative timeframes, called the Automated Prostate Positioning System (APPS). The APPS leverages the rotational geometry of the prostate and high speed structured illumination microscopy (SIM) to generate continuous gigapixel panoramas of the fresh intact prostate circumference, including areas of the prostate adjacent to the neurovascular bundles, the rectum, and the bladder wall. Our previous work using SIM and a manual prostate handling method demonstrated the promise of the imaging technique for accurate detection of positive surgical margins. Our work here advances the technology toward clinical adoption, by demonstrating 10% greater tissue surface coverage fraction, 1.6× faster imaging throughput, and reduced number of required operator steps, compared to our prior approach. The APPS may be operated by a single person in the operating room suite within intraoperative time limits, while simultaneously delivering nearly two orders of magnitude higher tissue surface coverage than destructive and labor-intensive frozen section analysis techniques.

Partial nephrectomy margin imaging using structured illumination microscopy.

Partial nephrectomy (PN) is the recommended procedure over radical nephrectomy (RN) for patients with renal masses less than 4 cm in diameter (Stage T1a). Patients with less than 4 cm renal masses can also be treated with PN, but have a higher risk for positive surgical margins (PSM). PSM, when present, are indicative of poor clinical outcomes. The current gold-standard histopathology method is not well-suited for the identification of PSM intraoperatively due to processing time and destructive nature. Here, video-rate structured illumination microscopy (VR-SIM) was investigated as a potential tool for PSM detection during PN. A clinical image atlas assembled from ex vivo renal biopsies provided diagnostically useful images of benign and malignant kidney, similar to permanent histopathology. VR-SIM was then used to image entire parenchymal margins of tumor resection covering up to >1800× more margin surface area than standard histology. Aided by the image atlas, the study pathologist correctly classified all parenchymal margins as negative for PSM with VR-SIM, compared to standard postoperative pathology. The ability to evaluate large surgical margins in a short time frame with VR-SIM may allow it to be used intraoperatively as a "safety net" for PSM detection, allowing more patients to undergo PN over RN.

DRAQ5 and Eosin ('D&E') as an Analog to Hematoxylin and Eosin for Rapid Fluorescence Histology of Fresh Tissues.

Real-time on-site histopathology review of biopsy tissues at the point-of-procedure has great potential for significant clinical value and improved patient care. For instance, on-site review can aid in rapid screening of diagnostic biopsies to reduce false-negative results, or in quantitative assessment of biospecimen quality to increase the efficacy of downstream laboratory and histopathology analysis. However, the only currently available rapid pathology method, frozen section analysis (FSA), is too time- and labor-intensive for use in screening large quantities of biopsy tissues and is too destructive for maximum tissue conservation in multiple small needle core biopsies. In this work we demonstrate the spectrally-compatible combination of the nuclear stain DRAQ5 and the anionic counterstain eosin as a dual-component fluorescent staining analog to hematoxylin and eosin intended for use on fresh, unsectioned tissues. Combined with optical sectioning fluorescence microscopy and pseudo-coloring algorithms, DRAQ5 and eosin ("D&E") enables very fast, non-destructive psuedohistological imaging of tissues at the point-of-acquisition with minimal tissue handling and processing. D&E was validated against H&E on a one-to-one basis on formalin-fixed paraffin-embedded and frozen section tissues of various human organs using standard epi-fluorescence microscopy, demonstrating high fidelity of the staining mechanism as an H&E analog. The method was then applied to fresh, whole 18G renal needle core biopsies and large needle core prostate biospecimen biopsies using fluorescence structured illumination optical sectioning microscopy. We demonstrate the ability to obtain high-resolution histology-like images of unsectioned, fresh tissues similar to subsequent H&E staining of the tissue. The application of D&E does not interfere with subsequent standard-of-care H&E staining and imaging, preserving the integrity of the tissue for thorough downstream analysis. These results indicate that this dual-stain pseudocoloring method could provide a real-time histology-like image at the time of acquisition and valuable objective tissue analysis for the clinician at the time of service.

Nondestructive Diagnosis of Kidney Cancer on 18-gauge Core Needle Renal Biopsy Using Dual-color Fluorescence Structured Illumination Microscopy.

OBJECTIVE: To present a novel imaging technique used for rapid, nondestructive histological assessment of renal neoplasias using a dual-component fluorescence stain and structured illumination microscopy (SIM). MATERIALS AND METHODS: After Institutional Review Board approval, 65 total biopsies were obtained from 19 patients undergoing partial or radical nephrectomy. Biopsies were stained with a dual-component fluorescent, and optically sectioned SIM images were obtained from the surface of the intact biopsies. Specimens were subsequently fixed and analyzed using hematoxylin and eosin (H&E) histopathologic methods and compared with SIM images. A single, board-certified pathologist blinded to specimens reviewed all SIM images and H&E slides, and determined the presence or absence of neoplasias. Results of blinded diagnosis of SIM were validated against traditional pathology. RESULTS: Of the 19 patients, 15 underwent robotic partial nephrectomies and 4 underwent laparoscopic nephrectomies. Indications included clinical suspicion of renal cell carcinoma. In total, 65 biopsy specimens were available for review. Twenty-one specimens were determined to be neoplastic on H&E, whereas 41 represented benign renal tissue. The final sensitivity and specificity of our study were 79.2% and 95.1%, respectively. CONCLUSION: SIM is a promising technology for rapid, near-patient, ex vivo renal biopsy assessment. By improving the ability to rapidly assess sufficiency of biopsy specimens and enabling immediate diagnostic capability, SIM aids in more effective biopsy performance, tissue triage, and patient counseling regarding management options. Additionally, because tissue is preserved, effective utilization of downstream diagnostic tests and molecular assessments are possible.

Gigapixel surface imaging of radical prostatectomy specimens for comprehensive detection of cancer-positive surgical margins using structured illumination microscopy.

Achieving cancer-free surgical margins in oncologic surgery is critical to reduce the need for additional adjuvant treatments and minimize tumor recurrence; however, there is a delicate balance between completeness of tumor removal and preservation of adjacent tissues critical for normal post-operative function. We sought to establish the feasibility of video-rate structured illumination microscopy (VR-SIM) of the intact removed tumor surface as a practical and non-destructive alternative to intra-operative frozen section pathology, using prostate cancer as an initial target. We present the first images of the intact human prostate surface obtained with pathologically-relevant contrast and subcellular detail, obtained in 24 radical prostatectomy specimens immediately after excision. We demonstrate that it is feasible to routinely image the full prostate circumference, generating gigapixel panorama images of the surface that are readily interpreted by pathologists. VR-SIM confirmed detection of positive surgical margins in 3 out of 4 prostates with pathology-confirmed adenocarcinoma at the circumferential surgical margin, and furthermore detected extensive residual cancer at the circumferential margin in a case post-operatively classified by histopathology as having negative surgical margins. Our results suggest that the increased surface coverage of VR-SIM could also provide added value for detection and characterization of positive surgical margins over traditional histopathology.

Continuous versus bolus tube feeds: Does the modality affect glycemic variability, tube feeding volume, caloric intake, or insulin utilization?

INTRODUCTION: Enteral nutrition (EN) is very important to optimizing outcomes in critical illness. Debate exists regarding the best strategy for enteral tube feeding (TF), with concerns that bolus TF (BTF) may increase glycemic variability (GV) but result in fewer nutritional interruptions than continuous TF (CTF). This study examines if there is a difference in GV, insulin usage, TF volume, and caloric delivery among intensive care patients receiving BTF versus CTF. We hypothesize that there are no significant differences between CTF and BTF when comparing the above parameters. MATERIALS AND METHODS: Prospective, randomized pilot study of critically ill adult patients undergoing percutaneous endoscopic gastrostomy (PEG) placement for EN was performed between March 1, 2012 and May 15, 2014. Patients were randomized to BTF or CTF. Glucose values, insulin use, TF volume, and calories administered were recorded. Data were organized into 12-h epochs for statistical analyses and GV determination. In addition, time to ≥80% nutritional delivery goal, demographics, Acute Physiology and Chronic Health Evaluation II scores, and TF interruptions were examined. When performing BTF versus CTF assessments, continuous parameters were compared using Mann-Whitney U-test or repeated measures t-test, as appropriate. Categorical data were analyzed using Fisher's exact test. RESULTS: No significant demographic or physiologic differences between the CTF (n = 24) and BTF (n = 26) groups were seen. The immediate post-PEG 12-h epoch showed significantly lower GV and median TF volume for patients in the CTF group. All subsequent epochs (up to 18 days post-PEG) showed no differences in GV, insulin use, TF volume, or caloric intake. Insulin use for both groups increased when comparing the first 24 h post-PEG values to measurements from day 8. There were no differences in TF interruptions, time to ≥80% nutritional delivery goal, or hypoglycemic episodes. CONCLUSIONS: This study demonstrated no clinically relevant differences in GV, insulin use, TF volume or caloric intake between BTF and CTF groups. Despite some shortcomings, our data suggest that providers should not feel limited to BTF or CTF because of concerns for GV, time to goal nutrition, insulin use, or caloric intake, and should consider other factors such as resource utilization, ease of administration, and/or institutional/patient characteristics.

High-Resolution Rapid Diagnostic Imaging of Whole Prostate Biopsies Using Video-Rate Fluorescence Structured Illumination Microscopy.

Rapid assessment of prostate core biopsy pathology at the point-of-procedure could provide benefit in a variety of clinical situations. Even with advanced transrectal ultrasound guidance and saturation biopsy protocols, prostate cancer can be missed in up to half of all initial biopsy procedures. In addition, collection of tumor specimens for downstream histologic, molecular, and genetic analysis is hindered by low tumor yield due to inability to identify prostate cancer grossly. However, current point-of-procedure pathology protocols, such as frozen section analysis (FSA), are destructive and too time- and labor-intensive to be practical or economical. Ex vivo microscopy of the excised specimens, stained with fast-acting fluorescent histology dyes, could be an attractive nondestructive alternative to FSA. In this work, we report the first demonstration of video-rate structured illumination microscopy (VR-SIM) for rapid high-resolution diagnostic imaging of prostate biopsies in realistic point-of-procedure timeframes. Large mosaic images of prostate biopsies stained with acridine orange are rendered in seconds and contain excellent contrast and detail, exhibiting close correlation with corresponding hematoxylin and eosin histology. A clinically relevant review of VR-SIM images of 34 unfixed and uncut prostate core biopsies by two independent pathologists resulted in an area under the receiver operative curve (AUC) of 0.82-0.88, with a sensitivity ranging from 63% to 88% and a specificity ranging from 78% to 89%. When biopsies contained more than 5% tumor content, the sensitivity improved to 75% to 92%. The image quality, speed, minimal complexity, and ease of use of VR-SIM could prove to be features in favor of adoption as an alternative to destructive pathology at the point-of-procedure.

A systematic review of the need for MRI for the clearance of cervical spine injury in obtunded blunt trauma patients after normal cervical spine CT.

Clearance of cervical spine injury (CSI) in the obtunded or comatose blunt trauma patient remains controversial. In patients with unreliable physical examination and no evidence of CSI on computed tomography (CT), magnetic resonance imaging of the cervical spine (CS-MRI) is the typical follow-up study. There is a growing body of evidence suggesting that CS-MRI is unnecessary with negative findings on a multi-detector CT (MDCT) scan. This review article systematically analyzes current literature to address the controversies surrounding clearance of CSI in obtunded blunt trauma patients. A literature search through MEDLINE database was conducted using all databases on the National Center for Biotechnology Information (NCBI) website (www.ncbi.nlm.nih.gov) for keywords: "cervical spine injury," "obtunded," and "MRI." The search was limited to studies published within the last 10 years and with populations of patients older than 18 years old. Eleven studies were included in the analysis yielding data on 1535 patients. CS-MRI detected abnormalities in 256 patients (16.6%). The abnormalities reported on CS-MRI resulted in prolonged rigid c-collar immobilization in 74 patients (4.9%). Eleven patients (0.7%) had unstable injury detected on CS-MRI alone that required surgical intervention. In the obtunded blunt trauma patient with unreliable clinical examination and a normal CT scan, there is still a role for CS-MRI in detecting clinically significant injuries when MRI resources are available. However, when a reliable clinical exam reveals intact gross motor function, CS-MRI may be unnecessary.

Veno-venous ECMO: a synopsis of nine key potential challenges, considerations, and controversies.

BACKGROUND: Following the 2009 H1N1 Influenza pandemic, extracorporeal membrane oxygenation (ECMO) emerged as a viable alternative in selected, severe cases of ARDS. Acute Respiratory Distress Syndrome (ARDS) is a major public health problem. Average medical costs for ARDS survivors on an annual basis are multiple times those dedicated to a healthy individual. Advances in medical and ventilatory management of severe lung injury and ARDS have improved outcomes in some patients, but these advances fail to consistently "rescue" a significant proportion of those affected. DISCUSSION: Here we present a synopsis of the challenges, considerations, and potential controversies regarding veno-venous ECMO that will be of benefit to anesthesiologists, surgeons, and intensivists, especially those newly confronted with care of the ECMO patient. We outline a number of points related to ECMO, particularly regarding cannulation, pump/oxygenator design, anticoagulation, and intravascular fluid management of patients. We then address these challenges/considerations/controversies in the context of their potential future implications on clinical approaches to ECMO patients, focusing on the development and advancement of standardized ECMO clinical practices. SUMMARY: Since the 2009 H1N1 pandemic ECMO has gained a wider acceptance. There are challenges that still must be overcome. Further investigations of the benefits and effects of ECMO need to be undertaken in order to facilitate the implementation of this technology on a larger scale.

Thoracostomy tubes: A comprehensive review of complications and related topics.

Tube thoracostomy (TT) placement belongs among the most commonly performed procedures. Despite many benefits of TT drainage, potential for significant morbidity and mortality exists. Abdominal or thoracic injury, fistula formation and vascular trauma are among the most serious, but more common complications such as recurrent pneumothorax, insertion site infection and nonfunctioning or malpositioned TT also represent a significant source of morbidity and treatment cost. Awareness of potential complications and familiarity with associated preventive, diagnostic and treatment strategies are fundamental to satisfactory patient outcomes. This review focuses on chest tube complications and related topics, with emphasis on prevention and problem-oriented approaches to diagnosis and treatment. The authors hope that this manuscript will serve as a valuable foundation for those who wish to become adept at the management of chest tubes.

Clevidipine for perioperative blood pressure control in infants and children.

Various pharmacologic agents have been used for perioperative BP control in pediatric patients, including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. Of the calcium antagonists, the majority of the clinical experience remains with the dihydropyridine nicardipine. Clevidipine is a short-acting, intravenous calcium channel antagonist of the dihydropyridine class. It undergoes rapid metabolism by non-specific blood and tissue esterases with a half-life of less than 1 minute. As a dihydropyridine, its cellular and end-organ effects parallel those of nicardipine. The clevidipine trials in the adult population have demonstrated efficacy in rapidly controlling BP in various clinical scenarios with a favorable adverse effect profile similar to nicardipine. Data from large clinical trials regarding the safety and efficacy of clevidipine in children is lacking. This manuscript aims to review the commonly used pharmacologic agents for perioperative BP control in children, discuss the role of calcium channel antagonists such as nicardipine, and outline the preliminary data regarding clevidipine in the pediatric population.

In vitro assessment of clevidipine using the profilin1 hypertensive mouse model.

Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic arterial resistance. The aim was to assess the effect of clevidipine on the hypertrophic vessels of profilin1 hypertensive transgenic mice compared to sodium nitroprusside (SNP) and labetalol using wire myograph techniques. The effects of clevidipine, SNP and labetalol on the hypertrophic vessels were studied on mesenteric arterial function from 8 profilin1 hypertrophic mice and eight non-transgenic controls. Our results showed a significant difference between the effects of the three drugs on the hypertrophic mesenteric arteries of transgenic profilin1 mice compared to the non-transgenic controls. The half maximal effective concentration (EC50) of clevidipine, SNP and labetalol in profilin1 mice (1.90 ± 0.05, 0.97 ± 0.07, 2.80 ± 0.05 nM, respectively) were significantly higher than the EC50 in non-transgenic controls (0.91 ± 0.06, 0.32 ± 0.06, 0.80 ± 0.09 nM, respectively). Moreover, the increase in the EC50 for clevidipine (2-fold) to produce the same effect on both normal and hypertrophic arteries was less than that of SNP (3-fold) and labetalol (3.5-fold). Therefore, we concluded clevidipine exhibited the lowest dose shift to relax the hypertrophic vessels compared to SNP and labetalol in the profilin1 hypertrophic animal mouse model.

Evaluation of a model for glycemic prediction in critically ill surgical patients.

We evaluated a neural network model for prediction of glucose in critically ill trauma and post-operative cardiothoracic surgical patients. A prospective, feasibility trial evaluating a continuous glucose-monitoring device was performed. After institutional review board approval, clinical data from all consenting surgical intensive care unit patients were converted to an electronic format using novel software. This data was utilized to develop and train a neural network model for real-time prediction of serum glucose concentration implementing a prediction horizon of 75 minutes. Glycemic data from 19 patients were used to "train" the neural network model. Subsequent real-time simulated testing was performed in 5 patients to whom the neural network model was naive. Performance of the model was evaluated by calculating the mean absolute difference percent (MAD%), Clarke Error Grid Analysis, and calculation of the percent of hypoglycemic (≤70 mg/dL), normoglycemic (>70 and <150 mg/dL), and hyperglycemic (≥150 mg/dL) values accurately predicted by the model; 9,405 data points were analyzed. The models successfully predicted trends in glucose in the 5 test patients. Clark Error Grid Analysis indicated that 100.0% of predictions were clinically acceptable with 87.3% and 12.7% of predicted values falling within regions A and B of the error grid respectively. Overall model error (MAD%) was 9.0% with respect to actual continuous glucose modeling data. Our model successfully predicted 96.7% and 53.6% of the normo- and hyperglycemic values respectively. No hypoglycemic events occurred in these patients. Use of neural network models for real-time prediction of glucose in the surgical intensive care unit setting offers healthcare providers potentially useful information which could facilitate optimization of glycemic control, patient safety, and improved care. Similar models can be implemented across a wider scale of biomedical variables to offer real-time optimization, training, and adaptation that increase predictive accuracy and performance of therapies.

Arterial embolism.

Surgical and intensive care patients are at a heightened risk for arterial embolization due to pre-existing conditions such as age, hypercoagulability, cardiac abnormalities and atherosclerotic disease. Most arterial emboli are clots that originate in the heart and travel to distant vascular beds where they cause arterial occlusion, ischemia, and potentially infarction. Other emboli form on the surface of eroded arterial plaque or within its lipid core. Thromboemboli are large clots that dislodge from the surface of athesclerotic lesions and occlude distal arteries causing immediate ischemia. Atheroemboli, which originate from fracturing the lipid core tend to cause a process of organ dysfunction and systemic inflammation, termed cholesterol embolization syndrome. The presentation of arterial emboli depends on the arterial bed that is affected. The most common manifestations are strokes and acute lower limb ischemia. Less frequently, emboli target the upper extremities, mesenteric or renal arteries. Treatment involves rapid diagnosis, which may be aided by precise imaging studies and restoration of blood flow. The type of emboli, duration of presentation, and organ system affected determines the treatment course. Long-term therapy includes supportive medical care, identification of the source of embolism and prevention of additional emboli. Patients who experienced arterial embolism as a result of clots formed in the heart should be anticoagulated. Arterial emboli from atherosclerotic disease of the aorta or other large arteries should prompt treatment to reduce the risk for atherosclerotic progression, such as anti-platelet therapy and the use of statin drugs. The use of anticoagulation and surgical intervention to reduce the risk of arterial embolization from atherosclerotic lesions is still being studied.

Advances in management of acute hypertension: a concise review.

Chronic hypertension affects >1 billion people worldwide and >70 million people in the United States. Acute hypertensive episodes (AHE) are defined as severe spikes in blood pressure that may result in end-organ damage. Although AHE may arise independently as de novo events, they are more likely to occur in patients with pre-existing hypertension. One of the controversies regarding the clinical approach to AHE is the selection of anti-hypertensive medication. Depending on the clinical presentation of the patient and the threat of end-organ damage resulting from blood pressure elevation, appropriate and prompt treatment is warranted. There are multiple agents available for the management of hypertension. However, the greatest challenge lies in the acute care setting where the need exists for better initial and sustained control of blood pressure spikes. Many anti-hypertensive agents effectively lower blood pressure, yet only few have the capacity to achieve strict control of hypertension in the acute setting. Clevidipine butyrate is an ultra short-acting intravenous dihydropyridine calcium-channel blocker. Clevidipine has unique pharmacodynamic and pharmacokinetic properties that enable the fast, safe, and adequate reduction of blood pressure in hypertensive emergencies, with the ability to provide highly precise titration necessary to maintain a narrowly-defined target blood pressure range. Several recently published phase I, II, and III clinical studies have shown Clevidipine to be an effective blood pressure modulator in such capacity.