Delta-Aminolevulinic Acid-Mediated Photodiagnoses in Surgical Oncology: A Historical Review of Clinical Trials.

Fluorescence imaging is an emerging clinical technique for real-time intraoperative visualization of tumors and their boundaries. Though multiple fluorescent contrast agents are available in the basic sciences, few fluorescence agents are available for clinical use. Of the clinical fluorophores, delta aminolevulinic acid (5ALA) is unique for generating visible wavelength tumor-specific fluorescence. In 2017, 5ALA was FDA-approved for glioma surgery in the United States. Additionally, clinical studies suggest this agent may have utility in surgical subspecialties outside of neurosurgery. Data from dermatology, OB/GYN, urology, cardiothoracic surgery, and gastrointestinal surgery show 5ALA is helpful for intraoperative visualization of malignant tissues in multiple organ systems. This review summarizes data from English-language 5ALA clinical trials across surgical subspecialties. Imaging systems, routes of administration, dosing, efficacy, and related side effects are reviewed. We found that modified surgical microscopes and endoscopes are the preferred imaging devices. Systemic dosing across surgical specialties range between 5 and 30 mg/kg bodyweight. Multiple studies discussed potential for skin irritation with sun exposure, however this side effect is infrequently reported. Overall, 5ALA has shown high sensitivity for labeling malignant tissues and providing a means to visualize malignant tissue not apparent with standard operative light sources

Pediatric diffuse intrinsic anaplastic astrocytoma of the medulla oblongata

Focal tumors of the brain stem are classically low grade astrocytomas. We present the rare case of a child with an anaplastic astrocytoma confined to the medulla oblongata. An 11-year-old male found to have an intrinsic tumor of the medulla oblongata; the initial MRI was equivocal for determining the focal or diffuse nature of the tumor. After a subtotal resection followed by aggressive adjuvant therapy, rapid deterioration and death occurred at 16 months after initial diagnosis and surgery. Diffuse intrinsic anaplastic astrocytomas confined to the medulla oblongata are extremely rare. Diffuse tension imaging, a short period of symptoms, and presence of cranial nerve deficits are suggestive of a malignant histopathology. Prognosis is poor

A Case Series: Pre-Operative Internal Maxillary Artery Embolization Before Temporomandibular Joint Reconstruction

Introduction: Temporomandibular joint (TMJ) ankylosis is an often-disfiguring pathology causing significant reduction in mandibular mobility leading to disability in mastication, digestion, speech, and oral hygiene. Caused by trauma, radiation, infection, and iatrogenic injury, TMJ ankylosis requires complete excision of the ankylosing mass following by arthroplasty. Substantial hemorrhage during this procedure, up to 3.7L, resulting from injury to the internal maxillary artery (IMA) as it courses around the ankylosing mass may occur. There are few data to recommend pre-operative IMA embolization, though a case series describing two patients who underwent the procedure describes significant decrease in intra-operative blood loss. Our aim is to interrogate the efficacy and safety of pre-operative bilateral IMAX embolization in TMJ replacement. Methods: Two patients from October 2016 to April 2017 underwent cerebral angiogram with pre-operative selective embolization of bilateral internal maxillary arteries immediately deep to the ankylosing mass with platinum micro-coils. After embolization, both patients were taken for bilateral temporomandibular joint replacements with arthroplasty of the temporomandibular joints, glenoid fossa and zygomatic arches. Blood loss during each procedure was documented and compared to blood loss from the same surgeon’s previous similar procedures. Patients 1 and 2 were followed up for 6 months and 1 year, respectively and outcomes compared to similar patients who did not undergo embolization. Results: Bilateral selective internal maxillary artery embolization was successful in decreasing intraoperative blood loss in both patients. Each patient sustained 200cc of estimated blood loss during subsequent temporomandibular joint reconstruction compared to patients not undergoing embolization. At 6 months and 1 year, patients had significant improvement in their maximal incisural opening and functional status with no evidence of necrosis or wound break down. Conclusions: In our cases, after embolization, both patients had successful TMJ reconstruction with 200cc blood loss, compared to the reported possibility of hemorrhage resulting in up to 3.7L of estimated blood loss. Upon follow up at 6 months and 1 year, neither patient had evidence of tissue necrosis or wound break down. Based on these observations, pre-operative embolization has shown to be a safe and effective procedure for minimizing hemorrhage during TMJ reconstruction

Real-Time Visualization of Human Malignant Brain Tumor Cells with Delta-Aminolevulinic Acid (5ALA)

Poster and abstract under embargo until 5/8/2020

Acute neurological injury in pediatric patients with single-ventricle congenital heart disease.

OBJECTIVE: Single-ventricle congenital heart disease (CHD) in pediatric patients with Glenn and Fontan physiology represents a unique physiology requiring the surgical diversion of the systemic venous return from the superior vena cava (Glenn) and then the inferior vena cava (Fontan) directly to the pulmonary arteries. Because many of these patients are on chronic anticoagulation therapy and may have right-to-left shunts, arrhythmias, or lymphatic disorders that predispose them to bleeding and/or clotting, they are at risk of experiencing neurological injury requiring intubation and positive pressure ventilation, which can significantly hamper pulmonary blood flow and cardiac output. The aim of this study was to describe the complex neurological and cardiopulmonary interactions of these pediatric patients after acute central nervous system (CNS) injury. METHODS: The authors retrospectively analyzed the records of pediatric patients who had been admitted to a quaternary children\u27s hospital with CHD palliated to bidirectional Glenn (BDG) or Fontan circulation and acute CNS injury and who had undergone intubation and mechanical ventilation. Patients who had been admitted from 2005 to 2019 were included in the study. Clinical characteristics, surgical outcomes, cardiovascular and pulmonary data, and intracranial pressure data were collected and analyzed. RESULTS: Nine pediatric single-ventricle patients met the study inclusion criteria. All had undergone the BDG procedure, and the majority (78%) were status post Fontan palliation. The mean age was 7.4 years (range 1.3-17.3 years). At the time of acute CNS injury, which included traumatic brain injury, intracranial hemorrhage, and cerebral infarct, the median time interval from the most recent cardiac surgical procedure was 3 years (range 2 weeks-11 years). Maintaining normocarbia to mild hypercarbia for most patients during intubation periods did not cause neurological deterioration, and hemodynamic profiles were more favorable as compared to periods of hypocarbia. Hypocarbia was associated with unfavorable hemodynamics but was necessary to decrease intracranial hypertension. Most patients were managed using low mean airway pressure (MAWP) in order to minimize the impact on preload and cardiac output. CONCLUSIONS: The authors highlight the complex neurological and cardiopulmonary interactions with respect to partial pressure of arterial CO2 (PaCO2) and MAWP when pediatric CHD patients with single-ventricle physiology require mechanical ventilation. The study data demonstrated that tight control of PaCO2 and minimizing MAWP with the goal of early extubation may be beneficial in this population. A multidisciplinary team of pediatric critical care intensivists, cardiac intensivists and anesthesiologists, and pediatric neurosurgeons and neurologists are recommended to ensure the best possible outcomes

Head of bed elevation in pediatric patients with severe traumatic brain injury.

OBJECTIVE: Head of bed (HOB) elevation to 30° after severe traumatic brain injury (TBI) has become standard positioning across all age groups. This maneuver is thought to minimize the risk of elevated ICP in the hopes of decreasing cerebral blood and fluid volume and increasing cerebral venous outflow with improvement in jugular venous drainage. However, HOB elevation is based on adult population data due to a current paucity of pediatric TBI studies regarding HOB management. In this prospective study of pediatric patients with severe TBI, the authors investigated the role of different head positions on intracranial pressure (ICP), cerebral perfusion pressure (CPP), and cerebral venous outflow through the internal jugular veins (IJVs) on postinjury days 2 and 3 because these time periods are considered the peak risk for intracranial hypertension. METHODS: Patients younger than 18 years with a Glasgow Coma Scale score ≤ 8 after severe TBI were prospectively recruited at a single quaternary pediatric intensive care unit. All patients had an ICP monitor placed, and no other neurosurgical procedure was performed. On the 2nd and 3rd days postinjury, the degree of HOB elevation was varied between 0° (head-flat or horizontal), 10°, 20°, 30°, 40°, and 50° while ICP, CPP, and bilateral IJV blood flows were recorded. RESULTS: Eighteen pediatric patients with severe TBI were analyzed. On each postinjury day, 13 of the 18 patients had at least 1 optimal HOB position (the position that simultaneously demonstrated the lowest ICP and the highest CPP). Six patients on each postinjury day had 30° as the optimal HOB position, with only 2 being the same patient on both postinjury days. On postinjury day 2, 3 patients had more than 1 optimal HOB position, while 5 patients did not have an optimal position. On postinjury day 3, 2 patients had more than 1 optimal HOB position while 5 patients did not have an optimal position. Interestingly, 0° (head-flat or horizontal) was the optimal HOB position in 2 patients on postinjury day 2 and 3 patients on postinjury day 3. The optimal HOB position demonstrated lower right IJV blood flow than a nonoptimal position on both postinjury days 2 (p = 0.0023) and 3 (p = 0.0033). There was no significant difference between optimal and nonoptimal HOB positions in the left IJV blood flow. CONCLUSIONS: In pediatric patients with severe TBI, the authors demonstrated that the optimal HOB position (which decreases ICP and improves CPP) is not always at 30°. Instead, the optimal HOB should be individualized for each pediatric TBI patient on a daily basis

Provision of rapid and specific ex vivo diagnosis of central nervous system lymphoma from rodent xenograft biopsies by a fluorescent aptamer.

OBJECTIVE: Differentiating central nervous system (CNS) lymphoma from other intracranial malignancies remains a clinical challenge in surgical neuro-oncology. Advances in clinical fluorescence imaging contrast agents and devices may mitigate this challenge. Aptamers are a class of nanomolecules engineered to bind cellular targets with antibody-like specificity in a fraction of the staining time. Here, the authors determine if immediate ex vivo fluorescence imaging with a lymphoma-specific aptamer can rapidly and specifically diagnose xenografted orthotopic human CNS lymphoma at the time of biopsy. METHODS: The authors synthesized a fluorescent CNS lymphoma-specific aptamer by conjugating a lymphoma-specific aptamer with Alexa Fluor 488 (TD05-488). They modified human U251 glioma cells and Ramos lymphoma cells with a lentivirus for constitutive expression of red fluorescent protein and implanted them intracranially into athymic nude mice. Three to 4 weeks postimplantation, acute slices (biopsies, n = 28) from the xenografts were collected, placed in aptamer solution, and imaged with a Zeiss fluorescence microscope. Three aptamer staining concentrations (0.3, 1.0, and 3.0 μM) and three staining times (5, 10, and 20 minutes) followed by a 1-minute wash were tested. A file of randomly selected images was distributed to neurosurgeons and neuropathologists, and their ability to distinguish CNS lymphoma from negative controls was assessed. RESULTS: The three staining times and concentrations of TD05-488 were tested to determine the diagnostic accuracy of CNS lymphoma within a frozen section time frame. An 11-minute staining protocol with 1.0-μM TD05-488 was most efficient, labeling 77% of positive control lymphoma cells and less than 1% of negative control glioma cells (p \u3c 0.001). This protocol permitted clinicians to positively identify all positive control lymphoma images without misdiagnosing negative control images from astrocytoma and normal brain. CONCLUSIONS: Ex vivo fluorescence imaging is an emerging technique for generating rapid histopathological diagnoses. Ex vivo imaging with a novel aptamer-based fluorescent nanomolecule could provide an intraoperative tumor-specific diagnosis of CNS lymphoma within 11 minutes of biopsy. Neurosurgeons and neuropathologists interpreted images generated with this molecular probe with high sensitivity and specificity. Clinical application of TD05-488 may permit specific intraoperative diagnosis of CNS lymphoma in a fraction of the time required for antibody staining

Provision of rapid and specific ex vivo diagnosis of central nervous system lymphoma from rodent xenograft biopsies by a fluorescent aptamer

OBJECTIVE: Differentiating central nervous system (CNS) lymphoma from other intracranial malignancies remains a clinical challenge in surgical neuro-oncology. Advances in clinical fluorescence imaging contrast agents and devices may mitigate this challenge. Aptamers are a class of nanomolecules engineered to bind cellular targets with antibody-like specificity in a fraction of the staining time. Here, the authors determine if immediate ex vivo fluorescence imaging with a lymphoma-specific aptamer can rapidly and specifically diagnose xenografted orthotopic human CNS lymphoma at the time of biopsy. METHODS: The authors synthesized a fluorescent CNS lymphoma-specific aptamer by conjugating a lymphoma-specific aptamer with Alexa Fluor 488 (TD05-488). They modified human U251 glioma cells and Ramos lymphoma cells with a lentivirus for constitutive expression of red fluorescent protein and implanted them intracranially into athymic nude mice. Three to 4 weeks postimplantation, acute slices (biopsies, n = 28) from the xenografts were collected, placed in aptamer solution, and imaged with a Zeiss fluorescence microscope. Three aptamer staining concentrations (0.3, 1.0, and 3.0 μM) and three staining times (5, 10, and 20 minutes) followed by a 1-minute wash were tested. A file of randomly selected images was distributed to neurosurgeons and neuropathologists, and their ability to distinguish CNS lymphoma from negative controls was assessed. RESULTS: The three staining times and concentrations of TD05-488 were tested to determine the diagnostic accuracy of CNS lymphoma within a frozen section time frame. An 11-minute staining protocol with 1.0-μM TD05-488 was most efficient, labeling 77% of positive control lymphoma cells and less than 1% of negative control glioma cells (p \u3c 0.001). This protocol permitted clinicians to positively identify all positive control lymphoma images without misdiagnosing negative control images from astrocytoma and normal brain. CONCLUSIONS: Ex vivo fluorescence imaging is an emerging technique for generating rapid histopathological diagnoses. Ex vivo imaging with a novel aptamer-based fluorescent nanomolecule could provide an intraoperative tumor-specific diagnosis of CNS lymphoma within 11 minutes of biopsy. Neurosurgeons and neuropathologists interpreted images generated with this molecular probe with high sensitivity and specificity. Clinical application of TD05-488 may permit specific intraoperative diagnosis of CNS lymphoma in a fraction of the time required for antibody staining