Natalia Henao-Guerrero

Successful Treatment of a Large Soft Tissue Sarcoma With Irreversible Electroporation

Introduction Irreversible electroporation (IRE) is a promising technique for the focal treatment of pathologic tissues that involves placing minimally invasive electrodes within the targeted region. A series of short, intense electric pulses are then applied to destabilize the cell membrane, presumably by creating nanopores, inducing cell death in a nonthermal manner. The unique therapeutic mechanism of IRE does not rely on tissue temperature changes, as with hyperthermic or cryoablative procedures. Therefore, IRE preserves the extracellular matrix, major tissue vasculature, and other sensitive structures. Treated regions resolve rapidly, with submillimeter resolution between treated and unaffected cells, and are predictable with numerical modeling. Treatments promote an immune response, are unaltered by blood flow, can be administered quickly (approximately 5 minutes), and can be visualized in real time. IRE has been studied extensively in healthy tissue, and tumors have been treated with IRE in mice. IRE has been attempted in humans for prostate, lung, kidney, and liver cancers. Human treatments revealed negligible postablation pain and the ability to apply the pulses in proximity to vital structures. Overall, assessment of the therapeutic efficacy of IRE remains in its infancy. We hypothesize that IRE treatments can be designed and implemented to successfully treat soft tissue malignancies, including large and complex tumors, a crucial step for translation of the technology into routine clinical use. Here we report our treatment of a focal histiocytic sarcoma of the coxofemoral joint in a canine patient. Follow-up examinations demonstrated prolonged relief of cancerassociated pain, preservation of pelvic limb function, and complete tumor regression 6 months after initial treatment.

Non-Thermal Irreversible Electroporation (N-TIRE) and Adjuvant Fractionated Radiotherapeutic Multimodal Therapy for Intracranial Malignant Glioma in a Canine Patient

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.

Safety and feasibility of the NanoKnife system for irreversible electroporation ablative treatment of canine spontaneous intracranial gliomas

OBJECT Irreversible electroporation (IRE) is a novel nonthermal ablation technique that has been used for the treatment of solid cancers. However, it has not been evaluated for use in brain tumors. Here, the authors report on the safety and feasibility of using the NanoKnife IRE system for the treatment of spontaneous intracranial gliomas in dogs. METHODS Client-owned dogs with a telencephalic glioma shown on MRI were eligible. Dog-specific treatment plans were generated by using MRI-based tissue segmentation, volumetric meshing, and finite element modeling. After biopsy confirmation of glioma, IRE treatment was delivered stereotactically with the NanoKnife system using pulse parameters and electrode configurations derived from therapeutic plans. The primary end point was an evaluation of safety over the 14 days immediately after treatment. Follow-up was continued for 12 months or until death with serial physical, neurological, laboratory, and MRI examinations. RESULTS Seven dogs with glioma were treated. The mean age of the dogs was 9.3 ± 1.6 years, and the mean pretreatment tumor volume was 1.9 ± 1.4 cm(3). The median preoperative Karnofsky Performance Scale score was 70 (range 30-75). Severe posttreatment toxicity was observed in 2 of the 7 dogs; one developed fatal (Grade 5) aspiration pneumonia, and the other developed treatment-associated cerebral edema, which resulted in transient neurological deterioration. Results of posttreatment diagnostic imaging, tumor biopsies, and neurological examinations indicated that tumor ablation was achieved without significant direct neurotoxicity in 6 of the 7 dogs. The median 14-day post-IRE Karnofsky Performance Scale score of the 6 dogs that survived to discharge was 80 (range 60-90), and this score was improved over the pretreatment value in every case. Objective tumor responses were seen in 4 (80%) of 5 dogs with quantifiable target lesions. The median survival was 119 days (range 1 to > 940 days). CONCLUSION With the incorporation of additional therapeutic planning procedures, the NanoKnife system is a novel technology capable of controlled IRE ablation of telencephalic gliomas.

Comparison of four ventilatory protocols for computed tomography of the thorax in healthy cats

OBJECTIVE To identify ventilatory protocols that yielded good image quality for thoracic CT and hemodynamic stability in cats. Animals-7 healthy cats. PROCEDURES Cats were anesthetized and ventilated via 4 randomized protocols (hyperventilation, 20 seconds [protocol 1]; single deep inspiration, positive inspiratory pressure of 15 cm H(2)O [protocol 2]; recruitment maneuver [protocol 3]; and hyperventilation, 20 seconds with a positive end-expiratory pressure of 5 cm H(2)O [protocol 4]). Thoracic CT was performed for each protocol; images were acquired during apnea for protocols 1 and 3 and during positive airway pressure for protocols 2 and 4. Heart rate; systolic, mean, and diastolic arterial blood pressures; blood gas values; end-tidal isoflurane concentration; rectal temperature; and measures of atelectasis, total lung volume (TLV), and lung density were determined before and after each protocol. RESULTS None of the protocols eliminated atelectasis; the number of lung lobes with atelectasis was significantly greater during protocol 1 than during the other protocols. Lung density and TLV differed significantly among protocols, except between protocols 1 and 3. Protocol 2 TLV exceeded reference values. Arterial blood pressure after each protocol was lower than before the protocols. Mean and diastolic arterial blood pressure were higher after protocol 3 and diastolic arterial blood pressure was higher after protocol 4 than after protocol 2. CONCLUSIONS AND CLINICAL RELEVANCE Standardization of ventilatory protocols may minimize effects on thoracic CT images and hemodynamic variables. Although atelectasis was still present, ventilatory protocols 3 and 4 provided the best compromise between image quality and hemodynamic stability.

Evaluation of tissue oxygen saturation with near-infrared spectroscopy during experimental acute hemorrhagic shock and resuscitation in dogs

OBJECTIVE To evaluate tissue oxygen saturation (Sto2) by use of near-infrared spectroscopy in experimental acute hemorrhagic shock and resuscitation in dogs. ANIMALS 14 healthy adult purpose-bred Beagles. PROCEDURES Dogs were anesthetized with isoflurane via facemask, anesthesia was maintained with propofol and rocuronium bromide, and dogs were mechanically ventilated to maintain normocapnia. Dogs were studied under normovolemia (baseline), hypovolemia with target mean arterial blood pressure < 40 mm Hg achieved and maintained steady for 10 minutes (hypovolemia T1), then 20 minutes later (hypovolemia T2), following resuscitation with shed blood (after transfusion), and after administration of 20 mL of hetastarch/kg (hypervolemia). Conditions were executed sequentially during a single anesthetic episode, allowing stabilization between states (10 minutes). Hemoglobin concentration, mean arterial blood pressure, arterial blood gas concentrations, cardiac index, oxygen delivery indexed to body surface area, and Sto2 were monitored. RESULTS From baseline to hypovolemia T1, there was a significant reduction in mean ± SD oxygen delivery index (619 ± 257 mL/min/m(2) to 205 ± 76 mL/min/m(2)) and Sto2 (94 ± 4.4% to 78 ± 12.2%). Following resuscitation, Sto2 (80 ± 8.5% vs 92 ± 6.45%) and oxygen delivery index (211 ± 73 mL/min/m(2) vs 717 ± 221 mL/min/m(2)) significantly increased, returning to baseline values. Hypervolemia had no effect on Sto2 or oxygen delivery index. A strong correlation (r = 0.97) was detected between mean oxygen delivery index and Sto2 across all time points. CONCLUSIONS AND CLINICAL RELEVANCE Under the conditions of this study, there was a strong correlation between Sto2 and oxygen delivery, suggesting that Sto2 may be used to estimate oxygen delivery.

Evaluation of tissue hemoglobin saturation (StO2) using near-infrared spectroscopy during hypoxemia and hyperoxemia in Beagle dogs.

OBJECTIVE To determine the relationship between tissue oxygen saturation (StO2) and oxygen delivery (D˙O2) during hypoxemia and hyperoxemia. STUDY DESIGN Prospective, randomized study. ANIMALS Eight purpose-bred Beagle dogs. METHODS Dogs were anesthetized with isoflurane, ventilated to eucapnia, and instrumented for thermodilution cardiac output, invasive mean arterial pressure (MAP), sartorius muscle StO2 and airway gas monitoring. Dogs were administered rocuronium to facilitate mechanical ventilation and esmolol to minimize anesthetic effects on cardiac output. Instrumentation and baseline data collection were at 0.21 fractional inspired oxygen (FIO2). Dogs were evaluated at high (0.40 then 0.95) and low (0.15 then 0.10) FIO2 sequences in random order with a 60 minute rest period at FIO2 0.21 between sequences. Target FIO2 was achieved by manipulating nitrogen and oxygen flow rates. Data collected at each FIO2, after a 10 minute period of stabilization, included heart rate (HR), MAP, cardiac index (CI) and StO2. Arterial oxygen content (CaO2) and oxygen delivery index (D˙O2I) were calculated at each FIO2. Data analysis included Pearsons correlation analysis and mixed-model anova (p < 0.05). RESULTS There were no significant differences in HR, MAP or CI across all FIO2 values. Significant decreases occurred in mean ± standard deviation StO2 (90 ± 4% to 69 ± 18%; p = 0.0001), D˙O2I (458 ± 70 to 281 ± 100 mL minute(-1) m(-2); p = 0.0008) and CaO2 (13.2 ± 1.53 to 8.4 ± 2.05 mL dL(-1); p = 0.0001) from FIO2 0.21 to 0.10, but not at remaining FIO2 values. The correlation between StO2 and D˙O2I across all FIO2 values was strong (r = 0.97; p = 0.0013) and linear. CONCLUSIONS AND CLINICAL RELEVANCE In this model of hypoxemia and hyperoxemia, the strong correlation between StO2 and D˙O2I suggests that StO2 can be used to estimate D˙O2.

Cardiovascular effects of orotracheal intubation following anesthetic induction with propofol, ketamine-propofol, or ketamine-diazepam in premedicated dogs

OBJECTIVE To compare the hemodynamic responses to orotracheal intubation following induction of anesthesia with propofol, ketamine-propofol, and ketamine-diazepam in premedicated dogs. DESIGN Prospective, randomized, masked study. ANIMALS 10 healthy adult Beagles. PROCEDURES Dogs were randomly allocated to be anesthetized twice, with a 1-week wash-out interval, by means of 2 of 3 possible protocols (propofol [4 mg/kg {1.8 mg/lb}, n = 6 dogs], ketamine [2 mg/kg {0.9 mg/lb}] and propofol [2 mg/kg; 7], or ketamine [5 mg/kg {2.3 mg/lb}] and diazepam [0.2 mg/kg {0.09 mg/lb}; 6]). After instrumentation, continuous heart rate, systolic arterial blood pressure, mean arterial blood pressure, diastolic arterial blood pressure, cardiac index, stroke volume index, and systemic vascular resistance were recorded. Fifteen minutes after premedication, dogs were anesthetized; all anesthetics were administered IV. After 5 minutes, orotracheal intubation was performed without the use of a laryngoscope. Data were collected prior to intubation (baseline), at intubation, and 30, 60, 90, 120, 150, and 180 seconds thereafter. Results were compared among the 3 groups and over time. RESULTS No differences among groups were observed for any variables studied. In all groups, arterial blood pressures were significantly decreased at various time points after intubation. A significant increase in systolic arterial blood pressure was observed between baseline and the 30-second time point in the ketamine-diazepam group. No significant differences were detected over time for the other variables in any group. CONCLUSIONS AND CLINICAL RELEVANCE Intubation after anesthetic induction with ketamine-diazepam caused transitory hypertension, whereas intubation after induction with propofol or ketamine-propofol did not cause cardiovascular stimulation. In dogs in which hypertension is a concern, propofol or ketamine-propofol may be a better choice for induction prior to orotracheal intubation.