Joseph L. McDevitt

Image-guided local delivery strategies enhance therapeutic nanoparticle uptake in solid tumors.

Nanoparticles (NP) have emerged as a novel class of therapeutic agents that overcome many of the limitations of current cancer chemotherapeutics. However, a major challenge to many current NP platforms is unfavorable biodistribution, and limited tumor uptake, upon systemic delivery. Delivery, therefore, remains a critical barrier to widespread clinical adoption of NP therapeutics. To overcome these limitations, we have adapted the techniques of image-guided local drug delivery to develop nanoablation and nanoembolization. Nanoablation is a tumor ablative strategy that employs image-guided placement of electrodes into tumor tissue to electroporate tumor cells, resulting in a rapid influx of NPs that is not dependent on cellular uptake machinery or stage of the cell cycle. Nanoembolization involves the image-guided delivery of NPs and embolic agents directly into the blood supply of tumors. We describe the design and testing of our innovative local delivery strategies using doxorubicin-functionalized superparamagnetic iron oxide nanoparticles (DOX-SPIOs) in cell culture, and the N1S1 hepatoma and VX2 tumor models, imaged by high resolution 7T MRI. We demonstrate that local delivery techniques result in significantly increased intratumoral DOX-SPIO uptake, with limited off-target delivery in tumor-bearing animal models. The techniques described are versatile enough to be extended to any NP platform, targeting any solid organ malignancy that can be accessed via imaging guidance.

Utility of Readmission Rates as a Quality of Care Measure and Predictors of Readmission Within 30 Days After Spinal Surgery: a Single-Center, Multivariate Analysis.

Study Design. A retrospective review Objective. The aim of this study was to establish clinically relevant readmission rates that permit accurate comparisons, improve risk‐stratification, and direct efforts to minimize readmissions. Summary of Background Data. The 30‐day hospital readmission rate is a quality of care measure that is now being used to compare hospitals in a publicly available manner. Methods. Records from 1187 consecutive spinal surgeries at Northwestern Memorial Hospital in 2010 were retrospectively reviewed and data were collected that described the patient, surgical procedure, hospital course, complications, and readmissions. The primary outcome of interest was readmission to the hospital within 30 days. Potential risk factors were examined for association with the outcome first via bivariate analysis, with significant predictors further examined by a multivariable model. Identified readmissions were independently reviewed by attending spinal neurosurgeons not involved with the cases to determine whether the readmissions were procedure related or procedure unrelated with respect to accepted criteria. Results. The overall readmission rate was 6.1%. Of these readmissions, 37.5% were deemed procedure related upon attending review, leading to a procedure‐related readmission rate of 2.3%. Upon multivariate analysis, only 3 variables were found to be significant predictors of readmission: 2 or more patient comorbidities [odds ratio (OR) 3.72, 95% confidence interval (95% CI) 1.62–8.56], an admission to the ICU (OR 2.68, 95% CI 1.45–4.95), and each additional spinal level involved (OR 1.11, 95% CI 1.02–1.21). Conclusions. Our study suggests that predictors for all‐cause 30‐day readmission following spinal procedures include number of spinal levels performed during the surgery, number of patient comorbidities present at the time of surgery, and whether the admission required an ICU stay. Future work should focus on developing best practices to modify medical risk factors and comorbidities that have the potential to decrease 30‐day readmission rates. Level of Evidence: 3

Seven-tesla magnetic resonance imaging accurately quantifies intratumoral uptake of therapeutic nanoparticles in the McA rat model of hepatocellular carcinoma: Preclinical study in a rodent model

ObjectivesAfter inducing McA tumors in Sprague-Dawley rats (McA-SD), the following hypotheses were tested: first, that hypervascular McA tumors grown in Sprague-Dawley rats provide a suitable platform to investigate drug delivery; and second, that high-field MRI can be used to measure intratumoral uptake of DOX-SPIOs. Materials and MethodsMcA cells were implanted into the livers of 18 Sprague-Dawley rats. In successfully inoculated animals, 220-&mgr;L DOX-SPIOs were delivered to tumors via the intravenous or intra-arterial route. Pretreatment and posttreatment T2*-weighted images were obtained using 7-T MRI, and change in R2* value (&Dgr;R2*) was obtained from mean signal intensities of tumors in these images. Tumor iron concentration ([Fe]), an indicator of DOX-SPIO uptake, was measured using mass spectroscopy. The primary outcome variable was the Pearson correlation between &Dgr;R2* and [Fe]. ResultsTumors grew successfully in 13 of the 18 animals (72%). Mean (SD) maximum tumor diameter was 0.83 (0.25) cm. The results of phantom studies revealed a strong positive correlation between &Dgr;R2* and [Fe], with r = 0.98 (P < 0.01). The results of in vivo drug uptake studies demonstrated a positive correlation between &Dgr;R2* and [Fe], with r = 0.72 (P = 0.0004). ConclusionsThe McA tumors grown in the Sprague-Dawley rats demonstrated uptake of nanoparticle-based therapeutic agents. Magnetic resonance imaging quantification of intratumoral uptake strongly correlated with iron concentrations in pathological specimens, suggesting that MRI may be used to quantify uptake of iron-oxide nanotherapeutics.

Percutaneous Cryoablation for the Treatment of Primary and Metastatic Lung Tumors: Identification of Risk Factors for Recurrence and Major Complications

PURPOSE To identify risk factors for local recurrence and major complications associated with percutaneous cryoablation of lung tumors. MATERIALS AND METHODS All cases between April 2007 and September 2014 at 1 institution were retrospectively reviewed. Procedures were performed using computed tomography guidance and a double freeze-thaw protocol. Tumor progression was determined via World Health Organization guidelines, and complications were classified using SIR reporting standards. Measures of efficacy were calculated via Kaplan-Meier analysis. Predictors of local progression and major complications were identified by Cox proportional hazards and logistic regression. RESULTS There were 47 tumors (25 primary, 22 metastatic) treated with median follow-up of 11.1 months. Mean diameter before treatment was 2.4 cm, and an average of 2.1 cryoprobes were used per procedure. Major complications (most commonly, pneumothorax requiring chest tube) occurred in 12 (25%) cases, and minor complications occurred in 13 (27%) cases. Median time to local progression was 14 months (16 mo for primary tumors and 10 mo for metastatic tumors), and median overall survival was 33 months (43 mo for patients with primary tumors and 22 mo for patients with metastatic tumors). On multivariate analysis, tumor diameter > 3 cm was associated with local progression (hazard ratio = 3.2, P = .013), and use of multiple cryoprobes (relative risk [RR] = 7.2, P = .045) and previous local therapy (RR = 15, P = .030) were associated with major complications. CONCLUSIONS Percutaneous cryoablation of lung tumors is technically feasible with a complication rate comparable to other percutaneous ablation techniques. Percutaneous cryoablation is more efficacious and has fewer complications when offered to patients with small, previously untreated lesions.

Impact of Anemia and Transfusion on Readmission and Length of Stay After Spinal Surgery: A Single-center Study of 1187 Operations.

Study Design: Retrospective cohort study. Objective: To determine whether receipt of blood transfusion and preoperative anemia are associated with increased rates of 30-day all-cause readmission, and secondarily with a prolonged hospital stay after spinal surgery. Summary of Background Data: Increased focus on health care quality has led to efforts to determine postsurgical readmission rates and predictors of length of postoperative hospital stay. Although there are still no defined outcome measures specific to spinal surgery to which providers are held accountable, efforts to identify appropriate measures and to determine modifiable risk factors to optimize quality are ongoing. Methods: Records from 1187 consecutive spinal surgeries at Northwestern Memorial Hospital in 2010 were retrospectively reviewed and data were collected that described the patient, surgical procedure, hospital course, complications, and readmissions. Presence or absence of transfusion during the surgery and associated hospital course was treated as a binary variable. Multivariate negative binomial regression and logistic regression were used to model length of stay and readmission, respectively. Results: Nearly one fifth (17.8%) of surgeries received transfusions, and the overall readmission rate was 6.1%. After controlling for potential confounders, we found that the presence of a transfusion was associated with a 60% longer hospital stay [adjusted incidence rate ratio=1.60 (1.34–1.91), P<0.001], but was not significantly associated with an increased rate of readmission [adjusted odds ratio=0.81 (0.39–1.70), P=0.582]. Any degree of preoperative anemia was associated with increased length of stay, but only severe anemia was associated with an increased rate of readmission. Conclusions: Both receipt of blood transfusion and any degree of preoperative anemia were associated with increased length of hospital stay after controlling for other variables. Severe anemia, but not receipt of blood transfusion, was associated with increased rate of readmission. Our findings may help define actions to reduce length of stay and decrease rates of readmission.

Analysis of the RENAL and mRENAL Scores and the Relative Importance of Their Components in the Prediction of Complications and Local Progression after Percutaneous Renal Cryoablation

PURPOSE To determine if modified RENAL (mRENAL) score and its individual components have superior predictive value relative to the RENAL nephrometry score in prediction of complications and recurrence after percutaneous renal cryoablation. MATERIALS AND METHODS Primary masses treated with CT-guided percutaneous renal cryoablation between June 2007 and May 2016 were retrospectively reviewed. RENAL and mRENAL scores were used to stratify masses into low, medium, and high complexity tertiles. Complications were characterized by SIR criteria. Predictors of complications and local progression were analyzed using multivariate logistic regression and Kaplan-Meier analysis. RESULTS There were 95 renal cryoablation procedures in 86 patients. Of ablations, 89 had at least 1 follow-up imaging study, with median follow-up of 29 months. There were 11 (12.4%) complications, including 5 (6.5%) major complications. Mass complexity, as measured by mRENAL complexity tertile, was associated with increased risk of complications on multivariate analysis (P = .045). Endophytic location was the only individual ordinal component of the RENAL and mRENAL scores associated with complications (P = .021). Local progression occurred in 7 (8.3%) masses. Complexity as measured by either scoring system was not associated with local progression. Only diameter > 3 cm was associated with increased risk of local progression (hazard ratio = 9.9, 95% confidence interval = 2.1-45, P = .003). CONCLUSIONS mRENAL score was predictive of complications and tumor size was predictive of recurrence. Use of mRENAL score for complications and tumor size for recurrence should allow for simpler risk stratification and more accurate patient counseling.

MR Imaging Enables Measurement of Therapeutic Nanoparticle Uptake in Rat N1-S1 Liver Tumors after Nanoablation

PURPOSE To test the hypothesis that magnetic resonance (MR) imaging can quantify intratumoral superparamagnetic iron oxide (SPIO) nanoparticle uptake after nanoablation. MATERIALS AND METHODS SPIO nanoparticles functionalized with doxorubicin were synthesized. N1-S1 hepatomas were successfully induced in 17 Sprague-Dawley rats distributed into three dosage groups. Baseline tumor R2* values (the reciprocal of T2*) were determined using 7-tesla (T) MR imaging. After intravenous injection of SPIO nanoparticles, reversible electroporation (1,300 V/cm, 8 pulses, 100-μs pulse duration) was applied. Imaging of rats was performed to determine tumor R2* values after the procedure, and change in R2* (ΔR2*) was calculated. Inductively coupled plasma mass spectrometry was used to determine intratumoral iron (Fe) concentration after the procedure, which served as a proxy for SPIO nanoparticle uptake. Mean tumor Fe concentration [Fe] and ΔR2* for each subject were assessed for correlation with linear regression, and mean [Fe] for each dosage group was compared with analysis of variance. RESULTS ΔR2* significantly correlated with tumor SPIO nanoparticle uptake after nanoablation (r = 0.50, P = .039). On average, each 0.1-ms(-1) increase in R2* corresponded to a 0.1394-mM increase in [Fe]. There was no significant difference in mean SPIO nanoparticle uptake among dosage groups (P = .57). CONCLUSIONS Intratumoral SPIO nanoparticle uptake after nanoablation can be successfully quantified noninvasively with 7-T MR imaging. Imaging can be used as a method to estimate localized drug delivery after nanoablation.