IU Indianapolis ScholarWorks :: Browsing by Author "Langer, Mark P."

Browsing by Author "Langer, Mark P."

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Ability of the National Surgical Quality Improvement Program Risk Calculator to Predict Complications Following Total Laryngectomy
(JAMA, 2016-10) Schneider, Alexander L.; Deig, Christopher R.; Prasad, Kumar G.; Nelson, Benton G.; Mantravadi, Avinash V.; Brigance, Joseph S.; Langer, Mark P.; McDonald, Mark W.; Johnstone, Peter A.; Moore, Michael G.; Department of Otololaryngology-Head and Neck Surgery, School of Medicine
Importance The accuracy of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) risk calculator has been assessed in multiple surgical subspecialties; however, there have been no publications doing the same in the head and neck surgery literature. Objective To evaluate the accuracy of the calculator’s predictions in a single institution’s total laryngectomy (TL) population. Design, Setting, and Participants Total laryngectomies performed between 2013 and 2014 at a tertiary referral academic center were evaluated using the risk calculator. Predicted 30-day outcomes were compared with observed outcomes for return to operating room, surgical site infection, postoperative pneumonia, length of stay, and venous thromboembolism. Main Outcomes and Measures Comparison of the NSQIP risk calculator’s predicted postoperative complication rates and length of stay to what occurred in this patient cohort using percent error, Brier scores, area under the receiver operating characteristic curve, and Pearson correlation analysis. Results Of 49 patients undergoing TL, the mean (SD) age at operation was 59 (9.3) years, with 67% male. The risk calculator had limited efficacy predicting perioperative complications in this group of patients undergoing TL with or without free tissue reconstruction or preoperative chemoradiation or radiation therapy with a few exceptions. The calculator overestimated the occurrence of pneumonia by 165%, but underestimated surgical site infection by 7%, return to operating room by 24%, and length of stay by 13%. The calculator had good sensitivity and specificity of predicting surgical site infection for patients undergoing TL with free flap reconstruction (area under the curve, 0.83). For all other subgroups, however, the calculator had poor sensitivity and specificity for predicting complications. Conclusions and Relevance The risk calculator has limited utility for predicting perioperative complications in patients undergoing TL. This is likely due to the complexity of the treatment of patients with head and neck cancer and factors not taken into account when calculating a patient’s risk.
Construction of Confidence Regions for Uncertain Spatial Displacements With Dual Rodrigues Parameters
(ASME, 2024) Yu, Zihan; Ge, Qiaode Jeffrey; Langer, Mark P.; Radiation Oncology, School of Medicine
This paper follows our recent work on the computation of kinematic confidence regions from a given set of uncertain spatial displacements with specified confidence levels. Dual quaternion algebra is used to compute the mean displacement as well as relative displacements from the mean. In constructing a 6D confidence ellipsoid, however, we use dual Rodrigue parameters resulting from dual quaternions. The advantages of using dual quaternions and dual Rodrigues parameters are discussed in comparison with those of three translation parameters and three Euler angles, which were used for the development of the socalled the Rotational and Translational Confidence Limit (RTCL) method. The set of six dual Rodrigue parameters are used to define a parametric space in which a 6 × 6 covariance matrix and a 6D confidence ellipsoid are obtained. An inverse operation is then applied to first obtain dual quaternions and then to recover the rotation matrix and translation vector for each point on the 6D ellipsoid. Through examples, we demonstrate the efficacy of our approach by comparing it with the RTCL method known in literature. Our findings indicate that our method, based on the dual-Rodrigues formulation, yields more compact and effective swept volumes than the RTCL method, particularly in cases involving screw displacements.
Effect of Paclitaxel Stereochemistry on X-Ray-Triggered Release of Paclitaxel from CaWO4/Paclitaxel-Coloaded PEG-PLA Nanoparticles
(ACS, 2022) Sarkar, Kaustabh; Torregrossa-Allen, Sandra E.; Elzey, Bennett D.; Narayanan, Sanjeev; Langer, Mark P.; Durm, Gregory A.; Won, You-Yeon; Radiation Oncology, School of Medicine
For many locally advanced tumors, the chemotherapy-radiotherapy (CT-RT) combination ("chemoradiation") is currently the standard of care. Intratumoral (IT) CT-based chemoradiation has the potential to overcome the limitations of conventional systemic CT-RT (side effects). For maximizing the benefits of IT CT-RT, our laboratory has previously developed a radiation-controlled drug release formulation, in which anticancer drug paclitaxel (PTX) and radioluminescent CaWO4 (CWO) nanoparticles (NPs) are co-encapsulated with poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) block copolymers ("PEG-PLA/CWO/PTX NPs"). These PEG-PLA/CWO/PTX NPs enable radiation-controlled release of PTX and are capable of producing sustained therapeutic effects lasting for at least one month following a single IT injection. The present article focuses on discussing our recent finding about the effect of the stereochemical structure of PTX on the efficacy of this PEG-PLA/CWO/PTX NP formulation. Stereochemical differences in two different PTX compounds ("PTX-S" from Samyang Biopharmaceuticals and "PTX-B" from Biotang) were characterized by 2D heteronuclear/homonuclear NMR, Raman spectroscopy, and circular dichroism measurements. The difference in PTX stereochemistry was found to significantly influence their water solubility (WS); PTX-S (WS ≈ 4.69 μg/mL) is about 19 times more water soluble than PTX-B (WS ≈ 0.25 μg/mL). The two PTX compounds showed similar cancer cell-killing performances in vitro when used as free drugs. However, the subtle stereochemical difference significantly influenced their X-ray-triggered release kinetics from the PEG-PLA/CWO/PTX NPs; the more water-soluble PTX-S was released faster than the less water-soluble PTX-B. This difference was manifested in the IT pharmacokinetics and eventually in the survival percentages of test animals (mice) treated with PEG-PLA/CWO/PTX NPs + X-rays in an in vivo human tumor xenograft study; at short times (<1 month), concurrent PEG-PLA/CWO/PTX-S NPs produced a greater tumor-suppression effect, whereas PEG-PLA/CWO/PTX-B NPs had a longer-lasting radio-sensitizing effect. This study demonstrates the importance of the stereochemistry of a drug in a therapy based on a controlled release formulation.
Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy
(Elsevier, 2018) Shiue, Kevin; Cerra-Franco, Alberto; Shapiro, Ronald; Estabrook, Neil; Mannina, Edward M.; Deig, Christopher R.; Althouse, Sandra; Liu, Sheng; Wan, Jun; Zang, Yong; Agrawal, Namita; Ioannides, Pericles; Liu, Yongmei; Zhang, Chen; DesRosiers, Colleen; Bartlett, Greg; Ewing, Marvene; Langer, Mark P.; Watson, Gordon; Zellars, Richard; Kong, Feng-Ming; Lautenschlaeger, Tim; Radiation Oncology, School of Medicine
Introduction It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. Methods The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed. Results At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). Conclusions In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.
On the Computation of Mean and Variance of Spatial Displacements
(ASME, 2024) Ge, Qiaode Jeffrey; Yu, Zihan; Arbab, Mona; Langer, Mark P.; Radiation Oncology, School of Medicine
This paper studies the problem of computing an average (or mean) displacement from a set of given spatial displacements using three types of parametric representations: Euler angles and translation vectors, unit quaternions and translation vectors, and dual quaternions. It is shown that the use of Euclidean norm in the space of unit quaternions reduces the problem to that of computing the mean for each quaternion component separately and independently. While the resulting algorithm is simple, a change in the sign of a unit quaternion could lead to an incorrect result. A novel kinematic measure based on dual quaternions is introduced to capture the separation between two spatial displacements. This kinematic measure is used to define the variance of a set of displacements, which is then used to formulate a constrained least squares minimization problem. It is shown that the problem decomposes into that of finding the optimal translation vector and the optimal unit quaternion. The former is simply the centroid of the set of translation vectors and the latter is obtained as the eigenvector corresponding to the least eigenvalue of a 4 × 4 positive definite symmetric matrix. In addition, it is found that the weight factor used in combining rotations and translations in the formulation does not play a role in the final outcome. Examples are provided to show the comparisons of these methods.
On the Construction of Confidence Regions for Uncertain Planar Displacements
(ASME, 2024) Yu, Zihan; Ge, Qiaode Jeffrey; Langer, Mark P.; Arbab, Mona; Radiation Oncology, School of Medicine
This paper studies the statistical concept of confidence region for a set of uncertain planar displacements with a certain level of confidence or probabilities. Three different representations of planar displacements are compared in this context and it is shown that the most commonly used representation based on the coordinates of the moving frame is the least effective. The other two methods, namely the exponential coordinates and planar quaternions, are equally effective in capturing the group structure of SE(2). However, the former relies on the exponential map to parameterize an element of SE(2), while the latter uses a quadratic map, which is often more advantageous computationally. This paper focus on the use of planar quaternions to develop a method for computing the confidence region for a given set of uncertain planar displacements. Principal component analysis (PCA) is another tool used in our study to capture the dominant direction of movements. To demonstrate the effectiveness of our approach, we compare it to an existing method called rotational and translational confidence limit (RTCL). Our examples show that the planar quaternion formulation leads to a swept volume that is more compact and more effective than the RTCL method, especially in cases when off-axis rotation is present.
On the Construction of Kinematic Confidence Ellipsoids for Uncertain Spatial Displacements
(Springer, 2023) Yu, Zihan; Ge, Qiaode Jeffrey; Langer, Mark P.; Arbab, Mona; Radiation Oncology, School of Medicine
This paper deals with the problem of estimating confidence regions of a set of uncertain spatial displacements for a given level of confidence or probabilities. While a direct application of the commonly used statistic methods to the coordinates of the moving frame is straight-forward, it is also the least effective in that it grossly overestimate the confidence region. Based on the dual-quaternion representation, this paper introduces the notion of the kinematic confidence ellipsoids as an alternative to the existing method called rotation and translation confidence limit (RTCL). An example is provided to demonstrate how the kinematic confidence ellipsoids can be computed.
Predictors of Nodal and Metastatic Failure in Early Stage Non-Small Cell Lung Cancer after Stereotactic Body Radiation Therapy
(Elsevier, 2019) Cerra-Franco, Alberto; Liu, S.; Azar, M.; Shiue, Kevin; Freije, S.; Hinton, J.; Deig, Christopher R.; Edwards, D.; Estabrook, Neil C.; Ellsworth, S. G.; Huang, K.; Diab, K.; Langer, Mark P.; Zellars, Richard; Kong, Feng-Ming; Wan, Jun; Lautenschlaeger, Tim; Radiation Oncology, School of Medicine
Introduction/Background Many early-stage non-small cell lung cancer (ES-NSCLC) patients undergoing stereotactic body radiation therapy (SBRT) develop metastases, which is associated with poor outcomes. We sought to identify factors predictive of metastases after lung SBRT and created a risk stratification tool. Materials and Methods We included 363 patients with ES-NSCLC who received SBRT; median follow-up was 5.8 years. The following patient and tumor factors were retrospectively analyzed for their association with metastases (defined as nodal and/or distant failure): sex; age; lobe involved; centrality; previous NSCLC; smoking status; gross tumor volume (GTV); T-stage; histology; dose; minimum, maximum, and mean GTV dose; and parenchymal lung failure. A metastasis risk-score linear-model using beta coefficients from a multivariate Cox model was built. Results A total of 111/406 (27.3%) lesions metastasized. GTV volume and dose were significantly associated with metastases on univariate and multivariate Cox proportional hazards modeling (p<0.001 and HR=1.02 per mL, p<0.05 and HR=0.99 per Gy, respectively). Histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not associated with development of metastasis. A metastasis risk-score model using GTV volume and prescription dose was built: [risk score=(0.01611 x GTV)–(0.00525 x dose (BED10))]. Two risk-score cutoffs separating the cohort into low-, medium-, and high-risk subgroups were examined. The risk-score identified significant differences in time to metastases between low-, medium-, and high-risk patients (p<0.001), with 3-year estimates of 81.1%, 63.8%, and 38%, respectively. Conclusion GTV volume and radiation dose are associated with time to metastasis and may be used to identify patients at higher risk of metastasis after lung SBRT.
Radiologic Imaging of CAR T-Cell Therapy: Looking under the Hood to Move Us Forward
(Radiological Society of North America, 2022) Langer, Mark P.; Radiation Oncology, School of Medicine
Radioluminescent nanoparticles for radiation-controlled release of drugs
(Elsevier, 2019-06) Misra, Rahul; Sarkar, Kaustabh; Lee, Jaewon; Pizzuti, Vincenzo J.; Lee, Deborah S.; Currie, Melanie P.; Torregrosa-Allen, Sandra E.; Long, David E.; Durm, Gregory A.; Langer, Mark P.; Elzey, Bennett D.; Won, You-Yeon; Radiation Oncology, School of Medicine
The present work demonstrates a novel concept for intratumoral chemo-radio combination therapy for locally advanced solid tumors. For some locally advanced tumors, chemoradiation is currently standard of care. This combination treatment can cause acute and long term toxicity that can limit its use in older patients or those with multiple medical comorbidities. Intratumoral chemotherapy has the potential to address the problem of systemic toxicity that conventional chemotherapy suffers, and may, in our view, be a better strategy for treating certain locally advanced tumors. The present study proposes how intratumoral chemoradiation can be best implemented. The enabling concept is the use of a new chemotherapeutic formulation in which chemotherapy drugs (e.g., paclitaxel (PTX)) are co-encapsulated with radioluminecsnt nanoparticles (e.g., CaWO4 (CWO) nanoparticles (NPs)) within protective capsules formed by biocompatible/biodegradable polymers (e.g., poly(ethylene glycol)-poly(lactic acid) or PEG-PLA). This drug-loaded polymer-encapsulated radioluminescent nanoparticle system can be locally injected in solution form into the patient's tumor before the patient receives normal radiotherapy (e.g., 30–40 fractions of 2–3 Gy daily X-ray dose delivered over several weeks for locally advanced head and neck tumors). Under X-ray irradiation, the radioluminescent nanoparticles produce UV-A light that has a radio-sensitizing effect. These co-encapsulated radioluminescent nanoparticles also enable radiation-triggered release of chemo drugs from the polymer coating layer. The non-toxic nature (absence of dark toxicity) of this drug-loaded polymer-encapsulated radioluminescent nanoparticle (“PEG-PLA/CWO/PTX”) formulation was confirmed by the MTT assay in cancer cell cultures. A clonogenic cell survival assay confirmed that these drug-loaded polymer-encapsulated radioluminescent nanoparticles significantly enhance the cancer cell killing effect of radiation therapy. In vivo study validated the efficacy of PEG-PLA/CWO/PTX-based intratumoral chemo-radio therapy in mouse tumor xenografts (in terms of tumor response and mouse survival). Results of a small-scale NP biodistribution (BD) study demonstrate that PEG-PLA/CWO/PTX NPs remained at the tumor sites for a long period of time (> 1 month) following direct intratumoral administration. A multi-compartmental pharmacokinetic model (with rate constants estimated from in vitro experiments) predicts that this radiation-controlled drug release technology enables significant improvements in the level and duration of drug availability within the tumor (throughout the typical length of radiation treatment, i.e., > 1 month) over conventional delivery systems (e.g., PEG-PLA micelles with no co-encapsulated CaWO4, or an organic liquid, e.g., a 50:50 mixture of Cremophor EL and ethanol, as in Taxol), while it is capable of maintaining the systemic level of the chemo drug far below the toxic threshold limit over the entire treatment period. This technology thus has the potential to offer a new therapeutic option that has not previously been available for patients excluded from conventional chemoradiation protocols.

Browsing by Author "Langer, Mark P."

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