Statistical multi-level shape models for scalable modeling of multi-organ anatomies.

Statistical shape modeling is an indispensable tool in the quantitative analysis of anatomies. Particle-based shape modeling (PSM) is a state-of-the-art approach that enables the learning of population-level shape representation from medical imaging data (e.g., CT, MRI) and the associated 3D models of anatomy generated from them. PSM optimizes the placement of a dense set of landmarks (i.e., correspondence points) on a given shape cohort. PSM supports multi-organ modeling as a particular case of the conventional single-organ framework via a global statistical model, where multi-structure anatomy is considered as a single structure. However, global multi-organ models are not scalable for many organs, induce anatomical inconsistencies, and result in entangled shape statistics where modes of shape variation reflect both within- and between-organ variations. Hence, there is a need for an efficient modeling approach that can capture the inter-organ relations (i.e., pose variations) of the complex anatomy while simultaneously optimizing the morphological changes of each organ and capturing the population-level statistics. This paper leverages the PSM approach and proposes a new approach for correspondence-point optimization of multiple organs that overcomes these limitations. The central idea of multilevel component analysis, is that the shape statistics consists of two mutually orthogonal subspaces: the within-organ subspace and the between-organ subspace. We formulate the correspondence optimization objective using this generative model. We evaluate the proposed method using synthetic shape data and clinical data for articulated joint structures of the spine, foot and ankle, and hip joint.

Learning spatiotemporal statistical shape models for non-linear dynamic anatomies.

Numerous clinical investigations require understanding changes in anatomical shape over time, such as in dynamic organ cycle characterization or longitudinal analyses (e.g., for disease progression). Spatiotemporal statistical shape modeling (SSM) allows for quantifying and evaluating dynamic shape variation with respect to a cohort or population of interest. Existing data-driven SSM approaches leverage information theory to capture population-level shape variations by learning correspondence-based (landmark) representations of shapes directly from data using entropy-based optimization schemes. These approaches assume sample independence and thus are unsuitable for sequential dynamic shape observations. Previous methods for adapting entropy-based SSM optimization schemes for the spatiotemporal case either utilize a cross-sectional design (ignoring within-subject correlation) or impose other limiting assumptions, such as the linearity of shape dynamics. Here, we present a principled approach to spatiotemporal SSM that relaxes these assumptions to correctly capture population-level shape variation over time. We propose to incorporate modeling the underlying time dependency into correspondence optimization via a regularized principal component polynomial regression. This approach is flexible enough to capture non-linear temporal dynamics while encoding population-specific spatial regularity. We demonstrate our method's efficacy on synthetic data and left atrium segmented from cardiac MRI scans. Our approach better captures the population modes of variation and a statistically significant time dependency than existing methods.

Multi-level multi-domain statistical shape model of the subtalar, talonavicular, and calcaneocuboid joints.

Traditionally, two-dimensional conventional radiographs have been the primary tool to measure the complex morphology of the foot and ankle. However, the subtalar, talonavicular, and calcaneocuboid joints are challenging to assess due to their bone morphology and locations within the ankle. Weightbearing computed tomography is a novel high-resolution volumetric imaging mechanism that allows detailed generation of 3D bone reconstructions. This study aimed to develop a multi-domain statistical shape model to assess morphologic and alignment variation of the subtalar, talonavicular, and calcaneocuboid joints across an asymptomatic population and calculate 3D joint measurements in a consistent weightbearing position. Specific joint measurements included joint space distance, congruence, and coverage. Noteworthy anatomical variation predominantly included the talus and calcaneus, specifically an inverse relationship regarding talar dome heightening and calcaneal shortening. While there was minimal navicular and cuboid shape variation, there were alignment variations within these joints; the most notable is the rotational aspect about the anterior-posterior axis. This study also found that multi-domain modeling may be able to predict joint space distance measurements within a population. Additionally, variation across a population of these four bones may be driven far more by morphology than by alignment variation based on all three joint measurements. These data are beneficial in furthering our understanding of joint-level morphology and alignment variants to guide advancements in ankle joint pathological care and operative treatments.

Spatiotemporal Cardiac Statistical Shape Modeling: A Data-Driven Approach.

Clinical investigations of anatomy's structural changes over time could greatly benefit from population-level quantification of shape, or spatiotemporal statistic shape modeling (SSM). Such a tool enables characterizing patient organ cycles or disease progression in relation to a cohort of interest. Constructing shape models requires establishing a quantitative shape representation (e.g., corresponding landmarks). Particle-based shape modeling (PSM) is a data-driven SSM approach that captures population-level shape variations by optimizing landmark placement. However, it assumes cross-sectional study designs and hence has limited statistical power in representing shape changes over time. Existing methods for modeling spatiotemporal or longitudinal shape changes require predefined shape atlases and pre-built shape models that are typically constructed cross-sectionally. This paper proposes a data-driven approach inspired by the PSM method to learn population-level spatiotemporal shape changes directly from shape data. We introduce a novel SSM optimization scheme that produces landmarks that are in correspondence both across the population (inter-subject) and across time-series (intra-subject). We apply the proposed method to 4D cardiac data from atrial-fibrillation patients and demonstrate its efficacy in representing the dynamic change of the left atrium. Furthermore, we show that our method outperforms an image-based approach for spatiotemporal SSM with respect to a generative time-series model, the Linear Dynamical System (LDS). LDS fit using a spatiotemporal shape model optimized via our approach provides better generalization and specificity, indicating it accurately captures the underlying time-dependency.

Statistical shape modeling of multi-organ anatomies with shared boundaries.

Introduction: Statistical shape modeling (SSM) is a valuable and powerful tool to generate a detailed representation of complex anatomy that enables quantitative analysis of shapes and their variations. SSM applies mathematics, statistics, and computing to parse the shape into some quantitative representation (such as correspondence points or landmarks) which can be used to study the covariance patterns of the shapes and answer various questions about the anatomical variations across the population. Complex anatomical structures have many diverse parts with varying interactions or intricate architecture. For example, the heart is a four-chambered organ with several shared boundaries between chambers. Subtle shape changes within the shared boundaries of the heart can indicate potential pathologic changes such as right ventricular overload. Early detection and robust quantification could provide insight into ideal treatment techniques and intervention timing. However, existing SSM methods do not explicitly handle shared boundaries which aid in a better understanding of the anatomy of interest. If shared boundaries are not explicitly modeled, it restricts the capability of the shape model to identify the pathological shape changes occurring at the shared boundary. Hence, this paper presents a general and flexible data-driven approach for building statistical shape models of multi-organ anatomies with shared boundaries that explicitly model contact surfaces. Methods: This work focuses on particle-based shape modeling (PSM), a state-of-art SSM approach for building shape models by optimizing the position of correspondence particles. The proposed PSM strategy for handling shared boundaries entails (a) detecting and extracting the shared boundary surface and contour (outline of the surface mesh/isoline) of the meshes of the two organs, (b) followed by a formulation for a correspondence-based optimization algorithm to build a multi-organ anatomy statistical shape model that captures morphological and alignment changes of individual organs and their shared boundary surfaces throughout the population. Results: We demonstrate the shared boundary pipeline using a toy dataset of parameterized shapes and a clinical dataset of the biventricular heart models. The shared boundary model for the cardiac biventricular data achieves consistent parameterization of the shared surface (interventricular septum) and identifies the curvature of the interventricular septum as pathological shape differences.

Photoinduced Fabrication of Zinc Oxide Nanoparticles: Transformation of Morphological and Biological Response on Light Irradiance.

The photoinduced synthesis of zinc oxide nanoparticles (ZnO NPs) was carried out to unveil the effects of change in wavelength of photons. ZnO NPs were synthesized by the coprecipitation technique exposed to different light regimes [dark environment, daylight, and blue-, green-, yellow-, and red-colored light-emitting diodes (LEDs)] at room temperature. X-ray diffractogram (XRD) revealed the wurtzite structure of ZnO NPs. A small change in the size of ZnO NPs (17.11-22.56 nm) was observed with the variation in wavelength of lights from 350 to 700 nm. Spherical to hexagonal disks and rodlike surface morphologies were observed by scanning electron microscopy (SEM). The elemental composition and surface chemistry of NPs were studied by energy-dispersive X-ray diffractive (EDX) and Fourier transform infrared (FTIR) spectra. Maximum free radical quenching activity, cation radical scavenging, and total antioxidant capacity were found in ZnO NPs synthesized under green light (28.78 ± 0.18, 30.05 ± 0.21%, and 36.55 ± 2.63 µg AAE/mg, respectively). Daylight-synthesized NPs (DL-ZNPs) showed the greatest total reducing potential (15.81 ± 0.33 µg AAE/mg) and metal-chelating activity (37.77 ± 0.31%). Photoinduced ZnO NPs showed significant enzyme inhibitory effects on amylase, lipase, and urease by red-light NPs (87.49 ± 0.19%), green-light NPs (91.44 ± 0.29%), and blue-light NPs (92.17 ± 0.34%), respectively. Photoinduced ZnO NPs have been employed as nanozymes and found to exhibit intrinsic peroxidase-like activity as well. Blue-light-synthesized ZnO NPs displayed the strongest antibacterial activity (23 mm) against methicillin-resistant Staphylococcus aureus (MRSA). This study can be considered as a novel step toward the synthetic approach using LEDs to synthesize ZnO NPs with specific physicochemical properties and extends a great prospect in the environmental chemistry, food safety, and biomedical fields as nanozyme, antioxidant, antibacterial, anti-α-amylase, antiurease, and antilipase agents.

Synthesis, Crystal Structures, and Spectroscopic Characterization of Bis-aldehyde Monomers and Their Electrically Conductive Pristine Polyazomethines.

Bis-aldehyde monomers 4-(4'-formyl-phenoxy)benzaldehyde (3a), 3-methoxy-4-(4'-formyl-phenoxy)benzaldehyde (3b), and 3-ethoxy-4-(4'-formyl-phenoxy)benzaldehyde (3c) were synthesized by etherification of 4-fluorobenzaldehyde (1) with 4-hydroxybenzaldehyde (2a), 3-methoxy-4-hydroxybenzaldehyde (2b), and 3-ethoxy-4-hydroxybenzaldehyde (2c), respectively. Each monomer was polymerized with p-phenylenediamine and 4,4'-diaminodiphenyl ether to yield six poly(azomethine)s. Single crystal X-ray diffraction structures of 3b and 3c were determined. The structural characterization of the monomers and poly(azomethine)s was performed by FT-IR and NMR spectroscopic techniques and elemental analysis. Physicochemical properties of polymers were investigated by powder X-ray diffraction, thermogravimetric analysis (TGA), viscometry, UV-vis, spectroscopy and photoluminescence. These polymers were subjected to electrical conductivity measurements by the four-probe method, and their conductivities were found to be in the range 4.0 × 10-5 to 6.4 × 10-5 Scm-1, which was significantly higher than the values reported so far.

A novel insertion mutation on exon 20 of epidermal growth factor receptor, conferring resistance to erlotinib.

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein tyrosine kinase receptor. The small-molecule tyrosine kinase receptor inhibitors (TKIs) are in clinical use to treat non-small cell lung cancer with EGFR mutations. Variable tumor responses to erlotinib and gefitinib have been observed. The response to these TKIs varies by the type of EGFR mutations found in the tumor. The deletion on exon 19 and the L858R substitution on exon 21 constitute the most frequent mutations and are known to show good response to TKIs. However, mutations on exon 20 are less common and seem to respond poorly to TKIs. In clinical settings, the reported response of exon 20 mutations to reversible TKIs (both gefitinib and erlotinib) remains inconstant. The type of coexisting mutation seems to affect the response of these insertions to TKIs. We herein present a case of disease progression despite the use of erlotinib in a female patient who had a novel insertion mutation on exon 20. Our patient was a never-smoker and was identified to have a Pro772_His773insGlnCysPro mutation on exon 20. She had previously been treated with cisplatin and gemcitabine and then with carboplatin and pemetrexed. She was treated with erlotinib upon intolerance to second-line chemotherapy and did not respond. Our patient had a novel insertion mutation on exon 20, which was found to be resistant to erlotinib.

Postpartum spontaneous dissection of the first obtuse marginal branch of the left circumflex coronary artery causing acute coronary syndrome: a case report and literature review.

INTRODUCTION: Spontaneous coronary artery dissection is a rare but important cause of acute coronary syndrome. It can cause unstable angina, acute myocardial infarction, and sudden death. The condition commonly affects young females with about one-third of the cases occurring during pregnancy and the peripartum period. The diagnosis may occasionally be overlooked as the patients are often young and have no risk factors for coronary artery disease. CASE PRESENTATION: Here we report the case of a 29-year-old African American woman who presented with acute coronary syndrome due to spontaneous dissection of the first obtuse marginal branch of the left circumflex coronary artery at three weeks post-partum and recovered requiring only medical management, possibly by longitudinal distribution of the intramural hematoma leading to good distal flow. CONCLUSIONS: Spontaneous coronary artery dissection should be suspected in all young multiparous females presenting with chest pain in the peripartum period even in the absence of risk factors. Urgent diagnosis by angiography is required. It is recommended that treatment should be tailored to meet individual circumstances. Patients who present with single-vessel disease and hemodynamic stability, and who receive medical treatment with anticoagulation, nitrates and a beta-blocker, should experience good results.

Superparamagnetic bimetallic iron-palladium nanoalloy: synthesis and characterization.

Iron-palladium nanoalloy in the particle size range of 15-30 nm is synthesized by the relatively low temperature thermal decomposition of coprecipitated [Fe(Bipy)(3)]Cl(2) and [Pd(Bipy)(3)]Cl(2) in an inert ambient of dry argon gas. The silvery black Fe-Pd alloy nanoparticles are air-stable and have been characterized by EDX-RF, XRD, AFM, TEM, magnetometry, (57)Fe Mössbauer and impedance spectroscopy. This Fe-Pd nanoalloy is in single phase and contains iron sites having up to 11 nearest-neighboring atoms. It is superparamagnetic in nature with high magnetic susceptibility, low coercivity and hyperfine field.

Continuous infusion interleukin-2 and famotidine in metastatic kidney cancer.

Infusional interleukin-2 (IL-2) is able to elicit lymphokine-activated killer cell (LAK) cytotoxicity against kidney cancer in vitro and in vivo. Famotidine may be able to augment LAK cytotoxicity against neoplastic cells. Fifteen (15) patients were treated with continuous-infusion IL-2 (9-18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg intravenously twice per day. Cycles were repeated every 3 weeks. These patients had a median age of 60 years (range, 29-72), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, bone, lymph node, and liver. The most common toxicities of this regimen were hypophosphatemia, fever, nausea/emesis, rigors, elevated creatinine, and hypomagnesemia. One (1) complete and 6 partial responses have been seen (47% response rate). The median duration of response is 9 months. The median survival for all patients is 20 months. Five (5) patients are alive at a median of 36+ months. This combination of infusional IL-2 with famotidine is active in metastatic kidney cancer.

Continuous infusion interleukin-2 and intravenous famotidine in metastatic melanoma.

Lymphokine-activated killer cell (LAK) cytotoxicity against tumor cells is induced by the use of high-dose infusional interleukin-2 (IL-2). LAK cytotoxicity against neoplastic cells may be augmented by famotidine. Twelve (12) patients have been treated with continuous infusion IL-2 (18 MIU/m2/24 hours) for 72 hours and famotidine 20 mg IVPB twice per day. Cycles were repeated every 3 weeks. These patients were of median age--67 years (range, 25-79), had a median performance status of 1 (range, 0-1), and had metastatic sites, including lung, lymph node, subcutaneous/soft tissue, and liver. The most common toxicities of this regimen were fever, rigors, nausea/emesis, hypophosphatemia, and hypomagnesemia. Three (3) partial responses have been seen (25% response rate). One (1) of these responders has undergone complete surgical resection and is disease-free at 15+ months. Four (4) patients are alive at a median of > 25 months. The median survival for all patients is 13 months. This combination of infusional IL-2 with famotidine is active in metastatic melanoma.

Correlation between development of pulmonary edema and response of pulmonary metastases of metastatic melanoma and kidney cancer to high-dose continuous-infusion interleukin-2.

The administration of high-dose continuous intravenous infusion interleukin-2 (IL-2) is able to induce the presence of lymphokine-activated killer (LAK) cells. LAK are able to nonspecifically lyse tumor cells. They are also able to lyse endothelial cells, which accounts for, at least in part, the capillary leak syndrome seen as one of the toxicities with this therapy. A pulmonary manifestation of capillary leak syndrome is the presence of pulmonary edema. We postulated that capillary leak may also be a mechanism by which LAK could conceivably reach pulmonary metastases or could be a reflection of damage of endothelial cells in vasculature supplying metastases and that capillary leak syndrome may actually correlate with the response of pulmonary metastases. We examined our database of patients with lung metastases treated with high-dose continuous infusion IL-2 (18 MIU/m(2)/day for 3 days) regimens. Eighteen patients had the following characteristics: melanoma (11), renal cancer (7), median age of 67 years (range, 28-79 years), and males (15). All patients were treated by oncology nurses on either the stem cell transplant unit or oncology ward. Pulmonary edema was defined as the presence of pleural fluid on a chest X-ray, computed tomography (CT) scan, and/or as noted on a physical examination by at least 2 observers. No patients required endotracheal intubation, mechanical ventilation, or an intensive care unit transfer. The median number of cycles received was 6 (range, 1-13). All 8 responding patients (6 patients with melanoma, 2 patients with kidney cancer) manifested pulmonary edema during interleukin-2 therapy. Four patients with pulmonary edema were nonresponders. The presence of pulmonary edema correlated with the response to therapy (p = 0.01). The median duration of response of pulmonary nodules was 5 months (range, 1-16 months). There is a correlation between the development of pulmonary edema and the response of pulmonary metastases in patients with melanoma and kidney cancer treated with high-dose continuous infusion interleukin-2.

High-dose continuous infusion plus pulse interleukin-2 and famotidine in metastatic kidney cancer.

High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.

Repeated cycles with 72-hour continuous infusion interleukin-2 in kidney cancer and melanoma.

While high-dose bolus inpatient interleukin-2 is generally given on 8-week cycles, continuous infusion interleukin-2 could potentially allow for more rapidly repeated cycles. Fourteen (14) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, having either kidney cancer (6) or melanoma (8), have been treated with continuous infusion (CIV) interleukin-2 (IL-2) 18 MIU/m(2)/24 hours for 72 hours. Cycles were repeated every 3 weeks up to 4 cycles, then every 3-4 weeks for 2 cycles, then every 6-8 weeks, until progression or intolerable toxicity. All patients received famotidine 20 mg intravenously (i.v.) twice per day during the 72-hour infusions. Patient characteristics included a median ECOG performance status of 1; median age = 63 (range: 25-79); most common metastatic sites: lung (9), bone (5), lymph nodes (5), and the liver (3). No patients with metastatic kidney cancer underwent a nephrectomy prior to interleukin-2. Median number of cycles received = 5 (1-9). No patients required Intensive Care Unit (ICU) admission. There have been no treatment-related deaths. Most common toxicities have been rigors, fever, nausea/emesis, and the reversible elevation of creatinine. One complete response and three partial responses (67% response rate; 95% confidence interval: 30%-90%) have been seen in kidney cancer, and two partial responses (25% response rate; 95% confidence interval: 7%-60%) have occurred in melanoma. Median survival has not been reached at >9+ months. Responding sites include the liver, bone, lung, lymph node and subcutaneous sites. Inpatient 72-hour continuous infusion interleukin-2 at this dose and schedule is well tolerated by patients with an ECOG performance status of 0 or 1 and has activity in kidney cancer and melanoma.

Continuous infusion interleukin-2 and antihistamines in melanoma: a retrospective review showing activity of this combination.

A recent randomized trial suggests that there may be an advantage in terms of survival with the combination of histamine and subcutaneous interleukin-2 (IL-2), compared to IL-2 alone. It has been postulated, then, that antihistamines may actually be antagonistic to IL-2 and, therefore, interfere with its antitumor activity. Because antihistamines such as cimetidine and ranitidine are commonly used as prophylaxis against gastrointestinal toxicity commonly seen with IL-2, and, because antihistamines may increase natural killer cell activity, it is reasonable to examine the response rate for this combination. An OVID Medline literature search between 1985 and 2003 was done. Continuous infusion (CIV) interleukin- 2 was used as the reference therapy because of the relatively constant IL-2 levels generated by this approach. Included studies were those in which either cimetidine, ranitidine, or famotidine were regularly scheduled and administered concurrently with IL-2, typically for gastrointestinal ulcer prophylaxis. Six (6) studies were identified. A total of 21 patients responded to therapy. Total response rate was 11%, with a 95% Confidence Interval: 7-17%. Four (4) complete responses were noted. Complete response rate was 2%, with a 95% Confidence Interval: 1-6%. These response rates are consistent with previously noted IL-2 response rates. In this retrospective review of CIV IL-2 and antihistamines, this combination appears to be active in melanoma. There appears to be no deleterious effect of routine antihistamine on the CIV IL-2 response rate.

High-dose continuous infusion plus pulse interleukin-2 and famotidine in melanoma.

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56(+) cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56(+) cells may play a role in responding patients.