Pharmacokinetic Analysis of Gd-DTPA Enhancement in dynamic three-dimensional MRI of breast lesions

The purpose of this study was to demonstrate that dynamic MRI covering both breasts can provide sensitivity for tumor detection as well as specificity and sensitivity for differentiation of tumor malignancy. Three-dimensional gradient echo scans were used covering both breasts. Before Gd-DTPA bolus injection, two scans were obtained with different flip angles, and after injection, a dynamic series followed. Thirty-two patients were scanned according to this protocol. From these scans, in addition to enhancement, the value of T1 before injection was obtained. This was used to estimate the concentration of Gd-DTPA as well as the pharmacokinetic parameters governing its time course. Signal enhancement in three-dimensional dynamic scanning was shown to be a sensitive basis for detection of tumors. In our series, all but two mam-mographically suspicious lesions did enhance, and in three cases, additional enhancing lesions were found, two of which were in the contralateral breast. The parameter most suited for classification of breast lesions into benign or malignant was shown to be the pharmacokinetically defined permeability k31, which, for that test, gave a sensitivity of 92% and a specificity of 70%. Our three-dimensional dynamic MRI data are sensitive for detection of mammographically occult breast tumors and specific for classification of these as benign or malignant

Theoretical investigation of transgastric and intraductal approaches for ultrasound-based thermal therapy of the pancreas.

BackgroundThe goal of this study was to theoretically investigate the feasibility of intraductal and transgastric approaches to ultrasound-based thermal therapy of pancreatic tumors, and to evaluate possible treatment strategies.MethodsThis study considered ultrasound applicators with 1.2 mm outer diameter tubular transducers, which are inserted into the tissue to be treated by an endoscopic approach, either via insertion through the gastric wall (transgastric) or within the pancreatic duct lumen (intraductal). 8 patient-specific, 3D, transient, biothermal and acoustic finite element models were generated to model hyperthermia (n = 2) and ablation (n = 6), using sectored (210°-270°, n = 4) and 360° (n = 4) transducers for treatment of 3.3-17.0 cm3 tumors in the head (n = 5), body (n = 2), and tail (n = 1) of the pancreas. A parametric study was performed to determine appropriate treatment parameters as a function of tissue attenuation, blood perfusion rates, and distance to sensitive anatomy.ResultsParametric studies indicated that pancreatic tumors up to 2.5 or 2.7 cm diameter can be ablated within 10 min with the transgastric and intraductal approaches, respectively. Patient-specific simulations demonstrated that 67.1-83.3% of the volumes of four sample 3.3-11.4 cm3 tumors could be ablated within 3-10 min using transgastric or intraductal approaches. 55.3-60.0% of the volume of a large 17.0 cm3 tumor could be ablated using multiple applicator positions within 20-30 min with either transgastric or intraductal approaches. 89.9-94.7% of the volume of two 4.4-11.4 cm3 tumors could be treated with intraductal hyperthermia. Sectored applicators are effective in directing acoustic output away from and preserving sensitive structures. When acoustic energy is directed towards sensitive structures, applicators should be placed at least 13.9-14.8 mm from major vessels like the aorta, 9.4-12.0 mm from other vessels, depending on the vessel size and flow rate, and 14 mm from the duodenum.ConclusionsThis study demonstrated the feasibility of generating shaped or conformal ablative or hyperthermic temperature distributions within pancreatic tumors using transgastric or intraductal ultrasound

DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer

Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 BRCA1 pathogenic mutation carriers, 65 BRCAx (BRCA1-wild type), 38 BRCA1 test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (BACH2, C8orf31, and LOC654342) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G>A (IVS 19-12 G>A) (P>0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of BRCA1 variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Nanotechnology and cancer

The biological picture of cancer is rapidly advancing from models built from phenomenological descriptions to network models derived from systems biology, which can capture the evolving pathophysiology of the disease at the molecular level. The translation of this (still academic) picture into a clinically relevant framework can be enabling for the war on cancer, but it is a scientific and technological challenge. In this review, we discuss emerging in vitro diagnostic technologies and therapeutic approaches that are being developed to handle this challenge. Our discussion of in vitro diagnostics is guided by the theme of making large numbers of measurements accurately, sensitively, and at very low cost. We discuss diagnostic approaches based on microfluidics and nanotechnology. We then review the current state of the art of nanoparticle-based therapeutics that have reached the clinic. The goal of the presentation is to identify nanotherapeutic strategies that are designed to increase efficacy while simultaneously minimizing the toxic side effects commonly associated with cancer chemotherapies

TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

Tumor antigen-driven selection may expand T cells having T cell receptors (TCRs) of shared antigen specificity but different amino acid or nucleotide sequence in a process known as TCR convergence. Substitution sequencing errors introduced by TCRβ (TCRB) repertoire sequencing may create artifacts resembling TCR convergence. Given the anticipated differences in substitution error rates across different next-generation sequencing platforms, the choice of platform could be consequential. To test this, we performed TCRB sequencing on the same peripheral blood mononuclear cells (PBMC) from individuals with cancer receiving anti-CTLA-4 or anti-PD-1 using an Illumina-based approach (Sequenta) and an Ion Torrent-based approach (Oncomine TCRB-LR). While both approaches found similar TCR diversity, clonality, and clonal overlap, we found that Illumina-based sequencing resulted in higher TCR convergence than with the Ion Torrent approach. To build upon this initial observation we conducted a systematic comparison of Illumina-based TCRB sequencing assays, including those employing molecular barcodes, with the Oncomine assay, revealing differences in the frequency of convergent events, purportedly artifactual rearrangements, and sensitivity of detection. Finally, we applied the Ion Torrent-based approach to evaluate clonality and convergence in a cohort of individuals receiving anti-CTLA-4 blockade for cancer. We found that clonality and convergence independently predicted response and could be combined to improve the accuracy of a logistic regression classifier. These results demonstrate the importance of the sequencing platform in assessing TCRB convergence

3D digital breast cancer models with multimodal fusion algorithms

Breast cancer image fusion consists of registering and visualizing different sets of a patient synchronized torso and radiological images into a 3D model. Breast spatial interpretation and visualization by the treating physician can be augmented with a patient-specific digital breast model that integrates radiological images. But the absence of a ground truth for a good correlation between surface and radiological information has impaired the development of potential clinical applications. A new image acquisition protocol was designed to acquire breast Magnetic Resonance Imaging (MRI) and 3D surface scan data with surface markers on the patient's breasts and torso. A patient-specific digital breast model integrating the real breast torso and the tumor location was created and validated with a MRI/3D surface scan fusion algorithm in 16 breast cancer patients. This protocol was used to quantify breast shape differences between different modalities, and to measure the target registration error of several variants of the MRI/3D scan fusion algorithm. The fusion of single breasts without the biomechanical model of pose transformation had acceptable registration errors and accurate tumor locations. The performance of the fusion algorithm was not affected by breast volume. Further research and virtual clinical interfaces could lead to fast integration of this fusion technology into clinical practice.publishersversionpublishe

Respiration-Induced Intraorgan Deformation of the Liver: Implications for Treatment Planning in Patients Treated With Fiducial Tracking.

Stereotactic body radiation therapy is a well-tolerated modality for the treatment of primary and metastatic liver lesions, and fiducials are often used as surrogates for tumor tracking during treatment. We evaluated respiratory-induced liver deformation by measuring the rigidity of the fiducial configuration during the breathing cycle. Seventeen patients, with 18 distinct treatment courses, were treated with stereotactic body radiosurgery using multiple fiducials. Liver deformation was empirically quantified by measuring the intrafiducial distances at different phases of respiration. Data points were collected at the 0%, 50%, and 100% inspiration points, and the distance between each pair of fiducials was measured at the 3 phases. The rigid body error was calculated as the maximum difference in the intrafiducial distances. Liver disease was calculated with Child-Pugh score using laboratory values within 3 months of initiation of treatment. A peripheral fiducial was defined as within 1.5 cm of the liver edge, and all other fiducials were classified as central. For 5 patients with only peripheral fiducials, the fiducial configuration had more deformation (average maximum rigid body error 7.11 mm, range: 1.89-11.35 mm) when compared to patients with both central and peripheral and central fiducials only (average maximum rigid body error 3.36 mm, range: 0.5-9.09 mm, P = .037). The largest rigid body errors (11.3 and 10.6 mm) were in 2 patients with Child-Pugh class A liver disease and multiple peripheral fiducials. The liver experiences internal deformation, and the fiducial configuration should not be assumed to act as a static structure. We observed greater deformation at the periphery than at the center of the liver. In our small data set, we were not able to identify cirrhosis, which is associated with greater rigidity of the liver, as predictive for deformation. Treatment planning based only on fiducial localization must take potential intraorgan deformation into account

Intraoperative Guidance for Pediatric Brain Surgery based on Optical Techniques

For most of the patients with brain tumors and/or epilepsy, surgical resection of brain lesions, when applicable, remains one of the optimal treatment options. The success of the surgery hinges on accurate demarcation of neoplastic and epileptogenic brain tissue. The primary goal of this PhD dissertation is to demonstrate the feasibility of using various optical techniques in conjunction with sophisticated signal processing algorithms to differentiate brain tumor and epileptogenic cortex from normal brain tissue intraoperatively. In this dissertation, a new tissue differentiation algorithm was developed to detect brain tumors in vivo using a probe-based diffuse reflectance spectroscopy system. The system as well as the algorithm were validated experimentally on 20 pediatric patients undergoing brain tumor surgery at Nicklaus Children’s Hospital. Based on the three indicative parameters, which reflect hemodynamic and structural characteristics, the new algorithm was able to differentiate brain tumors from the normal brain with a very high accuracy. The main drawbacks of the probe-based system were its high susceptibility to artifacts induced by hand motion and its interference to the surgical procedure. Therefore, a new optical measurement scheme and its companion spectral interpretation algorithm were devised. The new measurement scheme was evaluated both theoretically with Monte Carlo simulation and experimentally using optical phantoms, which confirms the system is capable of consistently acquiring total diffuse reflectance spectra and accurately converting them to the ratio of reduced scattering coefficient to absorption coefficient (µs’(λ)/µa(λ)). The spectral interpretation algorithm for µs’(λ)/µa(λ) was also validated based on Monte Carlo simulation. In addition, it has been demonstrated that the new measurement scheme and the spectral interpretation algorithm together are capable of detecting significant hemodynamic and scattering variations from the Wistar rats’ somatosensory cortex under forepaw stimulation. Finally, the feasibility of using dynamic intrinsic optical imaging to distinguish epileptogenic and normal cortex was validated in an in vivo study involving 11 pediatric patients with intractable epilepsy. Novel data analysis methods were devised and applied to the data from the study; identification of the epileptogenic cortex was achieved with a high accuracy