Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m2 over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administratio

Shear and Ellipticity in Gravitational Lenses

Galaxies modeled as singular isothermal ellipsoids with an axis ratio distribution similar to the observed axis ratio distribution of E and S0 galaxies are statistically consistent with both the observed numbers of two-image and four-image lenses and the inferred ellipticities of individual lenses. However, no four-image lens is well fit by the model (typical $\chi^2/N_{dof} \sim 20$), the axis ratio of the model can be significantly different from that of the observed lens galaxy, and the major axes of the model and the galaxy may be slightly misaligned. We found that models with a second, independent, external shear axis could fit the data well (typical $\chi^2/N_{dof} \sim 1$), while adding the same number of extra parameters to the radial mass distribution does not produce such a dramatic improvement in the fit. An independent shear axis can be produced by misalignments between the luminous galaxy and its dark matter halo, or by external shear perturbations due to galaxies and clusters correlated with the primary lens or along the line of sight. We estimate that the external shear perturbations have no significant effect on the expected numbers of two-image and four-image lenses, but that they can be important perturbations in individual lens models. However, the amplitudes of the external shears required to produce the good fits are larger than our estimates for typical external shear perturbations (10-15% shear instead of 1-3% shear) suggesting that the origin of the extra angular structure must be intrinsic to the primary lens galaxy in most cases.Comment: 38 pages, 9 figures, submitted to Ap

The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child

A Systems Approach for Tumor Pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.National Institutes of Health (U.S.) (grant T32 CA079443

Recurrent <i>MDM2 </i>Amplification in the Spectrum of <i>HMGA2</i>-Altered Pleomorphic Adenoma, Atypical Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma

Introduction: Pleomorphic adenoma is the most common neoplasm of the salivary glands. While the overall risk of malignancy is relatively low, a distinct molecular sub-group harboring HMGA2 alterations seems to show an increased risk of malignant progression to carcinoma ex pleomorphic adenoma. Purpose: This study investigates MDM2 amplification in HMGA2-altered pleomorphic adenoma, atypical pleomorphic adenoma, and carcinoma ex pleomorphic adenoma. Methods: In this multicenter, retrospective case series analysis, we examined 37 cases of HMGA2-altered pleomorphic adenoma, carcinoma ex pleomorphic adenoma, and pleomorphic adenoma with atypical features. A total of 18 cases were included from our institutional archives, with 19 additional cases derived from published literature. The cases from our institutes were analyzed for MDM2 amplification using a stepped approach by immunohistochemistry and FISH. Results: Collectively, an MDM2 amplification was present in 27% of pleomorphic adenoma (4 of 15), compared to 78% of carcinoma ex pleomorphic adenoma (14 of 18) (p-value = 0.003). In the group of pleomorphic adenomas with atypical features, an MDM2 amplification was present in 50% of cases (2 of 4). These findings indicate an association between MDM2 amplification and malignancy. Strikingly, a mixed control group of 12 benign and malignant PLAG1-altered neoplasms showed no immunohistochemical staining for MDM2. Conclusion: Immunohistochemical MDM2 expression, including MDM2 amplification, is enriched in the group of HMGA2-altered pleomorphic adenoma, and potentially plays role in malignant progression. This study highlights the importance of recognizing the molecular sub-group of HMGA2-altered pleomorphic adenomas and integrate MDM2 analysis into routine diagnostics to corroborate the cytonuclear atypia in these challenging cases.</p

The five dimensions of B cell tolerance

B cell tolerance has been generally understood to be an acquired property of the immune system that governs antibody specificity in ways that avoid auto‐toxicity. As useful as this understanding has proved, it fails to fully explain the existence of auto‐reactive specificities in healthy individuals and contribution these may have to health. Mechanisms underlying B cell tolerance are considered to select a clonal repertoire that generates a collection of antibodies that do not bind self, ie tolerance operates more or less in three dimensions that largely spare autologous cells and antigens. Yet, most B lymphocytes in humans and probably in other vertebrates are auto‐reactive and absence of these auto‐reactive B cells is associated with disease. We suggest that auto‐reactivity can be embodied by extending the concept of tolerance by two further dimensions, one of time and circumstance and one that allows healthy cells to actively resist injury. In this novel concept, macromolecular recognition by the B cell receptor leading to deletion, anergy, receptor editing or B cell activation is extended by taking account of the time of development of normal immune responses (4th dimension) and the accommodation (or tolerance) of normal cells to bound antibody, activation of complement, and interaction with inflammatory cells (fifth dimension). We discuss how these dimensions contribute to understanding B cell biology in health or disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153034/1/imr12813.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153034/2/imr12813_am.pd

Relationship of serum bilirubin concentration to kidney function and 24-hour urine protein in Korean adults

<p>Abstract</p> <p>Background</p> <p>The relationships among serum bilirubin concentration, kidney function and proteinuria have yet to be fully elucidated, nor have these relationships been investigated in Korean adults.</p> <p>Method</p> <p>We retrospectively reviewed the medical records of Korean adults who were evaluated at Kosin University Gospel Hospital (Busan, Republic of Korea) during a five-year period from January 2005 to December 2009. We evaluated the relationships among serum bilirubin concentration, estimated glomerular filtration rate (eGFR) and 24-hour urinary protein excretion in a sample of 1363 Korean adults aged 18 years or older.</p> <p>Results</p> <p>The values of eGFR <60 mL/min/1.73 m²and 24-hour urine albumin ≥150 mg/day were observed in 26.1% (n = 356) and 40.5% (n = 553) of subjects, respectively. Fasting glucose levels ≥126 mg/dL were observed in 44.9% (n = 612) of the total sample. After adjustment for potential confounding factors including demographic characteristics, comorbidities and other laboratory measures, total serum bilirubin was positively associated with eGFR and negatively associated with proteinuria both in the whole cohort and in a subgroup of diabetic individuals.</p> <p>Conclusions</p> <p>To our knowledge, this is the first hospital-based study specifically aimed at examining the relationships among serum total bilirubin concentration, 24-hour urine protein and kidney function in Korean adults. We demonstrated that serum total bilirubin concentration was negatively correlated with 24-hour urine protein and positively correlated with eGFR in Korean non-diabetic and diabetic adults.</p

Exploring Potential Orbital Metastatic Pathways in Sinonasal Mucosal Melanoma: A Case Report

The following case potentially provides insight into the mechanisms of lymphogenic metastasis in sinonasal cancer. A 63-year-old patient who presented with progressive diplopia and left-sided periocular pain was diagnosed with a cT4bN0M0 mucosal melanoma of the ethmoid sinus. She underwent a combined endonasal and transcranial tumor resection, and an orbital exenteration. Upon histopathological examination, besides the primary tumor, two separate localizations of melanoma surrounded by lymphoid tissues and lymph follicles were identified. The tumor was upstaged to pT4bN1, and the patient received a combination of adjuvant immunotherapy and radiotherapy. At present, the patient displays no evidence of disease. The presence of orbital lymph nodes has previously never been confirmed. These findings indicate the potential involvement of lymphatic drainage through the retrobulbar fat in the regional spread of sinonasal tumors closely associated with the orbit

Improving the imaging performance of the 1.5 T MR-linac using a flexible, 32-channel, on-body receive array

High impedance coils (HICs) are suitable as a building block of receive arrays for MRI-guided radiotherapy (MRIgRT) as HICs do not require radiation-attenuating capacitors and dense support materials. Recently, we proved the feasibility of using HICs to create a radiation transparent (i.e. radiolucent) window. In this work, we constructed a fully functional 32-channel array based on this design. The anterior element is flexible and follows the shape of the subject, while the posterior element is rigid to support the subject. Both elements feature a 2 × 8 channel layout. Here, we discuss the construction process and characterize the array's radiolucency and imaging performance. The dosimetric impact of the array was quantified by assessing the surface dose increase and attenuation of a single beam. The imaging performance of the prototype was compared to the clinical array in terms of visual appearance, signal-to-noise ratio (SNR), and acceleration performance, both in phantom and in-vivo measurements. Dosimetry measurements showed that on-body placement changed the anterior and posterior surface dose by +3% and -16% of the dose maximum. Attenuation under the anterior support materials and conductors was 0.3% and ≤1.5%, respectively. Phantom and in-vivo imaging with this array demonstrated an improvement of the SNR at the surface and the image quality in general. Simultaneous irradiation did not affect the SNR. G-factors were reduced considerably and clinically used sequences could be accelerated by up to 45%, which would greatly reduce pre-beam imaging times. Finally, the maximally achievable temporal resolution of abdominal 3D cine imaging was improved to 1.1 s, which was > 5 × faster than could be achieved with the clinical array. This constitutes a big step towards the ability to resolve respiratory motion in 3D. In conclusion, the proposed 32-channel array is compatible with MRIgRT and can significantly reduce scan times and/or improve the image quality of all on-line scans