Multispectral upconversion luminescence intensity ratios for ascertaining the tissue imaging depth

Upconversion nanoparticles (UCNPs) have in recent years emerged as excellent contrast agents for in vivo luminescence imaging of deep tissues. But information abstracted from these images is in most cases restricted to 2-dimensions, without the depth information. In this work, a simple method has been developed to accurately ascertain the tissue imaging depth based on the relative luminescence intensity ratio of multispectral NaYF4:Yb3+,Er3+ UCNPs. A theoretical mode was set up, where the parameters in the quantitative relation between the relative intensities of the upconversion luminescence spectra and the depth of the UCNPs were determined using tissue mimicking liquid phantoms. The 540 nm and 650 nm luminescence intensity ratios (G/R ratio) of NaYF4:Yb3+,Er3+ UCNPs were monitored following excitation path (Ex mode) and emission path (Em mode) schemes, respectively. The model was validated by embedding NaYF4:Yb3+,Er3+ UCNPs in layered pork muscles, which demonstrated a very high accuracy of measurement in the thickness up to centimeter. This approach shall promote significantly the power of nanotechnology in medical optical imaging by expanding the imaging information from 2-dimensional to real 3-dimensional

Modeling BCR-ABL and MLL-AF9 leukemia in a human bone marrow-like scaffold based xenograft model

While NOD-SCID IL2Rγ(-/-) (NSG) xenograft mice are currently the most frequently used model to study human leukemia in vivo, the absence of a human niche severely hampers faithful recapitulation of the disease. We used NSG mice in which ceramic scaffolds seeded with human mesenchymal stromal cells were implanted to generate a human bone marrow (huBM-sc)-like niche. We observed that, in contrast to the murine bone marrow (mBM) niche, expression of BCR-ABL or MLL-AF9 was sufficient to induce both primary AML and ALL. Stemness was preserved within the human niches as demonstrated by serial transplantation assays. Efficient engraftment of AML MLL-AF9 and blast-crisis CML patient cells was also observed, whereby the immature blast-like phenotype was maintained in the huBM-sc niche, but to a much lesser extent in mBM niches. We compared transcriptomes of leukemias derived from mBM niches versus leukemias from huBM-like scaffold-based niches, which revealed striking differences in expression of genes associated with hypoxia, mitochondria and metabolism. Finally, we utilized the huBM-sc MLL-AF9 B-ALL model to evaluate the efficacy of the I-BET151 inhibitor in vivo. In conclusion, we have established human niche models in which the myeloid and lymphoid features of BCR-ABL(+) and MLL-AF9(+) leukemias can be studied in detail. Accepted article preview online 29 April 2016; Advance online publication 17 May 2016This work was supported by grants from the Dutch Cancer Society (2009-4411; VU2011-5127) and by the EU (ITN EuroCSC). I-BET151 was kindly provided by Nicholas Smithers (GSK R&D, UK)

A phase I and pharmacokinetic study of intraperitoneal topotecan

Purpose: To evaluate the feasibility and pharmacology of intraperitoneal (IP) topotecan. Patients and methods: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP topotecan doses (5–30 mg/m2) for pharmacokinetic analysis. Results: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m2 dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. Pharmacokinetics: Peak plasma levels of total topotecan were reached at 2.7 ± 1.1 h after IP instillation. The apparent V ss was 69.9 ± 25.4 L/m2, plasma clearance 13.4 ± 2.5 L/h/m2 and plasma T1/2 3.7 ± 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total topotecan was cleared from the peritoneal cavity at 0.4 ± 0.3 L/h.m2 with a T1/2 = 2.7 ± 1.7 h. The mean peritoneal/plasma AUC ratio for total topotecan was 54 ± 34. Conclusion: A substantial dose of topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m2 IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route. © 2001 Cancer Research Campaign http://www.bjcancer.co

Biphasic Oxidation of Oxy-Hemoglobin in Bloodstains

Background: In forensic science, age determination of bloodstains can be crucial in reconstructing crimes. Upon exiting the body, bloodstains transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO2) to methemoglobin (met-Hb) and hemichrome (HC). The fractions of HbO 2, met-Hb and HC in a bloodstain can be used for age determination of bloodstains. In this study, we further analyze the conversion of HbO2 to met-Hb and HC, and determine the effect of temperature and humidity on the conversion rates. Methodology: The fractions of HbO2, met-Hb and HC in a bloodstain, as determined by quantitative analysis of optical reflectance spectra (450–800 nm), were measured as function of age, temperature and humidity. Additionally, Optical Coherence Tomography around 1300 nm was used to confirm quantitative spectral analysis approach. Conclusions: The oxidation rate of HbO2 in bloodstains is biphasic. At first, the oxidation of HbO2 is rapid, but slows down after a few hours. These oxidation rates are strongly temperature dependent. However, the oxidation of HbO2 seems to be independent of humidity, whereas the transition of met-Hb into HC strongly depends on humidity. Knowledge of these decay rates is indispensable for translating laboratory results into forensic practice, and to enable bloodstain age determination on the crime scene

Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Assessment of Substrate for Ventricular Tachycardia With Hemodynamic Compromise.

Background: The majority of data regarding tissue substrate for post myocardial infarction (MI) VT has been collected during hemodynamically tolerated VT, which may be distinct from the substrate responsible for VT with hemodynamic compromise (VT-HC). This study aimed to characterize tissue at diastolic locations of VT-HC in a porcine model. Methods: Late Gadolinium Enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging was performed in eight pigs with healed antero-septal infarcts. Seven pigs underwent electrophysiology study with venous arterial-extra corporeal membrane oxygenation (VA-ECMO) support. Tissue thickness, scar and heterogeneous tissue (HT) transmurality were calculated at the location of the diastolic electrograms of mapped VT-HC. Results: Diastolic locations had median scar transmurality of 33.1% and a median HT transmurality 7.6%. Diastolic activation was found within areas of non-transmural scar in 80.1% of cases. Tissue activated during the diastolic component of VT circuits was thinner than healthy tissue (median thickness: 5.5 mm vs. 8.2 mm healthy tissue, p < 0.0001) and closer to HT (median distance diastolic tissue: 2.8 mm vs. 11.4 mm healthy tissue, p < 0.0001). Non-scarred regions with diastolic activation were closer to steep gradients in thickness than non-scarred locations with normal EGMs (diastolic locations distance = 1.19 mm vs. 9.67 mm for non-diastolic locations, p < 0.0001). Sites activated late in diastole were closest to steep gradients in tissue thickness. Conclusions: Non-transmural scar, mildly decreased tissue thickness, and steep gradients in tissue thickness represent the structural characteristics of the diastolic component of reentrant circuits in VT-HC in this porcine model and could form the basis for imaging criteria to define ablation targets in future trials

Childhood chronic anterior uveitis associated with vernal keratoconjunctivitis (VKC): successful treatment with topical tacrolimus. Case series

Uveitis treatment involves topical corticosteroids along with cycloplegic-mydriatics. Particularly severe cases may require systemic corticosteroids and immunosuppressive drugs. Vernal keratoconjunctivitis (VKC) treatment consists of a brief period of topical corticosteroids and/or cyclosporine. In patients refractory to traditional treatment, the use of 0.1% topical ophtalmic FK- 506 (tacrolimus) ointment has been occasionally reported

Segmentation of glioblastomas in early post-operative multi-modal MRI with deep neural networks

Extent of resection after surgery is one of the main prognostic factors for patients diagnosed with glioblastoma. To achieve this, accurate segmentation and classification of residual tumor from post-operative MR images is essential. The current standard method for estimating it is subject to high inter- and intra-rater variability, and an automated method for segmentation of residual tumor in early post-operative MRI could lead to a more accurate estimation of extent of resection. In this study, two state-of-the-art neural network architectures for pre-operative segmentation were trained for the task. The models were extensively validated on a multicenter dataset with nearly 1000 patients, from 12 hospitals in Europe and the United States. The best performance achieved was a 61% Dice score, and the best classification performance was about 80% balanced accuracy, with a demonstrated ability to generalize across hospitals. In addition, the segmentation performance of the best models was on par with human expert raters. The predicted segmentations can be used to accurately classify the patients into those with residual tumor, and those with gross total resection

A tool to balance benefit and harm when deciding about adjuvant therapy

Adjuvant therapy aims to prevent outgrowth of residual disease but can induce serious side effects. Weighing conflicting treatment effects and communicating this information with patients is not elementary. This study presents a scheme balancing benefit and harm of adjuvant therapy vs no adjuvant therapy. It is illustrated by the available evidence on adjuvant pelvic external beam radiotherapy (RT) for intermediate-risk stage I endometrial carcinoma patients. The scheme comprises five outcome possibilities of adjuvant therapy: patients who benefit from adjuvant therapy (some at the cost of complications) vs those who neither benefit nor contract complications, those who do not benefit but contract severe complications, or those who die. Using absolute risk differences, a fictive cohort of 1000 patients receiving adjuvant RT is categorised. Three large randomised clinical trials were included. Recurrences will be prevented by adjuvant RT in 60 patients, a majority of 908 patients will neither benefit nor suffer severe radiation-induced harm but 28 patients will suffer severe complications due to adjuvant RT and an expected four patients will die. This scheme readily summarises the different possible treatment outcomes and can be of practical value for clinicians and patients in decision making about adjuvant therapies

Segmentation of glioblastomas in early post-operative multi-modal MRI with deep neural networks

Extent of resection after surgery is one of the main prognostic factors for patients diagnosed with glioblastoma. To achieve this, accurate segmentation and classification of residual tumor from post-operative MR images is essential. The current standard method for estimating it is subject to high inter- and intra-rater variability, and an automated method for segmentation of residual tumor in early post-operative MRI could lead to a more accurate estimation of extent of resection. In this study, two state-of-the-art neural network architectures for pre-operative segmentation were trained for the task. The models were extensively validated on a multicenter dataset with nearly 1000 patients, from 12 hospitals in Europe and the United States. The best performance achieved was a 61\% Dice score, and the best classification performance was about 80\% balanced accuracy, with a demonstrated ability to generalize across hospitals. In addition, the segmentation performance of the best models was on par with human expert raters. The predicted segmentations can be used to accurately classify the patients into those with residual tumor, and those with gross total resection.Comment: 13 pages, 4 figures, 4 table