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To assess which specific morphologic features, enhancement patterns, or pharmacokinetic parameters on breast Magnetic Resonance Imaging (MRI) could predict a false-negative outcome of Proton MR Spectroscopy (1H MRS) exam in patients with invasive breast cancer. Sixteen patients with invasive ductal carcinoma of the breast were prospectively included and underwent both, contrast-enhanced breast MRI and 1H MRS examination of the breast. The MR images were reviewed and the lesions morphologic features, enhancement patterns and pharmacokinetic parameters (k21-value) were scored according to the ACR BI-RADS-MRI lexicon criteria. For the in vivo MRS studies, each spectrum was evaluated for the presence of choline based on consensus reading. Breast MRI and 1H MRS data were compared to histopathologic findings. In vivo 1H MRS detected a choline peak in 14/16 (88%) cancers. A false-negative 1H MRS study occurred in 2/16 (14%) cancer patients. K21 values differed between both groups: the 14 choline positive cancers had k21 values ranging from 0.01 to 0.20/second (mean 0.083/second), whereas the two choline-negative cancers showed k21 values of 0.03 and 0.05/second, respectively (mean 0.040/second). Also enhancement kinetics did differ between both groups; typically both cancers that were choline-negative showed a late phase plateau (100%), whereas this was only shown in 5/14 (36%) of the choline positive cases. There was no difference between both groups with regard to morphologic features on MRI. This study showed that false-negative 1H MRS examinations do occur in breast cancer patients, and that the presence of a choline peak on 1H MRS as malignancy marker is related to the k21 value of the invasive tumor being imaged. [ABSTRACT FROM AUTHOR]

Background: Caesarean section (CS) is the most common inpatient surgical procedure performed in Canada. CS is known to cause moderate-to-severe pain, which is suggested to be associated with postpartum depression and persistent pain. Existing limitations in multimodal analgesia and conscious attempts to avoid opioids highlight the need for non-pharmacological strategies. Photobiomodulation therapy (PBMT) uses light-emitting diode (LED) and laser and has suggested potential for improving pain control and wound healing. This study aims to evaluate the effectiveness of PBMT as part of existing multimodal analgesia after elective CSs., Methods: This placebo-controlled, two-arm, multi-centre, parallel-design randomized controlled trial includes women aged ≥16 years with planned CS under spinal anesthesia (Clinical Trials Registration: NCT05738239). Patients will be randomized post-CS to intervention (n = 90) or placebo (n = 90). Study interventions will be carried out using equipment supported by Meditech International Incorporated (approved by Health Canada for pain relief). Patients will receive a maximum of 5 post-surgical treatment sessions of active PBMT (intervention: LED therapy: DUO 240 [red at 660nm and near-infrared at 840nm] applied parallel to the abdominal incision scar, followed by BIOFLEX LDR-100 laser probe (660nm red light) and the LD1-200 laser probe (825nm near-infrared light), applied at the incision wound edges) or non-effective doses of LED array and laser therapy (placebo), 4-6 hrs post-CS, and at 8am and 7pm of postoperative days 1 and 2. Patients, research assistants involved in patient recruitment and follow-up, health care providers, and data analysts will be blinded. All patients will have access to routine multimodal analgesia. Patients will be followed up in hospital on the evening of surgery and on postoperative days 1 and 2 (morning, noon, and evening); at 6 weeks; and at 3 months by telephone. Primary outcome is pain intensity with movement (elicited by asking the patient to move from supine to sitting position) using 0-10 Numerical Rating Scale (0 = no pain, 10 = worst possible pain)., Significance: The results of this study may result in improved pain control, maternal satisfaction and wound healing; decrease the use of perioperative opioids; potentially decrease the incidence of postpartum depression and persistent pain; and overall lead to better postoperative outcomes thereby decreasing healthcare costs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Khaled et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The antitumor activity of adoptive T cell therapies (ACT) is highly dependent on the expansion, persistence, and continued activity of adoptively transferred cells. Clinical studies using ACTs have revealed that products that possess and maintain less differentiated phenotypes, including memory and precursor T cells, show increased antitumor efficacy and superior patient outcomes owing to their increased expansion, persistence, and ability to differentiate into effector progeny that elicit antitumor responses. Strategies that drive the differentiation into memory or precursor-type T cell subsets with high potential for persistence and self-renewal will enhance adoptively transferred T cell maintenance and promote durable antitumor efficacy. Because of the high costs associated with ACT manufacturing, ACTs are often only offered to patients after multiple rounds of systemic therapy. An essential factor to consider in producing autologous ACT medicinal products is the impact of the patient's initial T cell fitness and subtype composition, which will likely differ with age, disease history, and treatment with prior anti-cancer therapies. This study evaluated the impact of systemic anti-cancer therapy for non-small cell lung cancer treatment on the T cell phenotype of the patient at baseline and the quality and characteristics of the genetically modified autologous T cell therapy product after manufacturing., Competing Interests: A.B., M.B., S.H., J.C., J.W., J.H., E.H., W.L., and C.M.-E. are current or past employees and/or shareholders of GSK. S.P. is an employee of Enara Bio., (Crown Copyright © 2023.)

Background: The purpose of this study was to describe the topography, extension (volume), and timing of severe osteoradionecrosis (ORN) that required mandible resection in patients previously treated for head and neck cancer at a high-volume Veterans Affairs Medical Center., Materials and Methods: The records from a reference hyperbaric oxygen clinic were retrospectively analyzed (n = 50, 2018-2021). Inclusion criteria were: I) severe ORN defined as progressive ORN that required resection; II) pathologic confirmation of ORN; and III) availability of pre-operative CT-imaging. Using a radiotherapy (RT) imaging software, we performed a detailed volumetric (3D) analysis of the bone involvement by ORN. Time intervals from RT to surgery for ORN and from surgery to the last follow-up were calculated., Results: All patients that met inclusion criteria (n = 10) were male with significant smoking history (median 47.5 pack-years) and a median age of 57 years old at the time of RT. The primary tumors were: oropharynx (n = 6), oral cavity (n = 3) and nasopharynx (n = 1). The median time from RT to ORN surgery was 8 years. The most common ORN location was the posterior lateral body (molar) and six patients had associated fractures. The mean ORN volume was 3.6 cc (range: 0.6-8.3), corresponding to a mean 6.3% (range: 0.7-14) of the total mandibular volume. After a median follow-up of 13.5 months, no recurrence of ORN occurred. Three patients died of non-cancer and non-ORN-recurrence related causes (1 y OS 77.1%)., Conclusion: Severe ORN occurred after a median of 8 years from the previous RT and usually affected the posterior lateral body. Surgical resection achieved excellent ORN control., Competing Interests: Conflicts of interest None declared., (© 2022 Greater Poland Cancer Centre.)

Apicomplexa is a large monophyletic phylum of unicellular, parasitic organisms. Reptiles are hosts to both haemosporidian (Haemosporida) and hemogregarine (Eucoccidiorida) apicomplexan blood parasites. Within reptiles our understanding of their diversity remains limited, with a paucity of information from Australia, despite a high diversity of squamates (snakes and lizards). We provide a preliminary assessment of haemosporidian and hemogregarine diversity occurring in lizards across northern tropical Australia, building on existing data with results from a microscopy and genetic assessment. We screened total of 233 blood slides using microscopy and detected hemogregarines in 25 geckos, 2 skinks and 1 agamid, while haemosporidians were detected in 13 geckos. DNA sequencing of 28 samples of the hemogregarine 18S rRNA (∼900 bp) nuclear gene revealed five lineages of Australian lizard hemogregarines within heteroxenous adeleids. We sequenced 10 samples of Haemosporida mtDNA (cytb & coI: ∼1313 bp) and phylogenetic analysis with 30 previously published sequences revealed that the Australian Haemosporida grouped within the Haemoproteidae but were not supported as a monophyletic clade. Our results demonstrate that there is significant undocumented evolutionary diversity in Australian lizard haemosporidian and hemogregarine parasites, with preliminary evidence of significantly higher infection rates in geckos., (Copyright © 2021 Elsevier Inc. All rights reserved.)

With over 9000 species, squamates, which include lizards and snakes, are the largest group of reptiles and second-largest order of vertebrates, spanning a vast array of appendicular skeletal morphology. As such, they provide a promising system for examining developmental and molecular processes underlying limb morphology. Using the central bearded dragon (Pogona vitticeps) as the primary study model, we examined limb morphometry throughout embryonic development and characterized the expression of three known developmental genes (GHR, Pitx1 and Shh) from early embryonic stage through to hatchling stage via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). In this study, all genes were found to be transcribed in both the forelimbs and hindlimbs of P. vitticeps. While the highest level of GHR expression occurred at the hatchling stage, Pitx1 and Shh expression was greatest earlier during embryogenesis, which coincides with the onset of the differentiation between forelimb and hindlimb length. We compared our finding of Pitx1 expression-a hindlimb-determining gene-in the forelimbs of P. vitticeps to that in a closely related Australian agamid lizard, Ctenophorus pictus, where we found Pitx1 expression to be more highly expressed in the hindlimb compared with the forelimb during early and late morphogenesis-a result consistent with that found across other tetrapods. Expression of Pitx1 in forelimbs has only rarely been documented, including via in situ hybridization in a chicken and a frog. Our findings from both RT-qPCR and IHC indicate that further research across a wider range of tetrapods is needed to more fully understand evolutionary variation in molecular processes underlying limb morphology., (© 2016 The Authors.)

Exon-capture studies have typically been restricted to relatively shallow phylogenetic scales due primarily to hybridization constraints. Here, we present an exon-capture system for an entire class of marine invertebrates, the Ophiuroidea, built upon a phylogenetically diverse transcriptome foundation. The system captures approximately 90% of the 1,552 exon target, across all major lineages of the quarter-billion-year-old extant crown group. Key features of our system are 1) basing the target on an alignment of orthologous genes determined from 52 transcriptomes spanning the phylogenetic diversity and trimmed to remove anything difficult to capture, map, or align; 2) use of multiple artificial representatives based on ancestral state reconstructions rather than exemplars to improve capture and mapping of the target; 3) mapping reads to a multi-reference alignment; and 4) using patterns of site polymorphism to distinguish among paralogy, polyploidy, allelic differences, and sample contamination. The resulting data give a well-resolved tree (currently standing at 417 samples, 275,352 sites, 91% data-complete) that will transform our understanding of ophiuroid evolution and biogeography., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Molecular phylogenetics is increasingly highlighting the prevalence of cryptic species, where morphologically similar organisms have long independent evolutionary histories. When such cryptic species are known to be declining in numbers and are at risk of extinction due to a range of threatening processes, the disjunction between molecular systematics research and conservation policy becomes a significant problem. We investigate the taxonomic status of Tympanocryptis populations in Queensland, which have previously been assigned to T. tetraporophora, using three species delimitation approaches. The taxonomic uncertainties in this species-group are of particular importance in the Darling Downs Earless Dragon (T. cf. tetraporophora), which is ranked as an endangered 'species' of high priority for conservation by the Queensland Department of Environment and Heritage Protection. We undertook a morphological study, integrated with a comprehensive genetic study and species delimitation analyses, to investigate the species status of populations in the region. Phylogenetic analyses of two gene regions (mtDNA: ND2; nuclear: RAG1) revealed high levels of genetic divergence between populations, indicating isolation over long evolutionary time frames, and strongly supporting two independent evolutionary lineages in southeastern Queensland, from the Darling Downs, and a third in the Gulf Region of northern Queensland. Of the three species delimitation protocols used, we found integrative taxonomy the most applicable to this cryptic species complex. Our study demonstrates the utility of integrative taxonomy as a species delimitation approach in cryptic complexes of species with conservation significance, where limited numbers of specimens are available.

Purpose: For thoracic tumors, if four-dimensional computed tomography (4DCT) is unavailable, the internal margin can be estimated by use of breath-hold (BH) CT scans acquired at end inspiration (EI) and end expiration (EE). By use of external surrogates for tumor position, BH accuracy is estimated by minimizing the difference between respiratory extrema BH and mean equivalent-phase free breathing (FB) positions. We tested the assumption that an external surrogate for BH accuracy correlates with internal tumor positional accuracy during BH CT., Methods and Materials: In 16 lung cancer patients, 4DCT images, as well as BH CT images at EI and EE, were acquired. Absolute differences between BH and mean equivalent-phase (FB) positions were calculated for both external fiducials and gross tumor volume (GTV) centroids as metrics of external and internal BH accuracy, respectively, and the results were correlated., Results: At EI, the absolute difference between mean FB and BH fiducial displacement correlated poorly with the absolute difference between FB and BH GTV centroid positions on CT images (R(2) = 0.11). Similarly, at EE, the absolute difference between mean FB and BH fiducial displacements correlated poorly with the absolute difference between FB and BH GTV centroid positions on CT images (R(2) = 0.18)., Conclusions: External surrogates for tumor position are not an accurate metric of BH accuracy for lung cancer patients. This implies that care should be taken when using such an approach because an incorrect internal margin could be generated.

An internal target volume (ITV) accounting for respiratory-induced tumor motion is best obtained using 4DCT. However, when 4DCT is not available, inspiratory/expiratory breath-hold (BH insp, BH exp) CT images have been suggested as an alternative. In such cases, an external fiducial on the abdomen can be used as a substitute for tumor motion and CT images are acquired when the marker position matches - as judged by the therapist/physicist - its positions at previously determined free-breathing (FB) respiratory extrema (FB insp, FB exp). In this study we retrospectively determined the accuracy of these matches. Free breathing 4DCT images were acquired, followed by BH insp and BH exp CT images for 25 patients with non-small-cell lung cancer. Respiration was monitored using a commercial external fiducial system, which generates positional information while CT studies are conducted. Software was written for statistically analyzing the displacement of the external fiducial during BH insp and BH exp CT acquisition and comparing these displacements with corresponding mean FB extrema positions (FB insp and FB exp, respectively) using a Student's t-test. In 72% of patients, mean positions at BH insp differed significantly from mean positions at FB insp (p < 0.05: 0.13 - 1.40 cm). In 92% of patients, mean positions at BH exp differed significantly from mean positions at FB exp (p < 0.05: 0.03 - 0.70 cm), although this difference was smaller than 0.5 cm in many cases (median = 0.34 cm). Our findings indicate that relying solely on abdominal external markers for accurate BH CT imaging in order to accurately estimate FB extrema positions may be subject to significant error.

Purpose: To assess three-dimensional tumor motion caused by respiration and internal target volume (ITV) for radiotherapy of lung cancer., Methods and Materials: Respiration-induced tumor motion was analyzed for 166 tumors from 152 lung cancer patients, 57.2% of whom had Stage III or IV non-small-cell lung cancer. All patients underwent four-dimensional computed tomography (4DCT) during normal breathing before treatment. The expiratory phase of 4DCT images was used as the reference set to delineate gross tumor volume (GTV). Gross tumor volumes on other respiratory phases and resulting ITVs were determined using rigid-body registration of 4DCT images. The association of GTV motion with various clinical and anatomic factors was analyzed statistically., Results: The proportions of tumors that moved >0.5 cm along the superior-inferior (SI), lateral, and anterior-posterior (AP) axes during normal breathing were 39.2%, 1.8%, and 5.4%, respectively. For 95% of the tumors, the magnitude of motion was less than 1.34 cm, 0.40 cm, and 0.59 cm along the SI, lateral, and AP directions. The principal component of tumor motion was in the SI direction, with only 10.8% of tumors moving >1.0 cm. The tumor motion was found to be associated with diaphragm motion, the SI tumor location in the lung, size of the GTV, and disease T stage., Conclusions: Lung tumor motion is primarily driven by diaphragm motion. The motion of locally advanced lung tumors is unlikely to exceed 1.0 cm during quiet normal breathing except for small lesions located in the lower half of the lung.

Purpose: Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. We present a quality assurance procedure for MRSI-derived metabolic data acquired ultimately for guiding conformal radiotherapy., Methods and Materials: An MRSI phantom filled with brain-mimicking solutions was custom-built with an insert holding eight vials containing calibration solutions of precisely varying metabolite concentrations that emulated increasing grade/density of brain tumor. Phantom metabolite ratios calculated from fully relaxed 1D, 2D, and 3D MRS data for each vial were compared with calibrated metabolite ratios acquired at 9.4 T. Additionally, 3D ratio maps were "discretized" to eight pseudoabnormality levels on a slice-by-slice basis and the accuracy of this procedure was verified., Results: Regression analysis revealed expected linear relationships between experimental and calibration metabolite ratios with intercepts close to zero for the three acquisition modes. 1D MRS data agreed most with theoretical considerations (regression coefficient, b = 0.969; intercept 0.008). The 2D (b = 1.049; intercept -0.199) and 3D (correlation coefficient r(2) = 0.9978-0.7336 for five slices) MRSI indicated reduced MRS data quality in regions of degraded B(0) and B(1) homogeneity. Pseudoabnormality levels were found to be consistent with expectations within regions of adequate B(0) homogeneity., Conclusions: This simple phantom-based approach to generate baseline calibration curves for all MRS acquisition modes may be useful to identify temporal deviations from acceptable data quality in a routine clinical environment or for testing new MRS and MRSI acquisition software.

We recently described a novel approach to measuring regional tumor oxygen tension. This approach is based on 19F pulse burst saturation recovery NMR echo planar imaging relaxometry of hexafluorobenzene or "FREDOM" (Fluorocarbon Relaxometry using Echo planar imaging for Dynamic Oxygen Mapping). We have now compared oxygen tension measurements using FREDOM with a traditional polarographic method (the Eppendorf Histograph) in a group of size matched Dunning prostate rat tumors R3327-AT1. We also compare MR and electrode approaches to monitoring dynamic changes with respect to interventions and demonstrate extension of the MR technique to rat breast tumors.

Radiation therapy is an image-guided process whose success critically depends on the imaging modality used for treatment planning and the level of integration of the available imaging information. In this work, we establish a dose optimization framework for incorporating metabolic information from functional imaging modalities into the intensity-modulated radiation therapy (IMRT) inverse planning process and to demonstrate the technical feasibility of planning deliberately non-uniform dose distributions in accordance with functional imaging data. For this purpose, a metabolic map from functional images is discretized into a number of abnormality levels (ALs) and then fused with CT images. To escalate dose to the metabolically abnormal regions, we assume, for a given spatial point, a linear relation between the AL and the prescribed dose. But the formalism developed here is independent of the assumption and any other relation between AL and prescription is applicable. For a given AL and prescription relation, it is only necessary to prescribe the dose to the lowest AL in the target and the desired doses to other regions with higher AL values are scaled accordingly. To accomplish differential sparing of a sensitive structure when its functional importance (FI) distribution is known, we individualize the tolerance doses of the voxels within the structure according to their Fl levels. An iterative inverse planning algorithm in voxel domain is used to optimize the system with in homogeneous dose prescription. To model intra-structural trade-off, a mechanism is introduced through the use of voxel-dependent weighting factors, in addition to the conventional structure specific weighting factors which model the inter-structural trade-off. The system is used to plan a phantom case with a few hypothetical functional distributions and a brain tumour treatment with incorporation of magnetic resonance spectroscopic imaging data. The results indicated that it is technically feasible to produce deliberately non-uniform dose distributions according to the functional imaging requirements. Integration of functional imaging information into radiation therapy dose optimization allows for consideration of patient-specific biologic information and provides a significant opportunity to truly individualize radiation treatment. This should enhance our capability to safely and intelligently escalate dose and lays the technical foundation for future clinical studies of the efficacy of functional imaging-guided IMRT.

We recently described a novel approach to measuring regional tumor oxygen tension using (19)F pulse burst saturation recovery (PBSR) nuclear magnetic resonance (NMR) echo planar imaging (EPI) relaxometry of hexafluorobenzene. We now compare oxygen tension measurements in a group of size-matched R3327-AT1 Dunning prostate rat tumors made using this new method with those using a traditional polarographic method: the Eppendorf histograph. Similar oxygen tension distributions were found using the two methods, and both techniques showed that tumors with volume greater than 3.5 cm(3) were significantly (P < 0.0001) less well oxygenated than smaller tumors (volume less than 2 cm(3)). Using the (19)F EPI approach, we also examined the response to respiratory challenge. Increasing the concentration of inspired oxygen from 33% to 100% O(2) produced a significant increase (P < 0.0001) in tumor oxygenation for a group of small tumors. In contrast, no change was observed in the mean pO(2) for a group of large tumors. Consideration of individual tumor regions irrespective of tumor size showed a strong correlation between the maximum pO(2) observed when breathing 100% O(2) compared with mean baseline pO(2). These results further demonstrate the usefulness of (19)F EPI to assess changes in regional tumor oxygenation.

We have synthesized a series of novel fluorinated vitamin B6 analogues (6-fluoropyridoxol derivatives) as potential 19F NMR pH indicators for use in vivo. Modifications included addition of aldehyde, carboxyl or aminomethyl groups at the 4- or 5-ring position, and examination of a trifluoromethyl moiety as an internal chemical shift standard. The variation in chemical shift with respect to acid-base titration showed pKa values in the range 7.05-9.5 with a chemical shift sensitivity in the range 7.4-12 ppm. Several of the molecules readily cross cell membranes providing estimates of both intra- and extra-cellular pH in whole blood. 6-Fluoropyridoxamine (6-FPAM) exhibits a pKa = 7.05, which is closer to normal physiological pH than the parent molecule 6-fluoropyridoxol (6-FPOL) (pKa = 8.2), and should thus, be useful for precise and accurate measurements of pH in vivo. Enhanced spectral resolution for 6-FPAM over 6-FPOL is demonstrated in whole blood and the perfused rat heart.

6-Fluoropyridoxol (6-FPOL) was evaluated as a simultaneous indicator of intracellular and extracellular pH and, hence, pH gradient in perfused rat hearts. After infusion, 19F NMR spectra rapidly showed two well-resolved peaks assigned to the intracellular and extracellular compartments, and pH was calculated on the basis of chemical shift with respect to a sodium trifluoroacetate standard. To demonstrate use of this molecule, dynamic changes in myocardial pH were assessed with a time resolution of 2 min during respiratory and metabolic alkalosis or acidosis and ischemia. For a typical heart, intracellular pH (pHi) = 7.14+/-0.01 and extracellular pH (pHe) = 7.52+/-0.02. In response to metabolic alkalosis, pHi remained relatively constant and the pH gradient increased. In contrast, respiratory challenge caused a significant increase in pHi. Independent measurements using pH electrodes and 31P NMR confirmed validity of the 19F NMR results.

We demonstrate a novel approach to measuring regional tumor oxygen tension using 19F pulse burst saturation recovery echo planar imaging (EPI) relaxometry of hexafluorobenzene. Hexafluorobenzene offers exceptional sensitivity to changes in oxygen tension, and has a single resonance making it ideal for imaging studies. By combining a pulse burst saturation recovery preparation sequence with EPI, the relaxation experiments were performed in approximately 20 min facilitating measurements of dynamic changes in pO2 accompanying interventions. Direct intratumoral administration of hexafluorobenzene permitted labeling of specific regions of interest, and imaging provided maps of pO2, confirming distinct intra tumoral heterogeneity. For a group of three Dunning prostate adenocarcinoma R3327-AT1 tumors interrogation of the central tumor region showed skewed pO2 distributions with considerable radiobiological hypoxia (approximately 90% voxels had pO2 < 15 torr) when rats breathed 33% O2. Altering the inspired gas to pure oxygen caused distributions to shift towards increased pO2 with significant increases in mean oxygen tension (p < 0.05) in two cases. Interrogation of both central and peripheral regions in a fourth tumor showed bimodal distribution for tumor oxygenation including approximately 75% voxels with pO2 > 15 torr. EPI allows the fate of individual voxels to be traced: upon altering the inspired gas to pure oxygen those voxels with baseline pO2 > 30 torr showed significant changes (p < 0.05), whereas those with pO2 < 16 torr showed minimal response. The precision of the measurements, together with the ability to simultaneously examine dynamic changes in multiple regions should provide a useful technique for investigating tumor hypoxia with respect to therapy.