Miracle-dz/UniFAR-FTUs huggingface dataset:
Performance variations among clinically available deformable image registration tools in adaptive radiotherapy — how should we evaluate and interpret the result?

The purpose of this study is to evaluate the performance variations in commercial deformable image registration (DIR) tools for adaptive radiation therapy and further to interpret the differences using clinically available terms. Three clinical examples (prostate, head and neck (HN), and cranial spinal irradiation (CSI) with L‐spine boost) were evaluated in this study. Firstly, computerized deformed CT images were generated using simulation QA software with virtual deformations of bladder filling (prostate), neck flexion/bite‐block repositioning/tumor shrinkage (HN), and vertebral body rotation (CSI). The corresponding transformation matrices served as a “reference” for the following comparisons. Three commercialized DIR algorithms: the free‐form deformation from MIMVista 5.5 and the RegRefine from MIMMaestro 6.0, the multipass B‐spline from VelocityAI v3.0. 1, and the adaptive demons from OnQ rts 2.1. 15, were applied between the initial images and the deformed CT sets. The generated adaptive contours and dose distributions were compared with the “reference” and among each other. The performance in transferring contours was comparable among all three tools with an average Dice similarity coefficient of 0.81 for all the organs. However, the dose warping accuracy appeared to rely on the evaluation end points and methodologies. Point‐dose differences could show a difference of up to 23.3 Gy inside the PTVs and to overestimate up to 13.2 Gy for OARs, which was substantial for a 72 Gy prescription dose. Dosevolume histogram‐based evaluation might not be sensitive enough to illustrate all the detailed variations, while isodose assessment on a slice‐by‐slice basis could be tedious. We further explored the possibility of using 3D gamma index analysis for warping dose variation assessment, and observed differences in dose warping using different DIR tools. Overall, our results demonstrated that evaluation based only on the performance of contour transformation could not guarantee the accuracy in dose warping, while dose‐transferring validation strongly relied on the evaluation endpoint. As dose‐transferring errors could cause misinterpretations when attempting to accumulate dose for adaptive radiation therapy and more DIR tools are available for clinical use, a standard and clinically meaningful quality assurance criterion should be established for DIR QA in the near future. PACS number(s): 87.57
Simultaneous geometry and cross-section optimization of aluminum trusses

Purpose – Trusses constitute a fertile field to demonstrate the application of optimization techniques because of the possibility of several different configurations. Using such techniques allows the search for designs that minimize the use of material to safely comply with the imposed loads. Truss optimization can be classified into three categories: cross-section, shape, and topology. The purpose of this paper is to present a numerical and experimental study developed to minimize the weight of aluminum trusses, taking both the cross-sectional dimensions of the elements and the nodal coordinates as design variables. Design/methodology/approach – Initially, several numerical computer simulations were performed with an optimization program developed by combining the displacement method and a simulated annealing optimization method. Subsequently, two aluminum trusses were selected and built in order to validate the numerical results obtained. Findings – Experimental tests verified the excellent performance .
Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer.

BACKGROUND MCC-465 is an immunoliposome-encapsulated doxorubicin (DXR). The liposome is tagged with polyethylene glycol (PEG) and the F(ab')2 fragment of human monoclonal antibody GAH, which positively reacts to >90% of cancerous stomach tissues, but negatively to all normal tissues. In preclinical studies, MCC-465 showed superior cytotoxic activity against several human stomach cancer cells compared with DXR or DXR-incorporated PEG liposomes. The main purpose of this trial was to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), recommended phase II dose and pharmacokinetics (PK) of MCC-465. PATIENTS AND METHODS Patients with metastatic or recurrent stomach cancer were eligible for entry. The initial dose was 6.5 mg/m2. MCC-465 was administered as a 1-h infusion every 3 weeks and the treatment continued for up to six cycles. RESULTS Twenty-three patients received a total of 62 cycles at the 6.5-45.5 mg/m2 dose level. DLTs were myelosuppression and appetite loss at the 45.5 mg/m2 dose level. Other toxicities were mild. Neither palmar-plantar erythrodysesthesia nor cardiotoxicity was observed. Acute reactions related to infusion were observed commonly in 16 patients over the entire dose range. While no antitumor response was observed, stable disease (SD) was observed in 10 out of 18 evaluable patients. The pharmacokinetic study showed a similar AUC and Cmax to Doxil. CONCLUSION MCC-465 was well tolerated. The recommended dose for a phase II study of MCC-465, for a 3-week schedule, is considered to be 32.5 mg/m2 in an equivalent amount of DXR.
Immunotherapy in kidney cancer: the past, present, and future

Purpose of review Kidney cancer, in particular clear cell renal cell carcinoma (ccRCC) has long been considered to be sensitive to immunotherapies. With the recent breakthroughs in immunotherapy for solid tumors and the recent approval of the first immune checkpoint inhibitor for ccRCC, we are reviewing the history of immunotherapy in kidney cancer, describing its current state and look into the future of a rapidly evolving landscape in immunotherapy for kidney cancer. Recent findings Systemic treatment options over the past decade have been dominated by targeted therapies inhibiting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. With the approval of the immune checkpoint inhibitor nivolumab, a new era of potential combination therapies is about to shape the treatment landscape for kidney cancer. These include other immune checkpoint inhibitors (e.g., anti-CTLA4), modifiers of the tumor microenvironment (VEGF pathway, T cell agonists (anti-41BB and Ox40 antibodies), and novel vaccination strategies). Summary With the development of more effective combination immunotherapies, we will witness significant changes in the treatment landscape for kidney cancer over the next few years. Combination immunotherapies are expected to become the first line treatment option in kidney cancer.
Evaluation of backscatter dose from internal lead shielding in clinical electron beams using EGSnrc Monte Carlo simulations

Internal lead shielding is utilized during superficial electron beam treatments of the head and neck, such as lip carcinoma. Methods for predicting backscattered dose include the use of empirical equations or performing physical measurements. The accuracy of these empirical equations required verification for the local electron beams. In this study, a Monte Carlo model of a Siemens Artiste linac was developed for 6, 9, 12, and 15 MeV electron beams using the EGSnrc MC package. The model was verified against physical measurements to an accuracy of better than 2% and 2 mm. Multiple MC simulations of lead interfaces at different depths, corresponding to mean electron energies in the range of 0.2–14 MeV at the interfaces, were performed to calculate electron backscatter values. The simulated electron backscatter was compared with current empirical equations to ascertain their accuracy. The major finding was that the current set of backscatter equations does not accurately predict electron backscatter, particularly in the lower energies region. A new equation was derived which enables estimation of electron backscatter factor at any depth upstream from the interface for the local treatment machines. The derived equation agreed to within 1.5% of the MC simulated electron backscatter at the lead interface and upstream positions. Verification of the equation was performed by comparing to measurements of the electron backscatter factor using Gafchromic EBT2 film. These results show a mean value of 0.997±0.022 to 1σ of the predicted values of electron backscatter. The new empirical equation presented can accurately estimate electron backscatter factor from lead shielding in the range of 0.2 to 14 MeV for the local linacs. PACS numbers: 87.53. Bn, 87.55. K‐, 87.56. bd
Minimally Invasive Multilevel Percutaneous Pedicle Screw Fixation for Lumbar Spinal Diseases

Objective There are rare reports on the result of multilevel (≥3 levels) percutaneous pedicle screw fixation (PPF). The purpose of this study was to report the clinical experiences for multilevel PPF of the lumbar spine. Methods A total of 17 patients of lumbar spinal disease (7 degenerative diseases, 6 infectious diseases, and 4 traumatic instabilities) underwent neural decompression and multilevel PPF. There were 8 men and 9 women with a mean age of 61.4 years (range, 25-84) and a mean follow-up period of 23.2 months (range, 13-48). The average PPF level was 3.7. A retrospective review of clinical, radiological, and surgical data was conducted. Results "Excellent" or "good" clinical results were obtained in 15 patients (88.2%) according to the Odom's criteria. The average improvement of visual analogue scale was 5.2 points (from 9.3 to 4.1), and the average improvement of Oswestry Disability Index was 36.2 (from 71.2 to 35.0) at the last visit (p<0.05). The fusion rate was 88.2%, but, screw loosening was occurred in 2 patients, and adjacent segmental degeneration was occurred in 2 patients. There was no statistical significance in the change of total lumbar lordotic angle. The average operation time was 5.9 hours, with an estimated blood loss of 550 ml and bed rest duration of 2.0 days. Conclusion Although the current study examined a small sample with relatively short term follow up periods, our study results demonstrate that multilevel PPF is feasible and safe for selective lumbar spinal diseases.
Comparison of DVH‐based plan verification methods for VMAT: ArcCHECK‐3DVH system and dynalog‐based dose reconstruction

Abstract The purpose of this study was comparing dose‐volume histogram (DVH)‐based plan verification methods for volumetric modulated arc therapy (VMAT) pretreatment QA. We evaluated two 3D dose reconstruction systems: ArcCHECK‐3DVH system (Sun Nuclear corp.) and Varian dynalog‐based dose reconstruction (DBDR) system, developed in‐house. Fifteen prostate cancer patients (67.6 Gy/26 Fr), four head and neck cancer patient (66 Gy/33 Fr), and four esophagus cancer patients (60 Gy/30 Fr) treated with VMAT were studied. First, ArcCHECK measurement was performed on all plans; simultaneously, the Varian dynalog data sets that contained the actual delivered parameters (leaf positions, gantry angles, and cumulative MUs) were acquired from the Linac control system. Thereafter, the delivered 3D patient dose was reconstructed by 3DVH software (two different calculating modes were used: High Sensitivity (3DVH‐HS) and Normal Sensitivity (3DVH‐NS)) and in‐house DBDR system. We evaluated the differences between the TPS‐calculated dose and the reconstructed dose using 3D gamma passing rates and DVH dose index analysis. The average 3D gamma passing rates (3%/3 mm) between the TPS‐calculated dose and the reconstructed dose were 99.1 ± 0.6%, 99.7 ± 0.3%, and 100.0 ± 0.1% for 3DVH–HS, 3DVH–NS, and DBDR, respectively. For the prostate cases, the average differences between the TPS‐calculated dose and reconstructed dose in the PTV mean dose were 1.52 ± 0.50%, −0.14 ± 0.55%, and −0.03 ± 0.07% for 3DVH–HS, 3DVH–NS, and DBDR, respectively. For the head and neck and esophagus cases, the dose difference to the TPS‐calculated dose caused by an effect of heterogeneity was more apparent under the 3DVH dose reconstruction than the DBDR. Although with some residual dose reconstruction errors, these dose reconstruction methods can be clinically used as effective tools for DVH‐based QA for VMAT delivery.
Effects of Non-Assisted Posterior Shoulder Stretches on Shoulder Range of Motion Among Collegiate Baseball Pitchers

Maintenance of the posterior shoulder flexibility has implica tions for prevention of upper extremity injuries in athletes who use overhead throwing. Therefore, determination of stretching techniques that can be performed easily by these athletes and are most effective in improving flexibility is of great clinical interest. The purpose of this study was to evaluate the acute changes in glenohumeral internal rotation, external rotation, and horizontal adduction range of motion (ROM) after 3 onthe-field posterior shoulder stretches in 15 collegiate baseball pitchers. All stretches resulted in significant acute improvement in internal rotation and horizontal adduction ROM. However, there were no differences in improvements among the stretch es. This study demonstrated that the acute increase in internal rotation and horizontal adduction ROM could be achieved by the non-assisted stretches. Non-assisted stretches can be performed without the aid from a clinician or a treatment table, and therefore can be used readily and frequently by baseball players of all levels.
Endotoxin-induced impairment of vascular smooth muscle contractions elicited by different mechanisms.

The current study was designed to analyse the mechanisms which are impaired in the vascular hyporeactivity to contractile agents induced by E. coli lipopolysaccharide endotoxin (LPS). Endothelium-denuded aortic rings were prepared from thoracic aorta removed from control and LPS-pretreated rats (20 mg/kg i.p., 4 h before the experiment). In order to determine whether LPS treatment altered the contractile components that depend on intracellular calcium release and extracellular calcium entry to the same extent, rings were contracted under various experimental conditions. The responses elicited by indanidine, phenylephrine (without and with nitrendipine 1 microM), (-) Bay K 8644, (+) S 202-791 and the calcium ionophore calimycin in the presence of 1.25 mM external CaCl2 were all impaired by LPS pretreatment (maximal contractions 19, 63, 44, 28, 22 and 22% of controls, respectively). Concentration-effect curves for CaCl2 made in depolarizing medium (KCl 40 and 100 mM) and in the presence of calimycin (3 microM) were shifted to the right in rings from LPS-pretreated rats. However, the LPS-induced depression of contraction was overcome by the addition of CaCl2 (up to 30 mM). Additionally, in the absence of external CaCl2, the contraction induced by caffeine (50 mM) was not significantly altered by LPS treatment. It is concluded that LPS treatment does not reduce the ability of aortic smooth muscle cells to contract. The results suggest that LPS treatment impairs mechanisms involved in calcium handling within smooth muscle cells after stimulation of calcium entry through different pathways and activation of intracellular calcium release by alpha 1-adrenoceptor agonists.
Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity

Helping NK cells find their way MICA and MICB proteins can be expressed on tumors and act as “kill me” signals to the immune system. But tumors often disguise themselves by shedding these proteins, which prevents specialized natural killer (NK) cells from recognizing and destroying the cancer. Ferrari de Andrade et al. engineered antibodies directed against the site responsible for the proteolytic shedding of MICA and MICB (see the Perspective by Cerwenka and Lanier). The approach effectively locked MICA and MICB onto tumors so that NK cells could spot them for elimination. The antibodies exhibited preclinical efficacy in multiple tumor models, including humanized melanoma. Furthermore, the strategy reduced lung cancer metastasis after NK cell–mediated tumor lysis. Science, this issue p. 1537; see also p. 1460 Natural killer cell–mediated antitumor response is restored when tumors are prevented from sloughing off surface markers. MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

ABSTRACT Follicular helper CD4 T cells, TFH, residing in B-cell follicles within secondary lymphoid tissues, are readily infected by AIDS viruses and are a major source of persistent virus despite relative control of viral replication. This persistence is due at least in part to a relative exclusion of effective antiviral CD8 T cells from B-cell follicles. To determine whether CD8 T cells could be engineered to enter B-cell follicles, we genetically modified unselected CD8 T cells to express CXC chemokine receptor 5 (CXCR5), the chemokine receptor implicated in cellular entry into B-cell follicles. Engineered CD8 T cells expressing human CXCR5 (CD8hCXCR5) exhibited ligand-specific signaling and chemotaxis in vitro. Six infected rhesus macaques were infused with differentially fluorescent dye-labeled autologous CD8hCXCR5 and untransduced CD8 T cells and necropsied 48 h later. Flow cytometry of both spleen and lymph node samples revealed higher frequencies of CD8hCXCR5 than untransduced cells, consistent with preferential trafficking to B-cell follicle-containing tissues. Confocal fluorescence microscopy of thin-sectioned lymphoid tissues demonstrated strong preferential localization of CD8hCXCR5 T cells within B-cell follicles with only rare cells in extrafollicular locations. CD8hCXCR5 T cells were present throughout the follicles with some observed near infected TFH. In contrast, untransduced CD8 T cells were found in the extrafollicular T-cell zone. Our ability to direct localization of unselected CD8 T cells into B-cell follicles using CXCR5 expression provides a strategy to place highly effective virus-specific CD8 T cells into these AIDS virus sanctuaries and potentially suppress residual viral replication. IMPORTANCE AIDS virus persistence in individuals under effective drug therapy or those who spontaneously control viremia remains an obstacle to definitive treatment. Infected follicular helper CD4 T cells, TFH, present inside B-cell follicles represent a major source of this residual virus. While effective CD8 T-cell responses can control viral replication in conjunction with drug therapy or in rare cases spontaneously, most antiviral CD8 T cells do not enter B-cell follicles, and those that do fail to robustly control viral replication in the TFH population. Thus, these sites are a sanctuary and a reservoir for replicating AIDS viruses. Here, we demonstrate that engineering unselected CD8 T cells to express CXCR5, a chemokine receptor on TFH associated with B-cell follicle localization, redirects them into B-cell follicles. These proof of principle results open a pathway for directing engineered antiviral T cells into these viral sanctuaries to help eliminate this source of persistent virus.
Evolution of the 3-hydroxypropionate bicycle and recent transfer of anoxygenic photosynthesis into the Chloroflexi

Significance Photosynthesis supports life on our planet; however, we know very little about the origins of this metabolism. Anoxygenic photosynthesis existed prior to the evolution of its more complex counterpart, oxygenic photosynthesis. It is not known which groups of microbes performed anoxygenic photosynthesis on early Earth; one idea has argued that anoxygenic photosynthesis evolved in the bacterial phylum Chloroflexi. We compared the genomes of different members of the Chloroflexi, finding that acquisition of photosynthesis and their unique carbon fixation metabolism evolved remarkably late in Earth history—a time long after the rise of oxygen in the atmosphere. Various lines of evidence from both comparative biology and the geologic record make it clear that the biochemical machinery for anoxygenic photosynthesis was present on early Earth and provided the evolutionary stock from which oxygenic photosynthesis evolved ca. 2.3 billion years ago. However, the taxonomic identity of these early anoxygenic phototrophs is uncertain, including whether or not they remain extant. Several phototrophic bacterial clades are thought to have evolved before oxygenic photosynthesis emerged, including the Chloroflexi, a phylum common across a wide range of modern environments. Although Chloroflexi have traditionally been thought to be an ancient phototrophic lineage, genomics has revealed a much greater metabolic diversity than previously appreciated. Here, using a combination of comparative genomics and molecular clock analyses, we show that phototrophic members of the Chloroflexi phylum are not particularly ancient, having evolved well after the rise of oxygen (ca. 867 million years ago), and thus cannot be progenitors of oxygenic photosynthesis. Similarly, results show that the carbon fixation pathway that defines this clade—the 3-hydroxypropionate bicycle—evolved late in Earth history as a result of a series of horizontal gene transfer events, explaining the lack of geological evidence for this pathway based on the carbon isotope record. These results demonstrate the role of horizontal gene transfer in the recent metabolic innovations expressed within this phylum, including its importance in the development of a novel carbon fixation pathway.
Dynamics of nasopharyngeal pneumococcal carriage during the course of viral bronchiolitis

The effect of viral infection on nasopharyngeal carriage of Streptococcus pneumoniae during childhood is not well known. We studied dynamics of pneumococcal colonization by quantitative PCR during the natural course of viral bronchiolitis. At time of admission, 47 (47%) of 100 patients with bronchiolitis carried pneumococci. In patients with viral bronchiolitis who did not receive antibiotics, pneumococcal load decreased from time of admission to discharge (n = 35, cycle threshold 23 vs. 25, P = 0.0017) and from discharge to follow‐up (n = 22, cycle threshold 25 vs. 40, P = 0.003). We conclude that viral respiratory infection is negatively associated with pneumococcal colonization of the upper airways. Pediatr Pulmonol. 2016;51:863–867. © 2016 Wiley Periodicals, Inc.
Accurate PD-L1 Protocols for Non–Small Cell Lung Cancer can be Developed for Automated Staining Platforms With Clone 22C3

Treatment using immunotherapy against PD-L1 or PD-1 has become one of the hottest topics in Pathology and Oncology. Correct selection of patients eligible for treatment requires optimal immunohistochemical staining protocols. Treatment with pembrolizumab requires diagnostic examination of the patient's tumour using the companion diagnostic Ready-To-Use pharmDx kit from Dako Agilent based on the mAb 22C3 clone on the Autostainer platform. However, not all diagnostic pathology labs have access to this staining platform. This purpose of this study was to develop and validate protocols for PD-L1 detection for all major staining platforms using the concentrated format of 22C3 that would give similar staining result (equal Tumour Proportion Scores) to the pharmDx kit.