The assessment of the clinical impact of using a single set of radiotherapy planning data for two kilovoltage therapy units.

Kilovoltage therapy units are used for superficial radiotherapy treatment delivery. Peer reviewed studies for MV linear accelerators describe tolerances to dosimetrically match multiple linear accelerators enabling patient treatment on any matched machine. There is an absence of literature on using a single planning data set for multiple kilovoltage units which have limited ability for beam adjustment. This study reviewed kilovoltage dosimetry and treatment planning scenarios to evaluate the feasibility of using ACPSEM annual QA tolerances to determine whether two units (of the same make and model) were dosimetrically matched. The dosimetric characteristics, such as measured half value layer (HVL), percentage depth dose (PDD), applicator factor and output variation with stand-off distance for each kV unit were compared to assess the agreement. Independent planning data based on the measured HVL for each beam energy from each kV unit was prepared. Monitor unit (MU) calculations were performed using both sets of planning data for approximately 200 clinical scenarios and compared with an overall agreement between units of < 2%. Additionally, a dosimetry measurement comparison was completed at each site for a subset of nine scenarios. All machine characterisation measurements were within the ACPSEM Annual QA tolerances, and dosimetric testing was within 2.5%. This work demonstrates that using a single set of planning data for two kilovoltage units is feasible, resulting in a clinical impact within published uncertainty.

Identifying the location of locoregional recurrences after definitive radiotherapy for head and neck cancer using metabolic parameters of baseline and mid-treatment 18F-FDG-PET scans.

INTRODUCTION: Tumour recurrences after treatment of head and neck squamous cell carcinoma (HNSCC) are more likely to originate from regions of high-baseline FDG-PET uptake. Mid-treatment functional imaging can potentially predict for higher risk of tumour recurrence. The aim of this study is to correlate the location of locoregional tumour recurrence with baseline FDG-PET metabolic volumes and mid-treatment FDG-PET metabolic volumes in patients with HNSCC following definitive radiotherapy. METHODS: A total of 23 patients with 26 local and/or regional recurrences underwent baseline (W0-PET) and mid-treatment (W3-PET) 18F-FDG PET scans as part of their radiotherapy. FDG-PET-based metabolic volumes (MTV20%, MTV40%, MTV60%, MTV80%, SUV2.5, SUVpeak and PET_EDGE) were delineated onto the FDG-PET scans. The recurrence nidus was identified on FDG-PET at the time of recurrence (REC-PET). DIR-based fusion was performed for REC-PET to W0-PET, and REC-PET to W3-PET. The location of the recurrence nidus was correlated with the FDG-PET volumes. Further analysis included a comparison of the recurrence density to FDG-PET metabolic volumes. RESULTS: Most recurrences occurred within the MTV20%, MTV40% and SUV 2.5 volumes. Sixty-nine per cent of recurrences (18 of 26) occurred within both the W0 MTV40% and W3 MTV40% volumes. A higher recurrence density was seen for iso-SUV contours closer to the maximum SUV for both W0 and W3. For a number of the FDG-PET volumes, including MTV20%, MTV40% and SUV2.5, the recurrence density was improved for W3 compared to W0, however, this improvement was small in magnitude. The average volume of MTV40% contours was considerably smaller than MTV20% and SUV2.5 contours. CONCLUSION: The metabolic parameters of SUV2.5, MTV20% and MTV40% delineated on the baseline and mid-treatment FDG-PET scans encompassed the majority of recurrences. The MTV40% is significantly smaller, hence, we prefer this volume for future dose escalation studies.

Efficacy, safety, and immunogenicity of the DNA SARS-CoV-2 vaccine (ZyCoV-D): the interim efficacy results of a phase 3, randomised, double-blind, placebo-controlled study in India.

BACKGROUND: ZyCoV-D, a DNA-based vaccine, showed promising safety and immunogenicity in a phase 1/2 trial. We now report the interim efficacy results of phase 3 clinical trial with ZyCoV-D vaccine in India. METHODS: We conducted an interim analysis of a multicentre, double-blind, randomised, placebo-controlled phase 3 trial at 49 centres in India. Healthy participants aged at least 12 years were enrolled and randomly assigned (1:1) to receive either ZyCov-D vaccine (Cadila Healthcare; 2 mg per dose) or placebo. An interactive web response system was used for randomisation (blocks of four) of participants as well as to enrol those aged 60 years and older with or without comorbid conditions, and those aged 12-17 years. It was also used to identify 600 participants for immunogenicity (blocks of six). Participants, investigators, and outcome assessors were masked to treatment assignment. Three doses of vaccine or placebo were administered intradermally via a needle-free injection system 28 days apart. The primary outcome was the number of participants with first occurrence of symptomatic RT-PCR-positive COVID-19 28 days after the third dose, until the targeted number of cases (interim analysis n=79, full analysis n=158) have been achieved. The analysis was done in the per-protocol population, which consisted of all participants with negative baseline SARS-CoV-2 status who received three doses of vaccine or placebo. Assessment of safety and tolerability was based on the safety population, which consisted of all enrolled participants who were known to have received at least one dose of study vaccine or placebo. This trial is registered with Clinical Trial Registry India, CTRI/2021/01/030416, and is ongoing. FINDINGS: Between Jan 16, and June 23, 2021 (data cutoff), 33 194 individuals were screened, of whom 5241 did not meet screening criteria and 27 703 were enrolled and randomly assigned to receive ZyCoV-D (n=13 851) or placebo (n=13 852). Per-protocol, 81 cases were eligible and included in efficacy analysis (20 of 12 350 in the ZyCoV-D group and 61 of 12 320 in placebo group). The ZyCoV-D vaccine efficacy was found to be 66·6% (95% CI 47·6-80·7). The occurrence of solicited adverse events was similar between the treatment groups (623 [4·49%] in the ZyCoV-D group vs 620 [4·47%] in the placebo group). There were two deaths (one in each group) reported at the data cutoff, neither of which was considered related to the study treatments. INTERPRETATION: In this interim analysis, ZyCoV-D vaccine was found to be efficacious, safe, and immunogenic in a phase 3 trial. FUNDING: National Biopharma Mission, Department of Biotechnology, Government of India and Cadila Healthcare, Ahmedabad, Gujarat India.

Efficacy and safety of glycopyrronium/formoterol delivered via a dry powder inhaler in patients with moderate to severe chronic obstructive pulmonary disease: Results from a multi-centre, open-label, randomised study.

Background: We designed this randomised, open-label, parallel group, multi-centre study to investigate the efficacy and safety of glycopyrronium/formoterol, a long-acting muscarinic antagonist/long-acting ß2-agonist fixed dose combination, delivered through a dry powder inhaler (DPI) in patients with chronic obstructive pulmonary disease (COPD). Material and Methods: We randomised (1:1) patients with moderate to severe COPD (N = 356) to receive glycopyrronium 25 µg/formoterol 12 µg via DPI twice daily (GF-DPI) or glycopyrronium 50 µg monotherapy via DPI once daily (G-DPI). The primary study endpoint was the mean change from the baseline in pre-dose trough-forced expiratory volume in one second (FEV1) at 12 weeks. Results: At week 12, the mean increase from the baseline in pre-dose trough FEV1 was higher in the GF-DPI group (120 ml) than in the G-DPI (60 ml) group. The mean difference (MD) between treatment groups was 0.06 L (95% CI: 0.00-0.12 L, P < 0.0001 for non-inferiority). At week 12, the mean pre-dose forced vital capacity (FVC), 1 hour post-dose FEV1, and post-dose FVC increased significantly from the baseline only in the GF-DPI group (p < 0.0001). The reduction in the COPD assessment test score was greater in the GF-DPI group (p = 0.0379). The average daily number of puffs of rescue medication and the reduction in mean modified Medical Research Council scale, COPD, and Asthma Sleep Impact Scale score at week 12 were similar between groups (p > 0.05). Overall, 35 adverse events and two serious adverse events unrelated to study drugs were reported. Both groups had similar results for overall drug safety. Conclusion: The results demonstrate efficacy and safety of GF-DPI in Indian patients with moderate to severe COPD. Treatment with GF-DPI significantly improved the lung function and quality of life and was well tolerated.

Feasibility of bone marrow sparing volumetric modulated arc therapy to spare active bone marrow in cervical and vaginal cancer patients: a retrospective dosimetric analysis.

INTRODUCTION: Chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical and vaginal cancer. It is associated with high haematological toxicity (HT) that can lead to treatment interruptions and cancelled chemotherapy cycles, reducing the potential effectiveness of this regimen. Bone marrow sparing (BMS) utilising volumetric modulated arc therapy (VMAT) is one method to reduce dose to the active bone marrow (ABM) so that HT rates are reduced. The aim of this paper was to assess whether BMS-VMAT can effectively spare the ABM whilst maintaining clinically acceptable target and organ-at-risk (OAR) doses. METHODS: Twenty gynaecological cancer patients treated with definitive CRT at the Liverpool/Macarthur Cancer Therapy centres between 2015 and 2020 were retrospectively included. ABM was delineated based on fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Weekly blood tests and ABM dose parameters at the V10Gy, V20Gy, V30Gy, V40Gy and Dmean were assessed on original plans for any potential correlation with grade 2+ HT. Replanned with VMAT for BMS, various dose parameters were compared with the original plan to assess for any significant differences. RESULTS: Active bone marrow doses were significantly reduced (P < 0.001 for all parameters) in BMS-VMAT plans, and significant improvements in target and OAR coverage were found compared with the original plans. Compared with VMAT only, target and OARs were comparable. No significant correlations between HT and ABM doses were found. CONCLUSION: Bone marrow sparing volumetric modulated arc therapy can significantly reduce dose to the active bone marrow whilst maintaining acceptable target and OAR doses. Future prospective trials are needed to evaluate the clinical impact of BMS on toxicity and compliance.

Quantifying and Assessing the Dosimetric Impact of Changing Gas Volumes Throughout the Course of VMAT Radiation Therapy of Upper Gastrointestinal Tumors.

PURPOSE: This retrospective patient study assessed the consistency of abdominal gas presence throughout radiation therapy for patients with upper gastrointestinal cancer and determined the impact of variations in gas volume on the calculated dose distribution of volumetric modulated arc therapy. METHODS AND MATERIALS: Eight patients with pancreatic cancer were included for analysis. A plan library consisting of 3 reference plans per patient (Ref0.0, Ref0.5, and Ref1.0) was created based on planning computed tomography (CT) with density overrides of 0.0, 0.5, and 1.0 applied to gas volumes, respectively. Corresponding cone beam CT (CBCT) data sets were obtained and density overrides were applied to enable fractional dose calculation. Variation in gas volume relative to initial volume determined from CT was assessed. Dose metrics for targets and organs at risk were compared between the accumulated CBCT dose and the planned dose of the 3 reference plans for each patient. RESULTS: There was a significant decrease in gas present from CT to treatment CBCT, with a mean decrease in volume of 48.6% for the entire cohort. Dosimetrically, all accumulated target and organ-at-risk parameters, aside from the kidneys, exhibited the smallest mean deviation from the Ref0.0 plan and largest mean deviation from the Ref1.0 plan. A statistically significant difference in mean accumulated dose to Ref0.0 and Ref1.0 was observed for the dose delivered to 95% of the planning target volume. CONCLUSIONS: Significant variation in gas volumes from CT to treatment can occur throughout volumetric modulated arc therapy for pancreatic cancer. Through the use of a plan library, it was determined that initial assessment of a patient's treatment plan with an assigned gas density of 0.0 provided the most accurate prediction of the accumulated dose.

Higher-Order Structure Characterization of NKG2A/CD94 Protein Complex and Anti-NKG2A Antibody Binding Epitopes by Mass Spectrometry-Based Protein Footprinting Strategies.

NK group 2 member A (NKG2A), an immune checkpoint inhibitor, is an emerging therapeutic target in immuno-oncology. NKG2A forms a heterodimer with CD94 on the cell surface of NK and a subset of T cells and recognizes the nonclassical human leukocyte antigen (HLA-E) in humans. Therapeutic blocking antibodies that block the ligation between HLA-E and NKG2A/CD94 have been shown to enhance antitumor immunity in mice and humans. In this study, we illustrate the practical utilities of mass spectrometry (MS)-based protein footprinting in areas from reagent characterization to antibody epitope mapping. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) in the higher-order structure characterization of NKG2A in complex with CD94 provides novel insights into the conformational dynamics of NKG2A/CD94 heterodimer. To fully understand antibody/target interactions, we employed complementary protein footprinting methods, including HDX-MS and fast photochemical oxidation of proteins (FPOP)-MS, to determine the binding epitopes of therapeutic monoclonal antibodies targeting NKG2A. Such a combination approach provides molecular insights into the binding mechanisms of antibodies to NKG2A with high specificity, demonstrating the blockade of NKG2A/HLA-E interaction.

Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates.

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 µmol/kg).

Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Mapping binding epitopes of monoclonal antibodies targeting major histocompatibility complex class I chain-related A (MICA) with hydrogen/deuterium exchange and electron-transfer dissociation mass spectrometry.

Major histocompatibility complex class I chain-related A and B (MICA/B) are cell-surface proteins that act as ligands to natural killer cell receptors, NKG2D, expressed on immune cells. Prevention of proteolytic shedding of MICA/B to retain their integrity on the cell surface has become a therapeutic strategy in immuno-oncology. Given the unique mechanism of MICA/B shedding, structural characterization of MICA/B and therapeutic agent interaction is important in the drug discovery process. In this study, we describe the practical utility of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in epitope mapping studies of a cohort of four monoclonal antibodies targeting MICA in a rapid manner. HDX-MS followed by electron-transfer dissociation allows high-resolution refinement of binding epitopes. This integrated strategy offers, for the first time, molecular-level understanding of MICA's conformational dynamics in solution as well as the unique mechanism of actions of these antibodies in targeting MICA. Graphical abstract.

Design, synthesis and biological evaluation of phenol-linked uncialamycin antibody-drug conjugates.

Uncialamycin is one of the structurally simpler and newer members of enediyne family of natural products. It exhibits highly potent activity against several types of bacteria and cancer cells. Described herein is a strategy for the targeted delivery of this cytotoxic agent to tumors using an antibody-drug conjugate (ADC) approach. Central to the design of ADC were the generation of potent and chemically stable uncialamycin analogues and attachment of protease cleavable linkers to newly realized phenolic handles to prepare linker-payloads. Conjugation of the linker-payloads to tumor targeting antibody, in vitro activity and in vivo evaluation are presented.

Universal Affinity Capture Liquid Chromatography-Mass Spectrometry Assay for Evaluation of Biotransformation of Site-Specific Antibody Drug Conjugates in Preclinical Studies.

Antibody drug conjugates (ADCs) can undergo in vivo biotransformation (e.g., payload metabolism, deconjugation) leading to reduced or complete loss of activity. The location/site of conjugation of payload-linker can have an effect on ADC stability and hence needs to be carefully optimized. Affinity capture LC-MS of intact ADCs or ADC subfragments has been extensively used to evaluate ADC biotransformation. However, the current methods have certain limitations such as the requirement of specific capture reagents, limited mass resolution of low mass change metabolites, low sensitivity, and use of capillary or nanoflow LC-MS. To address these challenges, we developed a generic affinity capture LC-MS assay that can be utilized to evaluate the biotransformation of any site-specific ADC independent of antibody type and site of conjugation (Fab and Fc) in preclinical studies. The method involves a combination of some or all of these steps: (1) "mono capture" or "dual capture" of ADCs from serum with streptavidin magnetic beads coated with a generic biotinylated antihuman capture reagent, (2) "on-bead" digestion with IdeS and/or PNGase F, and (3) reduction of interchain disulfide bonds to generate ∼25 kDa ADC subfragments, which are finally analyzed by LC-HRMS on a TOF mass spectrometer. The advantages of this method are that it can be performed using commercially available generic reagents and requires sample preparation time of less than 7 h. Furthermore, by reducing the size of intact ADC (∼150 kDa) to subfragments (∼25 kDa), the identification of conjugated payload and its metabolites can be achieved with excellent sensitivity and resolution (hydrolysis and other small mass change metabolites). This method was successfully applied to evaluate the in vitro and in vivo biotransformation of ADCs conjugated at different sites (LC, HC-Fab, and HC-Fc) with various classes of payload-linkers.

Development of multi-purpose 3D printed phantoms for MRI.

This work describes the development and application of 3D printed MRI phantoms. Unlike traditional phantoms these test objects are made from solid materials which can be imaged directly without filling. The models were manufactured using both MRI visible and invisible materials. The MRI visible materials were imaged on a 3T system to quantify their T 1 and T 2 properties and CT to quantify the electron density. Three phantoms are described: a distortion phantom was imaged on an open bore MRI system to assess distortion over a 30 cm field-of-view; a solid tumour model was imaged using a motion simulator and compared to a standard water phantom to assess reduction in artefacts; finally, a test object created for textural analysis was evaluated on two 3T systems and reproducibility was assessed. Material 1 was the main material used in all phantom models and has a T 1 and T 2 of 152.3 ± 3.7 ms and 56.7 ± 2.5 ms and a CT density of 127.9 HU. Material 2 had a CT density of 115.1 HU and material 3 had a T 1 and T 2 of 149.5 ± 2.9 ms and 68.8 ± 7.8 ms and CT density of 15.3 HU. Image tests demonstrated the suitability and advantage of each phantom over more traditional versions: a high density set of control points enabled a comprehensive measurement of geometric accuracy; sufficient signal with a reduction in artefact was observed in the motion phantom, and the texture model provided reproducible measurements with an ICC > 0.9 for over 76% of texture features. Three different phantoms have been successfully manufactured and used to demonstrate the application of 3D printable materials for MRI phantoms.

Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy.

Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.

A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer.

Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178-89. ©2018 AACR.

Comparison of four dimensional computed tomography and magnetic resonance imaging in abdominal radiotherapy planning.

BACKGROUND AND PURPOSE: Four-dimensional (4D) computed tomography (CT) is widely used in radiotherapy (RT) planning and remains the current standard for motion evaluation. We assess a 4D magnetic resonance imaging (MRI) sequence in terms of motion and image quality in a phantom, healthy volunteers and patients undergoing RT. MATERIALS AND METHODS: The 4D-MRI sequence is a prototype T1-weighted 3D gradient echo with radial acquisition with self-gating. The accuracy of the 4D-MRI respiratory sorting based method was assessed using a MRI-CT compatible respiratory simulation phantom. In volunteers, abdominal viscera were evaluated for artefact, noise, structure delineation and overall image quality using a previously published four-point scoring system. In patients undergoing abdominal RT, the tumour (or a surrogate) was utilized to assess the range of motion on both 4D-CT and 4D-MRI. Furthermore, imaging quality was evaluated for both 4D-CT and 4D-MRI. RESULTS: In phantom studies 4D-MRI demonstrated amplitude of motion error of less than 0.2 mm for five, seven and ten bins. 4D-MRI provided excellent image quality for liver, kidney and pancreas. In patients, the median amplitude of motion seen on 4D-CT and 4D-MRI was 11.2 mm (range 2.8-20.3 mm) and 10.1 mm (range 0.7-20.7 mm) respectively. The median difference in amplitude between 4D-CT and 4D-MRI was -0.6 mm (range -3.4-5.2 mm). 4D-MRI demonstrated superior edge detection (median score 3 versus 1) and overall image quality (median score 2 versus 1) compared to 4D-CT. CONCLUSIONS: The prototype 4D-MRI sequence demonstrated promising results and may be used in abdominal targeting, motion gating, and towards implementing MRI-based adaptive RT.

Traumatic eye ball luxation: A stepwise approach to globe salvage.

Craniofacial trauma is often associated with orbital and ocular injuries. We report a case of a 21-year-old male with motor vehicular accident, orbital roof blow-in fracture, cerebrospinal fluid (CSF) leak, and left sided globe luxation with corneal abrasion and complete conjunctival denuding. The patient was managed by a multispeciality team and the eyeball was protected by amniotic membrane graft (AMG) biological dressing with novel use of inverted sterile metallic bowl as mechanical protection till the patient stabilized. During surgery, eyeball was reposited and ocular surface was reconstructed using amniotic membrane and symblepharon ring. Surgical correction and plating of the facial fractures and dural repair with autologus tensor fascia lata was done. Post surgery ocular surface was intact, ocular motility was well preserved and the globe was prephthisical. Traumatic eyeball luxation is a rare, but dramatic presentation which may occur in a blow in fracture when the intra orbital volume reduces and expels the eye ball out of the socket. This may be associated with extra ocular muscle rupture or optic nerve avulsion. The visual prognosis is nil in majority cases. However, the management is targeted towards globe preservation in view of psychological benefit and ease of cosmetic or prosthetic rehabilitation. Knowing the mechanism of luxation helps to plan the management. A stepwise approach for globe salvage is recommended. Team efforts to take care of various morbidities with special steps to safeguard the eye help to optimize outcomes.

A survey of modulated radiotherapy use in Australia & New Zealand in 2015.

A survey of radiation oncology medical physics departments across Australia and New Zealand was conducted to assess the usage, commissioning and quality assurance of modulated radiotherapy techniques such as IMRT and VMAT. Survey responses were collected in April-May 2015 to snapshot current practice and historical implementation. The survey asked 142 questions, and is the most detailed survey of its kind published to date. Analysis of results at overall department level, as well as sub-analysis for different equipment and techniques in use, was performed. Results show a high prevalence of IMRT and VMAT in use, and demonstrate the large heterogeneity in clinical practice and experience across the region.

A novel function of CXCL10 in mediating monocyte production of proinflammatory cytokines.

IFN-γ-inducible protein 10 (CXCL10), a chemokine that is abundantly secreted in response to inflammatory stimuli, has been implicated in the pathogenesis of multiple inflammatory diseases, such as inflammatory bowel disease. Whereas CXCL10 is traditionally recognized for recruiting pathogenic T cells to inflamed sites, its nonchemotactic role during inflammation remains poorly defined. In this report, we identified a novel function of CXCL10 in the regulation of the inflammatory potential of human monocytes to produce cytokines. We found that CXCL10 was necessary and sufficient for IFN-γ-primed human monocytes to induce a robust production of proinflammatory cytokines, such as IL-12 and IL-23. CXCL10-induced monocyte production of these cytokines depended on CXCR3 receptor engagement as well as on the Iκ B kinase and p38 MAPK signaling pathways. By using an innate-mediated murine colitis model, we demonstrated that anti-CXCL10 Ab treatment robustly suppressed the local production of myeloid-derived inflammatory cytokines and intestinal tissue damage. Together, our data unravel a previously unappreciated role of CXCL10 in the amplification of myeloid cell-mediated inflammatory responses. Targeting CXCL10 is therefore an attractive approach to treating inflammatory diseases that are driven by innate and adaptive immunity.

Clinical implementation of an exit detector-based dose reconstruction tool for helical tomotherapy delivery quality assurance.

PURPOSE: The aim of this study was to validate the accuracy of an exit detector-based dose reconstruction tool for helical tomotherapy (HT) delivery quality assurance (DQA). METHODS AND MATERIAL: Exit detector-based DQA tool was developed for patient-specific HT treatment verification. The tool performs a dose reconstruction on the planning image using the sinogram measured by the HT exit detector with no objects in the beam (i.e., static couch), and compares the reconstructed dose to the planned dose. Vendor supplied (three "TomoPhant") plans with a cylindrical solid water ("cheese") phantom were used for validation. Each "TomoPhant" plan was modified with intentional multileaf collimator leaf open time (MLC LOT) errors to assess the sensitivity and robustness of this tool. Four scenarios were tested; leaf 32 was "stuck open," leaf 42 was "stuck open," random leaf LOT was closed first by mean values of 2% and then 4%. A static couch DQA procedure was then run five times (once with the unmodified sinogram and four times with modified sinograms) for each of the three "TomoPhant" treatment plans. First, the original optimized delivery plan was compared with the original machine agnostic delivery plan, then the original optimized plans with a known modification applied (intentional MLC LOT error) were compared to the corresponding error plan exit detector measurements. An absolute dose comparison between calculated and ion chamber (A1SL, Standard Imaging, Inc., WI, USA) measured dose was performed for the unmodified "TomoPhant" plans. A 3D gamma evaluation (2%/2 mm global) was performed by comparing the planned dose ("original planned dose" for unmodified plans and "adjusted planned dose" for each intentional error) to exit detector-reconstructed dose for all three "Tomophant" plans. Finally, DQA for 119 clinical (treatment length <25 cm) and three cranio-spinal irradiation (CSI) plans were measured with both the ArcCHECK phantom (Sun Nuclear Corp., Melbourne, FL, USA) and the exit detector DQA tool to assess the time required for DQA and similarity between two methods. RESULTS: The measured ion chamber dose agreed to within 1.5% of the reconstructed dose computed by the exit detector DQA tool on a cheese phantom for all unmodified "Tomophant" plans. Excellent agreement in gamma pass rate (>95%) was observed between the planned and reconstructed dose for all "Tomophant" plans considered using the tool. The gamma pass rate from 119 clinical plan DQA measurements was 94.9% ± 1.5% and 91.9% ± 4.37% for the exit detector DQA tool and ArcCHECK phantom measurements (P = 0.81), respectively. For the clinical plans (treatment length <25 cm), the average time required to perform DQA was 24.7 ± 3.5 and 39.5 ± 4.5 min using the exit detector QA tool and ArcCHECK phantom, respectively, whereas the average time required for the 3 CSI treatments was 35 ± 3.5 and 90 ± 5.2 min, respectively. CONCLUSION: The exit detector tool has been demonstrated to be faster for performing the DQA with equivalent sensitivity for detecting MLC LOT errors relative to a conventional phantom-based QA method. In addition, comprehensive MLC performance evaluation and features of reconstructed dose provide additional insight into understanding DQA failures and the clinical relevance of DQA results.