Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion.

Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR-PHOX2B-HLA-A*24:02-ß2m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes.

Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): a phase 3, multicentre, randomised, controlled trial.

BACKGROUND: Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT. METHODS: DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete. FINDINGS: From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39·5 months (IQR 37·8-50·0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77·7 [SD 16·1] vs 70·6 [17·3]; mean difference 7·2 [95% CI 0·4-13·9]; p=0·037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths. INTERPRETATION: Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers. FUNDING: Cancer Research UK.

Structural principles of peptide-centric Chimeric Antigen Receptor recognition guide therapeutic expansion.

Peptide-Centric Chimeric Antigen Receptors (PC-CARs), which recognize oncoprotein epitopes displayed by human leukocyte antigens (HLAs) on the cell surface, offer a promising strategy for targeted cancer therapy 1 . We have previously developed a PC-CAR targeting a neuroblastoma- associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes 2 . Here, we determine the 2.1 Å structure of the PC-CAR:PHOX2B/HLA-A*24:02/ß2m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). The PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactivity group, covering a combined American population frequency of up to 25.2%. Comprehensive characterization using biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation and CAR-T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes.

ALL-RIC trial protocol: a comparison of reduced dose total body irradiation (TBI) and cyclophosphamide with fludarabine and melphalan reduced intensity conditioning in adults with acute lymphoblastic leukaemia (ALL) in complete remission.

INTRODUCTION: The usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high-with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL. METHODS AND ANALYSIS: The ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality. ETHICS AND DISSEMINATION: The protocol was approved by the East Midlands-Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-004800-23.ISRCTN99927695.

TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.•There is a strong translational component within TORPEdO. Imaging and physics data along with blood, tissue collection will inform future studies in refining patient selection for IMPT.

The acute impact of baseline renal function and contrast medium volume/estimated glomerular filtration rate ratio on reduced renal function following endovascular abdominal aortic aneurysm repair.

OBJECTIVE: The aim of this study was to determine the acute impact of baseline serum creatinine, estimated glomerular filtration rate (eGFR), and contrast medium volume (CMV) on the incidence of reduced renal function (RRF) after endovascular abdominal aortic aneurysm repair (EVAR). We aimed to determine if the CMV/eGFR ratio was a predictor of RRF. METHODS: This study is a retrospective review of EVAR patients in the Society for Vascular Surgery/Vascular Quality Initiative (SVS/VQI) from January 2015 to August 2020. Reduced renal function was defined as > 0.3 mg/dl (26.5 µmol/L), 50% increase from baseline, and temporary or permanent dialysis. Receiver operator characteristic (ROC) curve analyses were conducted for serum creatinine, eGFR, contrast volume, fluid volume, and CMV/eGFR ratio. Two data sets (training and test) were developed followed by multivariate analyses. RESULTS: SVS/VQI data for EVAR contained 38,701 records, of which 30,539 were divided into training (n = 18,283; 60%) and test (n = 12,256; 40%) data sets. RRF rate for the training set was 3.6% (n = 667) and 3.4% (n = 420) for the test data. RRF patients included more females (29.4 vs 19.0%, p < 0.001), were older in age (75.6 + 8.4 vs 73.3 + 8.7 years), had more congestive heart failure (22.3 vs 12.2%, p < 0.001), and more COPD (42.0 vs 34.2%, p < 0.001). An ROC analysis revealed that eGRF, creatinine, contrast, intravenous fluid, and contrast medium volume (CMV)/eGFR ratio were all significantly (p < 0.05) correlated with RRF. The eGFR and CMV/eGFR ratio had the largest area under the curve, (0.26) and (0.65), respectively, while fluid had the lowest (0.54). Negative predictive values were 93.7 (CMV/eGFR), 93.9 (creatinine), 94.2 (eGFR), 92.8 (contrast), and 92.6 (intravenous fluid). Multivariate analysis of the training data set resulted in the CMV/eGFR ratio as an independent predictor of RRF (odds ratio, OR: 1.9 with 95% CI: 1.6, 2.2, p < 0.015). For the test data, the CMV/eGFR ratio was an independent predictor of RRF (OR: 1.8, CI: 1.4 to 2.2, p < 0.001) as well as several other variables. CONCLUSION: RRF after EVAR is a dreaded and potentially devastating complication. Baseline serum creatinine, eGFR, contrast medium volume, and the ratio (CMV/eGFR) were all significantly associated with RRF. The optimal cut-off value for the CMV/eGFR ratio, ≤ 2, provides an easy-to-use equation to provide a suggested contrast target based on initial renal function with caution applied for high-risk patients.

A single-center experience of 30-day perioperative and one year clinical outcomes of transcarotid artery revascularization in 100 consecutive patients.

BACKGROUND: Transcarotid Artery Revascularization (TCAR) using the ENROUTE system (Silk Road) has been proposed as a safe and effective alternative to both carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TF-CAS). Two large registries (ROADSTER 1 and ROADSTER 2) have shown that TCAR has acceptable/low rates of perioperative stroke/death. This study will analyze the 30-day perioperative and 1-year clinical outcomes from a single-center. PATIENT POPULATION AND METHODS: This is a retrospective analysis of prospectively collected data from SVS/VQI TCAR surveillance project (TSP) of 100 consecutive patients (102 TCAR procedures) done in our institution. These procedures were done for high-risk patients for CEA, which included anatomical (previous CEA, high cervical lesion, neck radiation, stoma, arch type, etc.), physiological (CHF, severe coronary artery disease, COPD on O2 therapy, etc.) and combined anatomical/physiological reasons. These procedures were done by vascular surgeons after receiving the appropriate training. The perioperative stroke, death, and MI rates were analyzed. Kaplan Meyer analysis was used to estimate rate of freedom from stroke/death and the incidence of ≥50% and ≥80% in-stent restenosis at 1 year. RESULTS: 100 consecutive high-risk patients for CEA included: 38% anatomical, 44% physiological, and 18% combined anatomical and physiological reasons. The mean age was 72.5 years (range 52-90 years). Indications for TCAR were 34% for symptomatic lesions (TIA/stroke) and 66% for asymptomatic lesions. Mean ipsilateral treated stenosis was 80.4%. Contralateral ≥50% stenosis/occlusion was present in 31% of patients. Technical success rate was 100%. 92% had pre-stenting PTA and 26% had post-stenting PTA. The mean flow reversal time was 8.5 min (range 3-26 min). The 30-day perioperative stroke rate was 2.9% (1/67, 1.5% for asymptomatic patients), the stroke/death rate was 2.9%, and stroke/death and MI rate was 3.9% (4/102). Other perioperative complications included cranial nerve injury 3/102 (2.9%), carotid artery dissection (2%), and major hematoma (necessitated operation evacuation) (5.9%). Freedom from stroke rates and stroke/death rates at 1 year were: 90% and 89%. Freedom from ≥50% and ≥80% in-stent restenosis rates at 1 year were 82% and 90%, respectively. None of these restenosis were symptomatic except two (2/13). Freedom from reintervention rate at 1 year was 98%. CONCLUSION: Although the perioperative events were somewhat higher than what has been reported in previous registries, TCAR for patients who are high-risk for CEA has a low perioperative stroke and stroke/death rates with satisfactory outcome at 1 year. Further long-term data is probably needed to verify long-term outcome.

Critical analysis of vertebral artery flow patterns/subclavian steal detected by cerebrovascular duplex ultrasound examinations and its clinical implications.

BACKGROUND: The prevalence of subclavian steal (defined as retrograde/bidirectional vertebral artery flow) in the general population and in patients undergoing cerebrovascular duplex ultrasound (CDUS) examinations is variable. This is the largest study to date to analyze the incidence of duplex-suggested subclavian steal in 5615 CDUS examinations over a 1-year period and to examine its clinical implications. PATIENT POPULATION AND METHODS: All consecutive CDUS examinations performed over a 1-year period were analyzed for the presence of subclavian steal. Indications of testing, presence of posterior cerebral circulation/subclavian steal symptoms, and any interventions for subclavian steal were analyzed. RESULTS: A total of 171 of 5615 (3.1%) CDUS examinations were found to have subclavian steal (duplex-suggested). One hundred seventeen (2.1%) had retrograde flow and 54 (1%) had bidirectional flow. Of 171, 104 (60.8%) were left sided. Indications for CDUS were post-carotid endarterectomy/carotid artery stenting surveillance in 39 patients (22.8%), surveillance for progression of carotid stenosis in 76 patients (44.4%), transient ischemic attack/stroke in 26 patients (15%), asymptomatic screening/carotid bruit in 18 patients (10.5%), and isolated posterior cerebral circulation symptoms in 12 patients (7%). A total of 63% patients had associated >50% carotid stenosis. The mean arm Doppler pressure gradient was 32.2 mm Hg for asymptomatic patients vs 37 mm Hg for patients with posterior circulation symptoms (P = .3254). There were significant differences between the mean systolic arm pressure for patients with retrograde vs antegrade vs bidirectional flow (105 mm Hg vs 146 mm Hg vs 134 mm Hg, respectively, P < .0001). All patients with retrograde flow had >50% subclavian stenosis or occlusion (100 of 117 had subtotal/total occlusion) except for one patient. Meanwhile, 52 of 54 patients with bidirectional flow had >50% subclavian stenosis (6 of 54 with subtotal/total occlusion), whereas two patients were normal/<50% stenosis (P < .0001). Overall, 26 of 171 patients (15.2%) had interventions for disabling symptoms. Eleven of 26 of all interventions were for disabling arm claudication, and only 10 of 171 patients (5.8%) were intervened for disabling posterior circulation symptoms with complete resolution of symptoms in all except one. At a late follow-up with a mean of 18 months (range: 1-37 months), there was no late major stroke with only two lacunar infarcts (not subclavian steal related). There were also seven late deaths, none stroke related. CONCLUSIONS: The incidence of subclavian steal in patients who undergo CDUS is relatively rare. Most of these patients are asymptomatic and can be treated conservatively, and only a few may need intervention for disabling symptoms with good symptom resolution.

Impact of low iodine diets on ablation success in differentiated thyroid cancer: A mixed-methods systematic review and meta-analysis.

BACKGROUND: Debate remains regarding whether to recommend a low iodine diet (LID) before radioactive-iodine treatment and its duration and stringency. This mixed-methods review aimed to determine if iodine status affects treatment success, the most effective diet to reduce iodine status, and how LID impacts wellbeing. METHODS: Five electronic databases were searched until February 2021. An effectiveness synthesis (quantitative studies) and views synthesis (qualitative, survey, and experience-based evidence) were conducted individually and then integrated. Quality assessment was undertaken. RESULTS: Fifty-six quantitative and three qualitative studies were identified. There was greater ablation success for those with an iodine status of <50 mcg/L (or mcg/gCr) compared with ≥250 (odds ratio [OR] = 2.63, 95% confidence interval [CI], 1.18-5.86, n = 283, GRADE certainty of evidence very low). One study compared <50 mcg/L (or mcg/gCr) to 100-199 and showed similar rates of ablation success (OR = 1.59, 95% CI, 0.48-6.15, n = 113; moderate risk of bias). People following a stricter LID before ablation had similar rates of success to a less-strict diet (OR = 0.67, 95% CI, 0.26-1.73, n = 256, GRADE certainty of evidence very low). A stricter LID reduced iodine status more than a less strict (SMD = -0.40, 95% CI, -0.56 to -0.24, n = 816), and reduction was seen after 1 and 2 weeks. The main challenges were a negative impact on psychological health, over restriction, confusion, and difficulty for sub-groups. CONCLUSIONS: Although a LID of 1-2 weeks reduces iodine status, it remains unclear whether iodine status affects treatment success as only a few low-quality studies have examined this. LIDs are challenging for patients. Higher-quality studies are needed to confirm whether a LID is necessary.

Low iodine diet advice and differentiated thyroid cancer treatment: A historic exploration in three UK centres.

BACKGROUND AND AIMS: Patients with differentiated thyroid cancer are often advised to follow a low iodine diet (LID) one to two weeks before radioiodine remnant ablation (RRA). We describe treatment practices and ablation success rates in centres (C1, C2, C3) in the UK with different approaches to LID advice. METHODS: Historic cohort of patients with differentiated thyroid cancer treated with RRA in 2015/16 in C1 (n = 50, 1-week LID), C2 (n = 59, 2-week LID) and C3 (n = 108, no LID advice). Response to RRA was stratified as excellent, indeterminate, or incomplete by the adapted American Thyroid Association Dynamic Risk Stratification Score. RESULTS: There was little difference in age, sex and staging between centres, but the percentage receiving 1.1 GBq vs higher administered activities differed (C1:22%, C2:44%, C3:15%, p < 0.001). Excellent response was recorded for: C1:48%, C2:36%, C3:49% (p = 0.61). Differences in RRA preparation and outcome assessment at C3 precluded comparison across all centres. Adjusted odds ratio for excellent response at C2 vs C1 was 0.57 (95%CI: 0.25,1.32), p = 0.19. CONCLUSIONS: There was no evidence that advising a LID for 2-weeks before RRA improves outcomes compared to 1-week. For definitive recommendations on LIDs prior to RRA, a prospective multi-centre study with a more homogenous approach to patient management or, randomised controlled trial, is needed.

Clinical Outcome of Drug-Eluted Stenting (Zilver PTX) in Patients With Femoropopliteal Occlusive Disease a Single Center Experience.

BACKGROUND: Few industry sponsored trials reported satisfactory outcomes in the use of drug-eluting stents (DES) for treatment of femoropopliteal arterial disease. This study analyzed the early/late clinical outcome from a real world single center. PATIENT POPULATIONS/METHODS: A total of 115 limbs treated with Zilver PTX were analyzed for: major adverse limb event (MALE: above ankle limb amputation/major intervention at 1 year), major adverse events (MAEs; death, amputation, and target lesion thrombosis/reintervention), primary patency (based on duplex ultrasound ± ankle brachial indexes), limb salvage, and amputation free survival rates (AFS) at 1 and 2 years. RESULTS: Indications included claudication in 32% and critical limb threatening ischemia (CLTI) in 68%. Lesions treated included: superficial femoral artery (SFA) 66%, both SFA and popliteal artery (PA) 19% and PA 15%. Mean lesion length was 21 cm and 68% had total occlusion. 45% were Trans-Atlantic Inter-Society Consensus (TASC) TASC II D lesions and 55% A-C lesions. Mean follow-up was 18.4 months (1-76 months). Perioperative major morbidity rate was 8.7% with 0% mortality. MALE rate at 1 year was 17% (13.5% for claudication vs 19.2% for CLTI, p=0.4499). MAE rate was 30% for claudication versus 52% for CLTI (p=0.0392). Overall primary patency rates at 1 and 2 years were 75% and 54% (86% and 71% for claudication vs 70% and 46% for CLTI, respectively, p=0.0213). Primary patency rates at 1 and 2 years were 94% and 88% for TASC A-C lesions versus 50% and 16% for TASC D lesions (p<0.0001). Overall freedom from MALE rate at 1 and 2 years were 85% and 79% (86% and 86% for claudication vs 84% and 74% for CLTI, p=0.2391). These rates were 96% and 93% for TASC A-C lesions versus 70% and 50% for D lesions, respectively (p<0.0001). Limb salvage rates at 1 and 2 years were 93% and 86% (100% and 100% for claudication vs 89% and 78% for CLTI, p=0.012). Overall AFS rates at 1 and 2 years were 79% and 71% (93% and 82% for TASC A-C vs 59% and 59% for D lesions, p=0.001). CONCLUSION: Clinical outcomes after DES (Zilver PTX) in femoropopliteal arterial lesions were satisfactory for TASC A-C lesions but inferior/unsatisfactory for TASC D lesions.

Centralised RECIST Assessment and Clinical Outcomes with Lenvatinib Monotherapy in Recurrent and Metastatic Adenoid Cystic Carcinoma.

Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12-15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.

A feasibility study of hyoscine butylbromide (buscopan) to improve image quality of cone beam computed tomography during abdominal/pelvic Stereotactic Ablative Radiotherapy.

OBJECTIVES: Cone beam computed tomography (CBCT) is used for image guidance of stereotactic ablative radiotherapy (SABR), but it is susceptible to bowel motion artefacts. This trial evaluated the impact of hyoscine butylbromide (buscopan) on CBCT image quality and its feasibility within a radiotherapy workflow. METHODS: A single-centre feasibility trial (ISRCTN24362767) was performed in patients treated with SABR for abdominal/pelvic oligorecurrence. Buscopan was administered to separate cohorts by intramuscular (IM) or intravenous (i.v.) injection on alternate fractions, providing within-patient control data. 4-point Likert scales were used to assess overall image quality (ranging from excellent to impossible to use) and bowel motion artefact (ranging from none to severe). Feasibility was determined by patient/radiographer questionnaires and toxicity assessment. Descriptive statistics are presented. RESULTS: 16 patients were treated (8 by IM and 8 by i.v. buscopan). The percentage of images of excellent quality with/without buscopan was 47 vs 29% for IM buscopan and 65 vs 40% for i.v. buscopan. The percentage of images with no bowel motion artefact with/without buscopan was 24.6 vs 8.9% for IM buscopan and 25.8 vs 7% for i.v. buscopan. Four patients (25%) reported dry mouth. 14 patients (93%) would accept buscopan as routine. 11 radiographers (92%) reported no delay in treatments. CONCLUSIONS: A trend towards improved image quality/reduced bowel motion artefact was observed with IM/i.v. buscopan. Buscopan was well tolerated with limited impact on workflow. ADVANCES IN KNOWLEDGE: This is the first trial of buscopan within a radiotherapy workflow. It demonstrated a trend to improved image quality and feasibility of use.

Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Patient position verification in magnetic-resonance imaging only radiotherapy of anal and rectal cancers.

BACKGROUND AND PURPOSE: Magnetic resonance (MR)-only treatment pathways require either the MR-simulation or synthetic-computed tomography (sCT) as an alternative reference image for cone beam computed tomography (CBCT) patient position verification. This study assessed whether using T2 MR or sCT as CBCT reference images introduces systematic registration errors as compared to CT for anal and rectal cancers. MATERIALS AND METHODS: A total of 32 patients (18 rectum,14 anus) received pre-treatment CT- and T2 MR- simulation. Routine treatment CBCTs were acquired. sCTs were generated using a validated research model. The local clinical registration protocol, using a grey-scale registration algorithm, was performed for 216 CBCTs using CT, MR and sCT as the reference image. Linear mixed effects modelling identified systematic differences between modalities. RESULTS: Systematic translation and rotation differences to CT for MR were -0.3 to + 0.3 mm and -0.1 to 0.4° for anal cancers and -0.4 to 0.0 mm and 0.0 to 0.1° for rectal cancers, and for sCT were -0.4 to + 0.8 mm, -0.1 to 0.2° for anal cancers and -0.6 to + 0.2 mm, -0.1 to + 0.1° for rectal cancers. CONCLUSIONS: T2 MR or sCT can successfully be used as reference images for anal and rectal cancer CBCT position verification with systematic differences to CT <±1 mm and <±0.5°. Clinical enabling of alternative modalities as reference images by vendors is required to reduce challenges associated with their use.

Use of drug-eluting stents in patients with critical limb ischemia and infrapopliteal arterial disease: a real-world single-center experience.

BACKGROUND: Although no drug-eluting stent (DES) has been approved by the Food and Drug Administration to treat infrapopliteal arterial disease, several industry-sponsored trials have reported the outcomes with the use of paclitaxel or sirolimus DESs. To the best of our knowledge, only one study to date has reported on the use of everolimus DESs for infrapopliteal arterial disease. In the present study, we analyzed the clinical outcomes with everolimus DESs in our real-world, single-center experience. METHODS: A total of 107 limbs with critical limb threatening ischemia (98 patients; 118 lesions) treated with DESs (Xience; Abbott Vascular, Santa Clara, Calif) were analyzed. The postoperative early outcomes, major adverse limb events (above the ankle limb amputation or major intervention at 1 year), and major adverse events (death, amputation, target lesion thrombosis or reintervention) were analyzed. Kaplan-Meier analysis was used to estimate the primary patency rates (using duplex ultrasound), amputation-free rates, and amputation-free survival rates. RESULTS: Of the 118 lesions treated, 33% were in the anterior tibial artery, 28% were in the tibioperoneal (TP) artery, 21% were in the posterior tibial artery, 8% were in the peroneal artery, 5% were in the TP/posterior tibial artery, 4% were in the TP artery/PA, and 1% were in the TP/anterior tibial artery. The mean lesion length was 41 mm, and 59% were totally occluded (41% stenotic). The mean follow-up was 18.5 months (range, 1-70 months). The overall postoperative complication rate was 11% (2% major amputations), with 2% mortality. Late symptom improvement of one or more Rutherford category was obtained in 71%. The major adverse events rate at 30 days and 1 year was 12% and 45%, respectively. The major adverse limb events rate at 1 year was 15%. The overall primary patency rate was 42%. The primary patency rate at 1, 2, and 3 years was 57%, 45%, and 33%, respectively. The major amputation-free and overall amputation-free survival rates were 87%, 80%, and 77% and 76%, 65%, and 61% at 1, 2, and 3 years, respectively. CONCLUSIONS: The clinical outcomes after DES (Xience; Abbott Vascular) for infrapopliteal lesions were somewhat satisfactory at 1 year but inferior to the previously reported outcomes, especially at 3 years. Further data with long-term follow-up are needed.

Can dosimetry affect local control and survival in patients with early-stage lung cancer treated with Stereotactic Ablative Radiotherapy (SABR)? An analysis of the UK's largest cohort of lung SABR patients.

PURPOSE/OBJECTIVES: A recent study has shown that tight conformity of lung Stereotactic Ablative Radiotherapy (SABR) plans might worsen loco-regional control and can predict distant metastases. The study aims to report overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS), and dosimetry of early-stage lung cancer patients treated with SABR and to try to explore any dosimetric predictor of outcomes. MATERIAL AND METHODS: Patients treated in our institute (May 2009-August 2018) were included. Electronic medical records were reviewed for baseline characteristics, treatment details, and outcomes. Dosimetric data were extracted from Xio and Monaco software. Patients were treated according to the United Kingdom (UK) SABR consortium guidelines. Kaplan-Meier's analysis with log-rank test was used for survival analysis. The univariate and multivariable Cox regression model was used for correlating dosimetric variables and outcomes. RESULTS: We treated 1266 patients with median age of 75 years and 47.4% were male. Median follow up was 56 months. Median OS was 36 months with 1, 2, and 5 years OS of 84.2%, 64.5%, and 31.5%, respectively. Median for PFS and LRFS was not reached. One, 2, and 5 years PFS were 87.4%, 78.4%, and 72.5%, respectively. One, 2, and 5 years LRFS were 98.2%, 95.1%, and 92.5%, respectively. Planning target volume (PTV), dose to 99% volume of PTV (D99), and R50 (volume receiving the 50% dose/volume (PTV)) were significantly associated with OS. PTV, mean lung dose (MLD), V20 (volume of lung minus gross tumour volume (GTV) receiving 20 Gy), V12.5 (volume of lung minus GTV receiving 12.5 Gy), and dose fractionation were significantly associated with PFS. Nothing was associated with LRFS on univariate analysis. R100 of >1.1 was associated with better OS, PFS, and LRFS compared to R100 ≤ 1.1. CONCLUSION: SABR achieves good clinical outcomes in patients with early-stage lung cancer; even in elderly patients with multiple comorbidities. In the largest UK early lung cancer cohort treated with SABR, we found that dosimetry correlates with clinical outcomes. Further validation of these results is needed to guide future optimisation of SABR delivery.

Clinical and dosimetric predictors of radiation pneumonitis in early-stage lung cancer treated with Stereotactic Ablative radiotherapy (SABR) - An analysis of UK's largest cohort of lung SABR patients.

BACKGROUND: Stereotactic Ablative Radiotherapy (SABR) is the standard treatment for early-stage medically inoperable lung cancer. Predictors of radiation pneumonitis (RP) in patients treated with SABR are poorly defined. In this study, we investigate clinical and dosimetric parameters, which can predict symptomatic RP in early-stage lung cancer patients treated with SABR. MATERIALS AND METHODS: Patients treated with lung SABR between May 2009 and August 2018, in a single United Kingdom (UK) radiotherapy center were included. The patient's baseline characteristics, treatment details, and toxicity were retrieved from the electronic medical record. Dosimetric data was extracted from Xio and Monaco treatment planning systems. Patients were treated according to the UK SABR consortium guidelines. RP was graded retrospectively using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, based on available clinical and imaging information. Univariate and multivariate binary logistic regression was performed to determine predictive factors for grade ≥ 2 radiation pneumonitis, using Statistical Package for the Social Sciences (SPSS) statistics version 21 software. The goodness of fit was assessed using the Hosmer and Lemeshow test. The optimal diagnostic threshold was tested using the Receiver operating characteristics (ROC) curve. The chi-square test was carried out to test the different risk factors against the likelihood of developing grade ≥ 2 pneumonitis. RESULTS: A total of 1266 patients included in the analysis. The median age of patients was 75 years. Six hundred sixty-six patients (52.6%) were female. Median follow up was 56 months. Sixty-five percent of patients received 55 Gy in 5 fractions. Forty-three percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and 16.2% had PS of 3. The Median Charlson comorbidity index was 6 (range 2-11). Median Standardized Uptake Value (SUV) max of the tumor was 6.5. Four hundred two patients (31.8%) had confirmed histological diagnosis; other patients were treated based on a radiological diagnosis. The median tumor size was 20 mm (range 4 mm-63 mm). Median Planning Target Volume (PTV) was 30.3 cc. Median values of R100, R50, and D2cm were 1.1, 5.6, 32.8 Gy. The median value of mean lung dose, V20, and V12.5 were 3.9 Gy, 5 %and 9.3% respectively. Eighty-five (6.7%) patients developed symptomatic RP (grade ≥ 2) with only 5(0.4%) developing grade 3 RP. Five percent of patients developed rib fractures but only 28% of these were symptomatic. On univariate analysis lower lobe tumor location, larger tumor size, PTV, mean lung dose, lung V20Gy, and V12.5 Gy were significantly associated with grade ≥ 2 RP. On multivariate analysis, only mean lung dose was associated with grade ≥ 2 pneumonitis. ROC curve analysis showed optimal diagnostic threshold for tumour size, PTV, mean lung dose, V20 and V12.5; are 22.5 mm ((Area Under Curve (AUC)-0.565)), 27.15 cc (AUC-0.58), 3.7 Gy (AUC-0.633), 4.6% (AUC-0.597), 9.5% (AUC-0.616). The incidence of ≥grade 2 RP was significantly high for values higher than the ROC threshold. CONCLUSION: SABR treatment resulted in a very low rate of grade 3 pneumonitis. Lower lobe tumor location, larger tumor size, PTV, mean lung dose, V20, and V12.5 were found to be significant predictors of symptomatic radiation pneumonitis.

Patterns of Lymph Node Failure in Patients With Recurrent Prostate Cancer Postradical Prostatectomy and Implications for Salvage Therapies.

PURPOSE: There is increasing use of radical prostatectomy to treat patients with high-risk prostate cancer. This has contributed toward a pathologic stage migration, and a greater number of patients are subsequently being diagnosed with biochemical failure. There is increasing use of advanced imaging techniques in the setting of biochemical failure, including positron emission tomography-computed tomography (PET-CT). METHODS AND MATERIALS: This critical literature review highlights the evidence for PET-CT in postprostatectomy biochemical failure and identifies sites of pelvic lymph node relapse in the setting of biochemical failure and the potential implications that the locations of these relapses may have for salvage therapies. Potential future directions are then considered. RESULTS: The optimal PET-CT tracer remains uncertain but there is increasing use of prostate-specific membrane antigen PET-CT for investigating sites of nodal metastasis at low prostate-specific antigen levels, and this is leading to a blurring of the biochemical and radiologic recurrence phases. The optimal therapeutic approach remains undefined, with current trials investigating postoperative radiation therapy to the whole pelvis in addition to the prostatic fossa, the use of PET-CT in the setting of biochemical recurrence to guide delivery of salvage radiation therapy, and, for patients with node-only relapsed prostate cancer, the addition of whole pelvis radiation therapy to metastasis-directed therapies such as stereotactic ablative radiotherapy. CONCLUSIONS: The most appropriate target volume for salvage radiation therapy remains uncertain, and the findings of studies using PET-CT to map nodal recurrences suggest that there could be a role for extending whole pelvis radiation therapy volumes to increase coverage of superior nodal regions. The emerging fields of radiomics and radiogenomics could provide important prognostic information and aid decision making for patients with relapsed prostate cancer.