A contact binary satellite of the asteroid (152830) Dinkinesh.

Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect)1 to be a notable factor in their evolution2. (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum3,4 is typical of bodies in this part of the main belt5. Here we report observations by the Lucy spacecraft6,7 as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event.

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.

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.

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.

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.

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.

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 outcome of drug-coated balloon angioplasty in patients with femoropopliteal disease: A real-world single-center experience.

BACKGROUND: Several multicenter industry-sponsored clinical trials reported satisfactory results in the use of drug-coated balloons (DCBs) for treatment of femoropopliteal occlusive disease. However, few single-center studies have been published to verify the outcome from real-world experience. METHODS: In this study, 228 patients treated with DCB angioplasty (Lutonix 0.35; Bard, Tempe, Arizona) were analyzed. Perioperative major adverse events (death, amputation, target lesion thrombosis or reintervention) were calculated. Kaplan-Meier analysis was used to estimate primary patency rates (based on duplex ultrasound with or without ankle-brachial index) and limb salvage rates. RESULTS: Lesions treated were primarily TransAtlantic Inter-Society Consensus (TASC) type C and D lesions. Indications included claudication (Rutherford classes 2 and 3) in 40% and critical limb ischemia (CLI; Rutherford classes 4 and 5) in 60%. Lesions treated included 61% in the superficial femoral artery, 15% in the popliteal artery, and 24% in both superficial femoral artery and popliteal artery. Mean follow-up was 12.2 months (range, 1-42 months). Overall perioperative morbidity and mortality rates were 13% and 1%. The perioperative major adverse event rate was 3%. Symptom relief (improvement of one Rutherford category or more) was obtained in 64%. Primary patency rates were 56% and 39% at 1 year and 2 years, respectively. Limb salvage rates were 92% and 83% at 1 year and 2 years. Patients with claudication had a lower rate of early perioperative complications (4% vs 19%; P = .001). Symptom improvement was 76% for claudication vs 49% for CLI (P < .001). Overall, major amputation rate was 0% for claudication vs 13% for CLI (P < .001). The primary patency rates at 1 year and 2 years were 59% and 41% for claudication vs 54% and 37% for CLI (P = .307). The assisted primary patency rates at 1 year and 2 years were 72% and 52% for claudication vs 64% and 46% for CLI (P = .223). Primary patency rates at 1 year and 2 years were 82% and 71% for TASC A to C lesions vs 29% and 14% for TASC D lesions (P < .001). Limb salvage rates at 1 year and 2 years were 100% and 100% for claudication vs 85% and 74% for CLI (P < .001). CONCLUSIONS: Clinical outcomes after DCB angioplasty in femoropopliteal lesions were inferior to what has been reported in previous studies, particularly for TASC D lesions. Further investigation from real-world experience with long-term follow-up is needed to confirm these results.

The incidence of carotid in-stent stenosis is underestimated ≥50% or ≥80% and its clinical implications.

BACKGROUND: The incidence of carotid in-stent stenosis has been reported to vary between 1% and 30%. Most published studies have short follow-up, which may lead to underestimation of the incidence of in-stent stenosis. This study analyzed the incidence of ≥50% and ≥80% in-stent stenosis using validated duplex ultrasound criteria and its clinical implications. METHODS: This is a retrospective analysis of prospectively collected data of 450 carotid artery stenting (CAS) procedures (February 6, 2001-December 19, 2016). All patients had postoperative carotid duplex ultrasound examination, which was repeated at 1 month, 6 months, and every 6 to 12 months thereafter. A Kaplan-Meier analysis was used to estimate rates of freedom from ≥50% in-stent stenosis (internal carotid artery peak systolic velocity of ≥224 cm/s) and ≥80% in-stent stenosis (internal carotid artery peak systolic velocity of ≥325 cm/s), freedom from reintervention, and survival. RESULTS: The mean age was 68.3 years, with a mean follow-up of 40.3 months. A total of 201 patients (45% [201/450]) had CAS for symptomatic disease. Primary CAS was done in 291 patients (65%); in the remaining 35%, CAS was done for postcarotid endarterectomy (CEA) stenosis. A total of 101 patients (23%) had ≥50% late carotid in-stent stenosis, and of these, 33 (7.4%) had ≥80% in-stent stenosis. Nineteen patients (4.3%) developed late transient ischemic attack and three (0.7%) late stroke. Twenty-three (5.2%) patients had late reintervention. Rates of freedom from ≥50% in-stent stenosis in the whole series were 85%, 79%, 75%, 72%, and 70% at 1 year, 2 years, 3 years, 4 years, and 5 years, respectively. The rates of freedom from ≥50% in-stent stenosis for primary CAS and CAS for post-CEA stenosis were not statistically significant (P = .540). The rates of freedom from ≥80% in-stent stenosis for the whole series were 96%, 95%, 93%, 90%, and 89% at 1 year, 2 years, 3 years, 4 years, and 5 years, respectively. The rates of freedom from ≥80% in-stent stenosis for primary CAS and CAS for post-CEA stenosis were also not statistically significant (P = .516). Rates of freedom from reintervention were 98%, 96%, 93%, 93%, and 91% at 1 year, 2 years, 3 years, 4 years, and 5 years, respectively, and there were no significant differences between primary CAS and CAS for post-CEA stenosis (P = .939). The overall late survival rates were 99%, 97%, 96%, 94%, and 91% at 1 year, 2 years, 3 years, 4 years, and 5 years. CONCLUSIONS: The incidence of ≥50% in-stent stenosis is relatively high; however, the rates of ≥80% stenosis and late neurologic events are low. Longer follow-up of patients with ≥50% carotid in-stent stenosis may yield higher incidence of ≥80% stenosis.

Primary cutaneous acral CD8+ T-cell lymphoma of the ear: A case report.

Primary cutaneous acral CD8+ T-cell lymphoma (TCL) is a rare, distinct type of cutaneous TCL. Despite its worrisome histological appearance it has a benign clinical course. It is therefore important to recognize this as a distinct entity from other more aggressive CD8+ lymphomas, for which the management is very different.

DARS: a phase III randomised multicentre study of dysphagia- optimised intensity- modulated radiotherapy (Do-IMRT) versus standard intensity- modulated radiotherapy (S-IMRT) in head and neck cancer.

BACKGROUND: Persistent dysphagia following primary chemoradiation (CRT) for head and neck cancers can have a devastating impact on patients' quality of life. Single arm studies have shown that the dosimetric sparing of critical swallowing structures such as the pharyngeal constrictor muscle and supraglottic larynx can translate to better functional outcomes. However, there are no current randomised studies to confirm the benefits of such swallow sparing strategies. The aim of Dysphagia/Aspiration at risk structures (DARS) trial is to determine whether reducing the dose to the pharyngeal constrictors with dysphagia-optimised intensity- modulated radiotherapy (Do-IMRT) will lead to an improvement in long- term swallowing function without having any detrimental impact on disease-specific survival outcomes. METHODS/DESIGN: The DARS trial (CRUK/14/014) is a phase III multicentre randomised controlled trial (RCT) for patients undergoing primary (chemo) radiotherapy for T1-4, N0-3, M0 pharyngeal cancers. Patients will be randomised (1:1 ratio) to either standard IMRT (S-IMRT) or Do-IMRT. Radiotherapy doses will be the same in both groups; however in patients allocated to Do-IMRT, irradiation of the pharyngeal musculature will be reduced by delivering IMRT identifying the pharyngeal muscles as organs at risk. The primary endpoint of the trial is the difference in the mean MD Anderson Dysphagia Inventory (MDADI) composite score, a patient-reported outcome, measured at 12 months post radiotherapy. Secondary endpoints include prospective and longitudinal evaluation of swallow outcomes incorporating a range of subjective and objective assessments, quality of life measures, loco-regional control and overall survival. Patients and speech and language therapists (SLTs) will both be blinded to treatment allocation arm to minimise outcome-reporting bias. DISCUSSION: DARS is the first RCT investigating the effect of swallow sparing strategies on improving long-term swallowing outcomes in pharyngeal cancers. An integral part of the study is the multidimensional approach to swallowing assessment, providing robust data for the standardisation of future swallow outcome measures. A translational sub- study, which may lead to the development of future predictive and prognostic biomarkers, is also planned. TRIAL REGISTRATION: This study is registered with the International Standard Randomised Controlled Trial register, ISRCTN25458988 (04/01/2016).

PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer.

BACKGROUND: Human papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes. METHODS/DESIGN: The study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint. DISCUSSION: PATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov identifier NCT02215265 .

The maturation of antibody technology for the HIV epidemic.

Antibodies are one of our most useful biological tools. Indeed, improvements in antibody-based technologies have ushered in a new era of antibody-based therapeutics, research and diagnostic tools. Although improved technologies have led to the development of therapeutic antibodies for treatment of malignancies and inflammatory conditions, the use of advanced antibody technology in the therapy of viral infections is in its infancy. Non-human primate studies have demonstrated that antibodies against the HIV envelope can both prevent viral infection and control viremia. Despite the obvious potential of antibody therapies against HIV, there remain limitations in production and purification capacity that require further research. Recent advances in recombinant antibody technology have led to the development of a range of novel antibody fragments, such as single-domain nanobodies and bispecific antibodies, that are capable of targeting cancer cells to cytotoxic T cells. Novel antibody production techniques have also been designed, allowing antibodies to be obtained from non-mammalian cells, bovine colostrum and the periplasm and cytoplasm of bacteria. These advances may allow large-scale production of HIV antibodies that are capable of protecting against HIV infection or serving as therapeutics that reduce the need for life-long antiretroviral treatment. This review summarises recent advances in antibody-based technologies and discusses the possibilities and challenges of using these advances to design prophylactics and therapeutics against HIV.

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24.

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).

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.

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.

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.

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.