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In this issue of Structure , Chataigner et al. reveal that Contactin-2's homotypic interaction, a glycosylation-dependent process, generates a broad conformational landscape. This structural plasticity, driven by conformational equilibria and sugar coating, facilitates adaptation to diverse ligands and environmental conditions, highlighting its dynamic role in neuronal function. [ABSTRACT FROM AUTHOR]

In αI integrins, including leukocyte function-associated antigen 1 (LFA-1), ligand-binding function is delegated to the αI domain, requiring extra steps in the relay of signals that activate ligand binding and coordinate it with cytoplasmic signals. Crystal structures reveal great variation in orientation between the αI domain and the remainder of the integrin head. Here, we investigated the mechanisms involved in signal relay to the αI domain, including whether binding of the ligand intercellular adhesion molecule-1 (ICAM-1) to the αI domain is linked to headpiece opening and engenders a preferred αI domain orientation. Using small-angle X-ray scattering and negative-stain EM, we define structures of ICAM-1, LFA-1, and their complex, and the effect of activation by Mn2+. Headpiece opening was substantially stabilized by substitution of Mg2+ with Mn2+ and became complete upon ICAM-1 addition. These agents stabilized I-headpiece orientation, resulting in a well-defined orientation of ICAM-1 such that its tandem Ig-like domains pointed in the opposite direction from the β-subunit leg of LFA-1. Mutations in the integrin βI domain α1/α1' helix stabilizing either the open or the closed βI-domain conformation indicated that α1/α1' helix movements are linked to ICAM-1 binding by the αI domain and to the extended-open conformation of the ectodomain. The LFA-1-ICAM-1 orientation described here with ICAM-1 pointing anti-parallel to the LFA-1 β-subunit leg is the same orientation that would be stabilized by tensile force transmitted between the ligand and the actin cytoskeleton and is consistent with the cytoskeletal force model of integrin activation. [ABSTRACT FROM AUTHOR]

The present paper deals with the modelling of a Hall effect current sensor with open core magnetic concentrator. 3D magnetic field modelling is carried out using the finite element method (FEM) and Comsol Multiphysics software. Two rectangular core constructions are considered. Different geometric parameters of the magnetic concentrator are varied and their influence on the sensor characteristic is studied, with the aim of reducing the dependence on the output signal on the distance to the conductor. Of the studied parameters, core window length leads to the most significant change in the sensor characteristic. Future work can include the optimization of the sensor construction. [ABSTRACT FROM AUTHOR]

High-resolution crystal structures of the headpiece of lymphocyte function-associated antigen-1 (integrin αLβ2) reveal how the αI domain interacts with its platform formed by the α-subunit β-propeller and β-subunit βI domains. The αLβ2 structures compared with αXβ2 structures show that the αI domain, tethered through its N-linker and a disulfide to a stable β-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between αL and αX subunits. Rerefined β2 integrin structures reveal details including pyroglutamic acid at the β2 N terminus and bending within the EGF1 domain. Allostery is relayed to the αI domain by an internal ligand that binds to a pocket at the interface between the β-propeller and βI domains. Marked differences between the αL and αX subunit β-propeller domains concentrate near the binding pocket and αI domain interfaces. Remarkably, movement in allostery in the βI domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand. [ABSTRACT FROM AUTHOR]

A computational analysis of the reacting flow field, species diffusion and heat transfer processes with thermal boundary layer effects in a microchannel reactor with a coflow configuration was performed. Two parallel adjacent streams of aqueous reactants flow along a wide, shallow, enclosed channel in contact with a substrate, which is affixed to a temperature controlled plate. The Fluent computational fluid dynamics package solved the Navier–Stokes, mass transport and energy equations. The energy model, including the enthalpy of reaction as a nonuniform heat source, was validated by calculating the energy balance at several control volumes in the microchannel. Analysis reveals that the temperature is nearly uniform across the channel thickness, in the direction normal to the substrate surface; hence, measurements made by sensors at or near the surface are representative of the average temperature. Additionally, modeling the channel with a glass substrate and a silicone cover shows that heat transfer is predominantly due to the glass substrate. Finally, using the numerical results, we suggest that a microcalorimeter could be based on this configuration, and that temperature sensors such as optical nanohole array sensors could have sufficient spatial resolution to determine enthalpy of reaction. [ABSTRACT FROM AUTHOR]

The survival of Yersinia enterocolitica strain 0:9 was investigated during the manufacturing and ripening of Mihahliç cheese produced from raw milk. Mihahliç cheese was produced after inoculating 105 cfu/ml of Y. enterocolitica strain 0:9 into raw milk. All cheese samples were ripened at + 4 °C for 30 days in 18 to 22% of brine. Samples taken from raw milk, scalded and strained curd, and cheese on days 1,3, 5, 8, 15 and 21 of the ripening process were analyzed for Y. enterocolitica, pH values and salt content. In raw milk, where initial inoculated Y. enterocolitica counts were 105 cfu/ml, counts were 1.5 x 106-7.1 x 106 cfu/g in scalded curd, 4.2 x 106-3.0 x 107 cfu/g in strained curd, 2.4 x 104-3.4 x 106 cfu/g on day 1,3.8 x 10³-2.5 x 105 cfu/g on day 3, and 9.2 x 10²4.0 x 104 cfu/g on day 5. During the ripening process, due to the decrease in pH values and the increase in salt content, Y. enterocolitica was diminished in the 1st batch on day 8, in the 3rd and 4th batches on day 15, and in the 2nd batch on day 21. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT). NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m2 daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level. Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P =.35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P =.88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P <.05). Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival. [ABSTRACT FROM AUTHOR]

To the Editor: The PET-NECK randomized trial by Mehanna et al. (April 14 issue)(1) compared surveillance guided by positron-emission tomography-computed tomography (PET-CT) with planned neck dissection after chemoradiotherapy in patients with head and neck squamous-cell carcinoma (HNSCC) and stage N2 or N3 nodal metastases. Patients who had a complete metabolic response but residual lymphadenopathy underwent neck dissection. A complete metabolic response on PET-CT in the presence of residual enlarged nodes has a high negative predictive value in oropharyngeal carcinoma associated with human papillomavirus (HPV).(2) Therefore, although these patients would have undergone neck dissection according to the trial protocol, Mehanna et . . . [ABSTRACT FROM AUTHOR]

Background : Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. Methods: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1–T4, N1–N3 or T3–4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1–T4, N2b–N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2—induction chemotherapy followed by arm 1; arm 3—dose-escalated radiotherapy plus concomitant cisplatin; and arm 4—resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5—induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. Discussion: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. Trial registration: ISRCTN ISRCTN41478539. Registered on 29 April 2015 [ABSTRACT FROM AUTHOR]

Staphylococcus aureus protein A (SpA) is an IgG Fc-binding virulence factor that is widely used in antibody purification and as a scaffold to develop affinity molecules. A cyclized SpA Z domain could offer exopeptidase resistance, reduced chromatographic ligand leaching after single-site endopeptidase cleavage, and enhanced IgG binding properties by preorganization, potentially reducing conformational entropy loss upon binding. In this work, a Z domain trimer (Z3) was cyclized using protein intein splicing. Interactions of cyclic and linear Z3 with human IgG1 were characterized by differential scanning fluorimetry (DSF), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC). DSF showed a 5 ℃ increase in IgG1 melting temperature when bound by each Z3 variant. SPR showed the dissociation constants of linear and cyclized Z3 with IgG1 to be 2.9 nM and 3.3 nM, respectively. ITC gave association enthalpies for linear and cyclic Z3 with IgG1 of −33.0 kcal/mol and −32.7 kcal/mol, and −T∆S of association 21.2 kcal/mol and 21.6 kcal/mol, respectively. The compact cyclic Z3 protein contains 2 functional binding sites and exhibits carboxypeptidase Y-resistance. The results suggest cyclization as a potential approach toward more stable SpA-based affinity ligands, and this analysis may advance our understanding of protein engineering for ligand and drug development. [ABSTRACT FROM AUTHOR]

Summary: To determine the outcomes of patients managed with different routes of enteral feeding during chemoradiotherapy for oropharynx cancer. The hospital and dietetic records of consecutive patients with oropharynx squamous cell carcinoma treated between January 2007 and June 2009 with concurrent chemoradiotherapy were reviewed retrospectively. One hundred and four patients were analysed. Seventy-one received a prophylactic gastrostomy, 21 were managed with a strategy of NG tube as required and 12 received a therapeutic gastrostomy. Patients with a prophylactic gastrostomy commenced enteral feeding a median of 24days after commencing radiotherapy, compared with a median of 41days (p <0.001) for the NG as required group. Comparing prophylactic gastrostomy, NG as required and therapeutic gastrostomy, median number of unplanned inpatient days were 6, 14 and 7, respectively (p <0.01 for prophylactic gastrostomy vs. NG as required). Mean percentage weight loss at the end of treatment (6.1% vs. 7.1% vs. 5.2%, respectively) and at 6months post-radiotherapy (11.7%, 14.3% and 8.9%) were similar in all groups (p =0.23). There was no significant difference in type of diet post-radiotherapy between prophylactic gastrostomy and NG as required groups (p =0.22). Median duration of enteral feeding was 181, 64 and 644days, respectively (p <0.01 for prophylactic gastrostomy vs. NG as required). Use of a prophylactic gastrostomy (p <0.01) and higher T stage (p <0.01) were associated with increased duration of enteral feeding on a multivariate analysis. These data reinforce concerns regarding the detrimental impact of prophylactic gastrostomy placement upon long-term enteral feed dependence. [Copyright &y& Elsevier]

Abstract: This study has been conducted to determine the major contamination sources during frozen snail meat processing. Seventeen different control points and/or sample types (live snail, and snail meats after steaming, after shell removal, after first boiling, after gutting, after second boiling, after packaging and as frozen snail meat; air samples from gutting room, boiling room and packaging room; samples from gutting counter tops, package surfaces, scissors used during processing, forks used during processing, personnel hands, and potable water) have been examined for the enumeration of total aerobic mesophilic bacteria, coliforms, Escherichia coli, Enterobacteriaceae, coagulase positive staphylococci, Salmonella spp., Listeria spp., and yeast and molds. From the control points examined, raw material and environmental air were found as the primary contamination sources. Personnel hands and equipment used were determined as the secondary contamination sources. Second boiling and freezing stages during processing were determined to reduce the overall contamination rate, and therefore had positive effects on the microbiological quality of the final product. Programs approving the acceptance of snails only with low initial microbial counts to the plant, giving emphasis to processing in proper hygiene conditions with sufficient sanitary applications is strongly recommended. [Copyright &y& Elsevier]

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. 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. 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. DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375. • This phase III RCT does not support dose escalation using accelerated hypofractionation. • No benefit in local tumour control or survival was seen. • Two-year local tumour failure rate was approximately 30% in both treatment groups. • The larynx was preserved in about 90% patients in both treatment groups. [ABSTRACT FROM AUTHOR]

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3 Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn2+ agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show conformational changes of the αIIbβ3 activating trajectory and a unique twisting of the integrin legs, which is required for platelets accumulation. Our structure provides direct structural evidence for how the lower legs are involved in full-length integrin activation mechanisms and offers a new strategy to target the αIIbβ3 lower leg. [Display omitted] • Cryo-EM structures of full-length integrin αIIbβ3 purified from human platelets • Three integrin αIIbβ3 states are revealed that are involved in the activation process • Allosteric structural variations are likely important for the activation mechanism Tong et al. determine the cryo-EM structures of full-length integrin αIIbβ3 in different states, which facilitates the understanding of the activation mechanism of the integrin αIIbβ3. [ABSTRACT FROM AUTHOR]

The receptor‐binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus binding to angiotensin‐converting enzyme 2 (ACE2) receptors on human host cells. Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID‐19). Using a target‐based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD. Synthetic aptamers had high binding affinity for S/RBD‐coated virus mimics (KD≈7 nM) and also blocked interaction of S/RBD with ACE2 receptors (IC50≈5 nM). Importantly, aptamers were able to neutralize S protein‐expressing viral particles and prevent host cell infection, suggesting a promising COVID‐19 therapy strategy. [ABSTRACT FROM AUTHOR]

The receptor‐binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus binding to angiotensin‐converting enzyme 2 (ACE2) receptors on human host cells. Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID‐19). Using a target‐based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD. Synthetic aptamers had high binding affinity for S/RBD‐coated virus mimics (KD≈7 nM) and also blocked interaction of S/RBD with ACE2 receptors (IC50≈5 nM). Importantly, aptamers were able to neutralize S protein‐expressing viral particles and prevent host cell infection, suggesting a promising COVID‐19 therapy strategy. [ABSTRACT FROM AUTHOR]

Background: Prior reports have raised concerns that a prophylactic gastrostomy may be detrimental to long-term swallow function. This study evaluates patient-reported swallow function following chemoradiotherapy for oropharyngeal carcinoma in relation to the use of a prophylactic gastrostomy or nasogastric (NG) tube as required. Material and methods: The MD Anderson Dysphagia Inventory (MDADI) was posted to 204 disease-free patients at least 2 years following chemoradiotherapy for oropharyngeal carcinoma between 2010 and 2014. Results: Overall, 181/204 (89%) patients returned questionnaire at a median of 34 months post-treatment. 97/181 (54%) and 84/181 (46%) were managed with an approach of a prophylactic gastrostomy or NG tube as required, respectively. A prophylactic gastrostomy was associated with higher rates of enteral feeding (92% vs. 58%, p <.001), lower median percentage weight loss (7.0% vs. 9.4%, p <.001), increased duration of enteral feed (median 3.3 vs. 1.1 months, p <.001). There was no significant difference in patient-reported swallow function measured by MDADI summary scores and subscales for patients managed with an approach of prophylactic gastrostomy or NG as required. Duration of enteral feed correlated negatively with composite MDADI scores. A subgroup of 116/181 (64%) patients were documented as having been offered a choice of enteral feeding approach and therefore can be considered to represent clinical equipoise; there were no significant differences in MDADI scores according to route. Conclusions: Despite concern regarding the use of a prophylactic gastrostomy in prior studies, the approaches of using a prophylactic gastrostomy or an NG tube as required to support patients during/after chemoradiotherapy for oropharyngeal carcinoma were associated with similar long-term swallow outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background and purpose Limited data are available to inform on long term swallowing outcomes following concurrent chemoradiotherapy for oropharyngeal carcinoma. The aims of this study are to determine long term patient-reported swallowing outcomes across two large UK centres in routine clinical practice and identify associated factors. Material and methods All patients treated for oropharyngeal squamous cell carcinoma with concurrent chemoradiotherapy, and irradiation of the bilateral neck, between 2011 and 2013 were identified. Those requiring therapeutic enteral feeding prior to treatment, or having subsequent disease relapse, were excluded from the study. Patients were sent postal invitations to complete the MD Anderson Dysphagia Inventory (MDADI), at least two years following completion of treatment. Results Completed MDADI were received from 201/242 eligible patients (83%) at a median of 3.4 years (range 2–5) post treatment. Median composite MDADI score was 68.4. 64 (32%) had composite MDADI <60 classed as ‘poor’ function, 76 (38%) scores ≥60–<80 classed as adequate function, and 61 (31%) had scores ≥80 classed as optimal function. Patients with normal and abnormal pre-treatment diet had median composite MDADI scores of 70.5 versus 47.4 respectively. Patients who did not require enteral feeding during treatment and those who did had median composite MDADI scores of 76.3 versus 65.3 respectively. On multivariate analysis poorer performance status, abnormal pre-treatment diet, and use of enteral feeding during radiotherapy were all significantly associated with lower composite, global and subscale MDADI scores. Conclusions Patient reported swallowing dysfunction remains common in the long term post-chemoradiotherapy. Impaired pre-treatment diet and use of enteral feeding during treatment are key factors associated with poorer swallowing outcomes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The accuracy of response assessment positron emission tomography (PET)-computed tomography (CT) following radiotherapy with or without chemotherapy for laryngeal/hypopharyngeal squamous cell carcinoma is uncertain. METHODS: In all, 35 patients with laryngeal or hypopharyngeal squamous cell carcinoma who were treated between 2009 and 2014 with (chemo)radiotherapy were identified. The accuracy of response assessment PET-CT was made by correlation with clinical follow-up and pathological findings. RESuLTS: Of the 35 patients, 20 (57%) had an overall complete metabolic response. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for response assessment [18Fluorine]-fluoro-2-deoxy-D-glucose (FDG) PET-CT for primary and nodal sites, respectively, were 100%, 73%, 46%, and 100% and 83%, 95%, 83%, and 95%. CONCLUSIONS: Response assessment FDG PET-CT following (chemo)radiotherapy for laryngeal and hypopharyngeal carcinomas has a high NPV for both primary site and lymph nodes and can be used to guide treatment decisions. The PPV of residual FDG uptake at the primary tumour site is limited and requires examination and biopsy confirmation. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this matched pair analysis is to assess patient-reported long term swallow function following chemoradiotherapy for locally advanced oropharyngeal cancer in relation to the use of a prophylactic gastrostomy or reactive nasogastric (NG) tube.Materials and Methods: The MD Anderson Dysphagia Inventory (MDADI) was posted to 68 consecutive patients with stage III/IV oropharyngeal squamous cell carcinoma who had completed parotid sparing intensity modulated radiotherapy with concurrent chemotherapy between 2010 and 2012, had not required therapeutic enteral feeding prior to treatment, minimum 2years follow up post treatment, and who were disease free. 59/68 replies were received, and a matched pair analysis (matching for T and N stage) was performed for 52 patients, 26 managed with a prophylactic gastrostomy and 26 with an approach of an NG tube as needed.Results: There were no significant differences in patient demographics, pre-treatment diet and treatment factors between the two groups. Patient-reported swallowing function measured using the MDADI was superior for patients managed with an NG tube as required compared with a prophylactic gastrostomy: overall composite score 68.1 versus 59.4 (p=0.04), global score 67.7 versus 60 (p=0.04), emotional subscale 73.5 versus 60.4 (p<0.01), functional subscale 75.4 versus 61.7 (p<0.01), and physical subscale 59.6 versus 57.1 (p=0.38).Conclusions: Compared with an approach of an NG tube as required, the use of a prophylactic gastrostomy was associated with inferior long term patient-reported long term swallow outcomes. [ABSTRACT FROM AUTHOR]

Background: This study aimed to quantify the variation in oropharyngeal squamous cell carcinoma gross tumour volume (GTV) delineation between CT, MR and FDG PET-CT imaging.Methods: A prospective, single centre, pilot study was undertaken where 11 patients with locally advanced oropharyngeal cancers (2 tonsil, 9 base of tongue primaries) underwent pre-treatment, contrast enhanced, FDG PET-CT and MR imaging, all performed in a radiotherapy treatment mask. CT, MR and CT-MR GTVs were contoured by 5 clinicians (2 radiologists and 3 radiation oncologists). A semi-automated segmentation algorithm was used to contour PET GTVs. Volume and positional analyses were undertaken, accounting for inter-observer variation, using linear mixed effects models and contour comparison metrics respectively.Results: Significant differences in mean GTV volume were found between CT (11.9 cm(3)) and CT-MR (14.1 cm(3)), p < 0.006, CT-MR and PET (9.5 cm(3)), p < 0.0009, and MR (12.7 cm(3)) and PET, p < 0.016. Substantial differences in GTV position were found between all modalities with the exception of CT-MR and MR GTVs. A mean of 64 %, 74 % and 77 % of the PET GTVs were included within the CT, MR and CT-MR GTVs respectively. A mean of 57 % of the MR GTVs were included within the CT GTV; conversely a mean of 63 % of the CT GTVs were included within the MR GTV. CT inter-observer variability was found to be significantly higher in terms of position and/or volume than both MR and CT-MR (p < 0.05). Significant differences in GTV volume were found between GTV volumes delineated by radiologists (9.7 cm(3)) and oncologists (14.6 cm(3)) for all modalities (p = 0.001).Conclusions: The use of different imaging modalities produced significantly different GTVs, with no single imaging technique encompassing all potential GTV regions. The use of MR reduced inter-observer variability. These data suggest delineation based on multimodality imaging has the potential to improve accuracy of GTV definition.Trial Registration: ISRCTN Registry: ISRCTN34165059 . Registered 2nd February 2015. [ABSTRACT FROM AUTHOR]

Introduction: A wide variety of fractionation schedules have been employed for the treatment of early glottic cancer. The aim is to report our 10-year experience of using hypofractionated radiotherapy with 55Gy in 20 fractions at 2.75Gy per fraction.Methods: Patients treated between 2004 and 2013 with definitive radiotherapy to a dose of 55Gy in 20 fractions over 4 weeks for T1/2 N0 squamous cell carcinoma of the glottis were retrospectively identified. Patients with prior therapeutic minor surgery (eg. laser stripping, cordotomy) were included. The probabilities of local control, ultimate local control (including salvage surgery), regional control, cause specific survival (CSS) and overall survival (OS) were calculated.Results: One hundred thirty-two patients were identified. Median age was 65 years (range 33-89). Median follow up was 72 months (range 7-124). 50 (38 %), 18 (14 %) and 64 (48 %) of patients had T1a, T1b and T2 disease respectively. Five year local control and ultimate local control rates were: overall - 85.6 % and 97.3 % respectively, T1a - 91.8 % and 100 %, T1b - 81.6 and 93.8 %, and T2 - 80.9 % and 95.8 %. Five year regional control, CSS and OS rates were 95.4 %, 95.7 % and 78.8 % respectively. There were no significant associations of covariates (e.g. T-stage, extent of laryngeal extension, histological grade) with local control on univariate analysis. Only increasing age and transglottic extension in T2 disease were significantly associated with overall survival (both p <0.01). Second primary cancers developed in 17 % of patients. 13 (9.8 %) of patients required enteral tube feeding support during radiotherapy; no patients required long term enteral nutrition. One patient required a tracheostomy due to a non-functioning larynx on long term follow up.Conclusions: Hypofractionated radiation therapy with a dose of 55Gy in 20 fractions for early stage glottic cancer provides high rates of local control with acceptable toxicity. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the disease outcomes of patients treated with definitive and adjuvant radiotherapy for squamous cell carcinomas of the nasal cavity and paranasal sinuses in a single institution.Methods: Between 2007-2012 patients were retrospectively identified from electronic databases who had undergone surgery and adjuvant radiotherapy or definitive radiotherapy for sinonasal squamous cell carcinomas with curative intent.Results: Fourty three patients with sinonasal squamous cell carcinoma were identified (22 nasal cavity, 21 paranasal sinuses). 31/43 (72%) had T3 or T4 disease; nodal stage was N0 in 38, N1 in 4, Na/b in 0 and N2c in 1 patient. Median age was 67 years (range 41-86). 18 (42%) received definitive and 25 (58%) adjuvant radiotherapy. Radiotherapy was delivered using either conventional radiotherapy (n = 39) or intensity modulated radiotherapy (n = 4). Elective neck radiotherapy was delivered to two patients. Chemotherapy was delivered to 6/43 (14%) of patients. Two-year local control, regional control, distant metastases free survival, progression free survival, cause specific survival and overall survival were 81%, 90%, 95%, 71%, 84% and 80% respectively. There was no significant difference in outcome comparing patients who underwent surgery and adjuvant radiotherapy with patients receiving definitive radiotherapy (2 year locoregional disease free survival 75% and 70% respectively, p = 0.98). Pooly differentiated tumours were significantly associated with inferior disease outcomes. Local, regional, combined local and regional, and distant failure occurred in 7 (16%), 3 (7%), 1 (2%) and 2 (5%) of patients; all 3 regional recurrences were in patients with nasal cavity squamous cell carcinomas who had not undergone elective neck treatment.Conclusions: Definitive or adjuvant radiotherapy provides an effective treatment for sinonasal malignancies. The main pattern of failure remains local, suggesting the need for investigation of intensified local therapy. Whilst remaining uncommon, the cases of regional failure mean that the merits of elective lymph node treatment should be considered on an individual basis. [ABSTRACT FROM AUTHOR]

Background: The aim of the study is to investigate the prognostic role of pre-treatment of markers of the systemic inflammatory response (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and albumin) in patients with oropharyngeal carcinoma treated with chemoradiotherapy. Methods: A total of 251 patients with oropharyngeal squamous cell cancer treated with chemoradiotherapy between 2004 and 2010 were retrospectively identified. NLR, PLR, and albumin were recorded from baseline blood parameters. NLR threshold of 5 and PLR thresholds of 150, 150 and 300, and 300 were used for analysis. Results: Median follow-up was 46 months (range 9–98). The 3 year overall survival, local control, regional control, and distant control were 70%, 85%, 87%, and 87%, respectively. On multivariate analysis, locoregional control was associated with T stage (HR 3.3 (95% CI 1.5–6.9), P = 0.002) and NLR (HR 2.1 (95% CI 1.1–3.9), P = 0.023). Overall survival was associated with T stage (HR 2.47 (95% CI 1.45–4.2), P = 0.001) and grade (HR 0.61 (95% CI 0.38–0.99), P = 0.048). PLR and albumin were not significantly associated with disease outcomes or survival. Conclusions: The NLR is an independent prognostic factor for locoregional control in oropharyngeal cancer treated with chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Summary: Objectives: The optimal management of the N3 neck in head and neck squamous cell carcinoma (HNSCC) remains controversial. We report the outcomes of patients with N3 disease treated with a strategy of concurrent chemo-radiotherapy (CRT)±induction chemotherapy (ICT) without a planned neck dissection. Materials and methods: Forty patients with HNSCC N3 disease treated between January 2004 and December 2010 were retrospectively identified. Inclusion criteria for the study were: non-nasopharyngeal HNSCC, N3 nodal disease, intention to treat with CRT±ICT. Results: Median age was 60 (range 39–74). Median follow up was 32months (range 8–88). 34 (85%) of patients received ICT. 35 patients received cisplatin-CRT, 4 carboplatin-CRT and 1 patient was treated with radiotherapy alone due to ICT toxicity. 27 (67.5%) patients had a complete response (CR) to CRT. 5 (12.5%) patients had an incomplete response in both the primary and nodal sites. 8 (20%) patients had a CR in the primary site but incomplete in the nodal regions. The crude rate of regional failure following a CR was 3/27 (11.2%). Isolated regional failure occurred in 1/27 (3.7%) patients who had achieved a CR post-CRT. 3year overall survival, disease free survival, locoregional control, local control and regional control in the whole cohort were 51.4%, 49.6%, 65.7%, 77.3%, 69.3%, and in patients with a CR were 73.3%, 70.0%, 86.6%, 90.5% and 91.7% respectively. Conclusion: Isolated regional nodal failure is rare following a complete response to CRT for N3 HNSCC managed without a planned neck dissection. [ABSTRACT FROM AUTHOR]

We previously demonstrated that isoflurane targets lymphocyte function-associated antigen-1 (LFA-1), a critical adhesion molecule for leukocyte arrest. However, it remains to be determined how isoflurane interacts with the full ectodomain LFA-1 and modulates its conformation and function. Isoflurane binding sites on the full ectodomain LFA-1 were probed by photolabeling using photoacrivatable isoflurane (azi-isoflurane). The adducted residues were determined by liquid chromatography/mass spectrometry analysis. Separately, docking simulations were performed to predict binding sites. Point mutations were introduced around isoflurane binding sites. The significance of isoflurane's effect was assessed in both intracellular adhesion molecule-1 (ICAM-1) binding assays and epitope mapping of activation-sensirive antibodies using flow cytometry. Two isoflurane binding sites were identified using photolabeling and were further validated by the docking simulation: one at the hydrophobic pocket in the ICAM-1 binding domain (the αI domain); the other at the βI domain. Mutagenesis of the α'l helix showed that isoflurane binding sites at the βI domain were significantly important in modulating LFA-1 function and conformation. Epitope mapping using activation-sensitive antibodies suggested that isoflurane stabilized LFA-1 in the closed conformation. This study suggested that isoflurane binds to both the αI and βI domains allosteric to the ICAM-1 binding site, and that isoflurane binding stabilizes LFA-1 in the closed conformation. [ABSTRACT FROM AUTHOR]

Introduction. To determine the value of a FDG-PET-CT scan in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) prior to chemoradiotherapy. Materials and Methods. Consecutive patients with stage III or IV HNSCC who had undergone a staging FDG-PET-CT scan prior to chemoradiotherapy between August 2008 and April 2011 were included. Clinical details and conventional imaging (CT and/or MRI) were, retrospectively, reviewed, a TNM stage was assigned, and levels of cervical lymph node involvement were documented. This process was repeated with the addition of FDG-PET-CT. Radiotherapy plans were reviewed for patients with an alteration identified on TNM staging and/or nodal level identification with FDG-PET-CT and potential alterations in radiotherapy planning were documented. Results. 55 patients were included in the analysis. FDGPET- CT altered the TNM stage in 17/55 (31%) of patients, upstaging disease in 11 (20%) and downstaging in 6 (11%); distant metastases were identified by FDG-PET-CT in 1 (2%) patient. FDG-PET-CT altered the lymph node levels identified in 22 patients (40%), upclassifying disease in 16 (29%) and downclassifying in 6 (11%). Radiotherapy plans were judged retrospectively to have been altered by FDG-PET-CT in 10 patients (18%). Conclusions. The use of FDG-PET-CT potentially impacts upon both treatment decisions and radiotherapy planning. [ABSTRACT FROM AUTHOR]

Introduction. To determine the value of a FDG-PET-CT scan in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) prior to chemoradiotherapy. Materials and Methods. Consecutive patients with stage III or IV HNSCC who had undergone a staging FDG-PET-CT scan prior to chemoradiotherapy between August 2008 and April 2011 were included. Clinical details and conventional imaging (CT and/or MRI) were, retrospectively, reviewed, a TNM stage was assigned, and levels of cervical lymph node involvement were documented. This process was repeated with the addition of FDG-PET-CT. Radiotherapy plans were reviewed for patients with an alteration identified on TNM staging and/or nodal level identification with FDG-PET-CT and potential alterations in radiotherapy planning were documented. Results. 55 patients were included in the analysis. FDGPET- CT altered the TNM stage in 17/55 (31%) of patients, upstaging disease in 11 (20%) and downstaging in 6 (11%); distant metastases were identified by FDG-PET-CT in 1 (2%) patient. FDG-PET-CT altered the lymph node levels identified in 22 patients (40%), upclassifying disease in 16 (29%) and downclassifying in 6 (11%). Radiotherapy plans were judged retrospectively to have been altered by FDG-PET-CT in 10 patients (18%). Conclusions. The use of FDG-PET-CT potentially impacts upon both treatment decisions and radiotherapy planning. [ABSTRACT FROM AUTHOR]

Background: To establish recurrence patterns among locally advanced head and neck non-nasopharyngeal squamous cell carcinoma (HNSCC) patients treated with radical (chemo-) radiotherapy and to correlate the sites of loco-regional recurrence with radiotherapy doses and target volumes Method: 151 locally advanced HNSCC patients were treated between 2004-2005 using radical three-dimensional conformal radiotherapy. Patients with prior surgery to the primary tumour site were excluded. The sites of locoregional relapses were correlated with radiotherapy plans by the radiologist and a planning dosimetrist. Results: Median age was 59 years (range:34-89). 35 patients had stage III disease, 116 patients had stage IV A/B. 36 patients were treated with radiotherapy alone, 42 with induction chemotherapy, 63 with induction and concomitant chemoradiotherapy and 10 concomitant chemoradiotherapy. Median follow-up was 38 months (range 3-62). 3-year cause specific survival was 66.8%. 125 of 151 (82.8%) achieved a complete response to treatment. Amongst these 125 there were 20 local-regional recurrence, comprising 8 local, 5 regional and 7 simultaneous local and regional; synchronous distant metastases occurred in 7 of the 20. 9 patients developed distant metastases in the absence of locoregional failure. For the 14 local recurrences with planning data available, 12 were in-field, 1 was marginal, and 1 was out-of-field. Of the 11 regional failures with planning data available, 7 were in-field, 1 was marginal and 3 were out-of-field recurrences. Conclusion: The majority of failures following non-surgical treatment for locally advanced HNSCC were locoregional, within the radiotherapy target volume. Improving locoregional control remains a high priority. [ABSTRACT FROM AUTHOR]

Background: Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil. Methods: A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone. Results: Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively. Conclusion: Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer. [ABSTRACT FROM AUTHOR]

The activation of LFA-1 (lymphocyte function-associated antigen) is a critical event If or T cell co-stimulation. The mechanism of LFA-1 activation involves both affinity and avidity regulation, but the role of each in T cell activation remains unclear. We have identified antibodies that recognize and block different affinity states of the mouse LFA-1 I-domain. Monoclonal antibody 2D7 preferentially binds to the low affinity conformation, and this specific binding is abolished when LFA-1 is locked in the high affinity conformation. In contrast, M17/4 can bind both the locked high and low affinity forms of LFA-1. Although both 2D7 and M17/4 are blocking antibodies, 2D7 is significantly less potent than M17/4 in blocking LFA-1-mediated adhesion; thus, blocking high affinity LFA-1 is critical for preventing LFA-1-mediated adhesion. Using these reagents, we investigated whether LFA-1 affinity regulation affects T cell activation. We found that blocking high affinity LFA-1 prevents interleukin-2 production and T cell proliferation, demonstrated by TCR cross-linking and antigen-specific stimulation. Furthermore, there is a differential requirement of high affinity LFA-1 in the activation of CD4+ and CD8+ T cells. Although CD4+ T cell activation depends on both high and low affinity LFA-1, only high affinity LFA-1 provides co-stimulation for CD8+ T cell activation. Together, our data demonstrated that the I-domain of LFA-1 changes to the high affinity state in primary T cells, and high affinity LFA-1 is critical for facilitating T cell activation. This implicates LFA-1 activation as a novel regulatory mechanism for the modulation of T cell activation and proliferation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine thyroid dysfunction in the early phase of radiotherapy to the head and neck region. Forty-seven patients receiving neck irradiation including the thyroid gland were included. Twenty-eight patients had undergone either a functional or radical neck dissection and in 19 patients radiotherapy was the primary treatment. Compared to the pre-treatment values, there was a significant fall in the TSH level at completion of radiotherapy in the non-operated patients and a non-significant fall in the operated patients. The TSH was also significantly lower in the non-operated group at the end of treatment compared to the operated group. There was a significant fall in the FT3 and significant higher in the FT4 at the end of radiotherapy for both groups. This study shows that even during completion of radiotherapy to the head and neck region changes in thyroid function were observed for both previously operated and non-operated patients. [Copyright &y& Elsevier]

Background: To establish recurrence patterns among locally advanced head and neck non-nasopharyngeal squamous cell carcinoma (HNSCC) patients treated with radical (chemo-) radiotherapy and to correlate the sites of loco-regional recurrence with radiotherapy doses and target volumesMethod: 151 locally advanced HNSCC patients were treated between 2004-2005 using radical three-dimensional conformal radiotherapy. Patients with prior surgery to the primary tumour site were excluded. The sites of locoregional relapses were correlated with radiotherapy plans by the radiologist and a planning dosimetrist.Results: Median age was 59 years (range:34-89). 35 patients had stage III disease, 116 patients had stage IV A/B. 36 patients were treated with radiotherapy alone, 42 with induction chemotherapy, 63 with induction and concomitant chemoradiotherapy and 10 concomitant chemoradiotherapy. Median follow-up was 38 months (range 3-62). 3-year cause specific survival was 66.8%. 125 of 151 (82.8%) achieved a complete response to treatment. Amongst these 125 there were 20 local-regional recurrence, comprising 8 local, 5 regional and 7 simultaneous local and regional; synchronous distant metastases occurred in 7 of the 20. 9 patients developed distant metastases in the absence of locoregional failure. For the 14 local recurrences with planning data available, 12 were in-field, 1 was marginal, and 1 was out-of-field. Of the 11 regional failures with planning data available, 7 were in-field, 1 was marginal and 3 were out-of-field recurrences.Conclusion: The majority of failures following non-surgical treatment for locally advanced HNSCC were loco-regional, within the radiotherapy target volume. Improving locoregional control remains a high priority. [ABSTRACT FROM AUTHOR]

A fast, sensitive temperature sensor using changes in extraordinary optical transmission (EOT) through an array of nanoholes in a metallic film with a monochromatic collimated light source is analyzed and experimentally demonstrated. The device is composed of a dielectric material in contact with a metallic film with an array of nanoholes, (25 arrays per chip were treated as a single sensor), on a glass substrate. Although the present experiment used a volume of water in a test cell to demonstrate the phenomena, there are many configurations that implement this technology in a variety of applications. The fast response of the device is expected because it measures the average temperature of a thin layer of the dielectric material directly above the nanoholes, ∼100 nm. The thermal response parameter of the nanohole array sensing region is ∼108times smaller and orders of magnitude faster than that of the reference thermistor. The increased speed and sensitivity of the nanohole array temperature sensor over the thermistor is observed in the reported data. The configuration of this temperature sensor was used for simplicity and to demonstrate that EOT effects can be used for temperature sensing. [ABSTRACT FROM AUTHOR]