Clinical outcomes in relapsed oropharyngeal cancer after definitive (chemo) radiotherapy.

OBJECTIVES: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity-modulated (chemo)radiotherapy [(C)RT]. MATERIALS AND METHODS: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end-point was post-failure survival (PFS). RESULTS: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)-negative; n = 16 HPV-positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two-year PFS for the entire population was 30.6%; 20.5% for HPV-negative and 43.8% for HPV-positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11). CONCLUSION: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV-positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS.

Water soluble swallow for leak detection after total laryngectomy post radiotherapy.

AIM: Pharyngeal leak (PL) and pharyngocutaneous fistula (PCF) are serious complications following total laryngectomy and their incidence is higher in the salvage setting. The aim of this study is to describe the accuracy of water soluble swallow (WSS) to rule out salivary postoperative leak after salvage total laryngectomy (STL) to expedite start of oral intake. MATERIAL AND METHODS: Retrospective study including patients undergoing STL between 2008 and 2021 at Guy's Hospital. WSS was routinely performed within 15 days post operation. RESULTS: Sixty-six patients underwent STL. Nine developed clinically diagnosed PCF; one died before having WSS. Fifty-six patients underwent WSS post STL. WSS was performed within 15 days after STL when no postoperative complications occurred (76.8%). Among patients undergoing WSS with no clinical suspicion for fistula (56), PL was identified in 15 cases (26.8%). They were managed conservatively; PCF was avoided in 7(46.7%) cases. Three patients (7.3%) developed PCF after having started oral intake with a negative WSS. These three cases were further analysed, 2 cases where recorded at the beginning of the studied period when less experience was available possibly leading to incorrect results. Sensitivity and negative predictive value (NPV) for fistula prediction were 72.7% and 92.7%, respectively. CONCLUSION: Taking into account the high NPV of WSS, it is safe to start oral intake after negative WSS. Further studies to evaluate its accuracy earlier on after SLT are justified taking into account the results and the impact that delayed feeding has on patient's quality of life.

The impact of 2 weeks wait referral on survival of head and neck cancer patients.

PURPOSE: This study aims to evaluate the association between 2 weeks wait referral and survival in the head and neck cancer. METHODS: Retrospective cohort study of consecutively discussed new head and neck cancer patients at large United Kingdom Cancer Alliance including two tertiary referral hospitals and two district general hospital. RESULTS: A total of 276 cancer patients were included for analysis. Patients referred under the 2 weeks wait had were seen and diagnosed sooner from referral (p < 0.0001 and p < 0.0001 respectively). However, this did not translate into better survival outcomes. No survival differences were seen between those patients that were managed within the proposed cancer targets and those that were not. CONCLUSIONS: The 2 weeks wait head and neck cancer pathway did not offer a survival advantage. Targeting the delay in referral as well as delay in treatment to prevent late-stage cancer presentation is paramount. Fulfilment of cancer time targets do not translate into better outcomes and should not be prioritised to clinical judgement.

Structures and Spectroscopic Properties of Polysulfide Radical Anions: A Theoretical Perspective.

The potential involvement of polysulfide radical anions Sn•- is a recurring theme in discussions of the basic and applied chemistry of elemental sulfur. However, while the spectroscopic features for n = 2 and 3 are well-established, information on the structures and optical characteristics of the larger congeners (n = 4-8) is sparse. To aid identification of these ephemeral species we have performed PCM-corrected DFT calculations to establish the preferred geometries for Sn•- (n = 4-8) in the polar media in which they are typically generated. TD-DFT calculations were then used to determine the number, nature and energies of the electronic excitations possible for these species. Numerical reliability of the approach was tested by comparison of the predicted and experimental excitation energies found for S2•- and S3•-. The low-energy (near-IR) transitions found for the two acyclic isomers of S4•- (C2h and C2v symmetry) and for S5•- (Cs symmetry) can be understood by extension of the simple HMO π-only chain model that serves for S2•- and S3•-. By contrast, the excitations predicted for the quasi-cyclic structures Sn•- (n = 6-8) are better described in terms of σ → σ* processes within a localized 2c-3e manifold.

Association between delays to patient admission from the emergency department and all-cause 30-day mortality.

BACKGROUND: Delays to timely admission from emergency departments (EDs) are known to harm patients. OBJECTIVE: To assess and quantify the increased risk of death resulting from delays to inpatient admission from EDs, using Hospital Episode Statistics and Office of National Statistics data in England. METHODS: A cross-sectional, retrospective observational study was carried out of patients admitted from every type 1 (major) ED in England between April 2016 and March 2018. The primary outcome was death from all causes within 30 days of admission. Observed mortality was compared with expected mortality, as calculated using a logistic regression model to adjust for sex, age, deprivation, comorbidities, hour of day, month, previous ED attendances/emergency admissions and crowding in the department at the time of the attendance. RESULTS: Between April 2016 and March 2018, 26 738 514 people attended an ED, with 7 472 480 patients admitted relating to 5 249 891 individual patients, who constituted the study's dataset. A total of 433 962 deaths occurred within 30 days. The overall crude 30-day mortality rate was 8.71% (95% CI 8.69% to 8.74%). A statistically significant linear increase in mortality was found from 5 hours after time of arrival at the ED up to 12 hours (when accurate data collection ceased) (p<0.001). The greatest change in the 30-day standardised mortality ratio was an 8% increase, occurring in the patient cohort that waited in the ED for more than 6 to 8 hours from the time of arrival. CONCLUSIONS: Delays to hospital inpatient admission for patients in excess of 5 hours from time of arrival at the ED are associated with an increase in all-cause 30-day mortality. Between 5 and 12 hours, delays cause a predictable dose-response effect. For every 82 admitted patients whose time to inpatient bed transfer is delayed beyond 6 to 8 hours from time of arrival at the ED, there is one extra death.

Commentary: Global Alzheimer's disease and Alzheimer's disease related dementia research funding organizations support and engage the research community throughout the COVID-19 pandemic.

The COVID-19 pandemic has disproportionately affected more vulnerable populations, including those living with dementia. Over 50 million individuals worldwide are living with Alzheimer's disease (AD) or other dementia, and it is crucial to continue the fight against the condition during the global pandemic. Since the start of mandated lockdowns in March 2020, charity and non-profit organizations that fund AD and related dementia research continue to respond to the needs of the AD research community, ensuring the momentum continues and accelerates. Members of the International Alzheimer's and Related Dementia Research Funder Consortium, a group of nearly 40 funding organizations that informally convene throughout the year to share updates and information, have taken a number of steps to ensure the continued support of the research community. Even during times of uncertainty, it is essential that the field moves forward to uncover preventions, diagnoses, and treatments for these diseases that affect many millions globally.

Radical Dimerization in a Plastic Organic Crystal Leads to Structural and Magnetic Bistability with Wide Thermal Hysteresis.

The nitroxyl radical 1-methyl-2-azaadamantane N-oxyl (Me-AZADO) exhibits magnetic bistability arising from a radical/dimer interconversion. The transition from the rotationally disordered paramagnetic plastic crystal, Me-AZADO, to the ordered diamagnetic crystalline phase, (Me-AZADO)2, has been conclusively demonstrated by crystal structure determination from high-resolution powder diffraction data and by solid-state NMR spectroscopy. The phase change is characterized by a wide thermal hysteresis with high sensitivity to even small applied pressures. The molecular dynamics of the phase transition from the plastic crystal to the conventional crystalline phase has been tracked by solid-state (1H and 13C) NMR and EPR spectroscopies.

The Importance of Electronic Dimensionality in Multiorbital Radical Conductors.

The exceptional performance of oxobenzene-bridged bis-1,2,3-dithiazolyls 6 as single-component neutral radical conductors arises from the presence of a low-lying π-lowest unoccupied molecular orbital, which reduces the potential barrier to charge transport and increases the kinetic stabilization energy of the metallic state. As part of ongoing efforts to modify the solid-state structures and transport properties of these so-called multiorbital materials, we report the preparation and characterization of the acetoxy, methoxy, and thiomethyl derivatives 6 (R = OAc, OMe, SMe). The crystal structures are based on ribbonlike arrays of radicals laced together by S···N' and S···O' secondary bonding interactions. The steric and electronic effects of the exocyclic ligands varies, affording one-dimensional (1D) π-stacked radicals for R = OAc, 1D cofacial dimer π-stacks for R = SMe, and a pseudo two-dimensional (2D) brick-wall arrangement for R = OMe. Variable-temperature magnetic and conductivity measurements reveal strong antiferromagnetic interactions and Mott insulating behavior for the two radical-based structures (R = OAc, OMe), with lower room-temperature conductivities (σRT ≈ 1 × 10-4 and ∼1 × 10-3 S cm-1, respectively) and higher thermal activation energies ( Eact = 0.24 and 0.21 eV, respectively) than found for the ideal 2D brick-wall structure of 6 (R = F), where σRT ≈ 1 × 10-2 S cm-1 and Eact = 0.10 eV. The performance of R = OMe, OAc relative to that of R = F, is consistent with the results of density functional theory band electronic structure calculations, which indicate a lower kinetic stabilization energy of the putative metallic state arising from their reduced electronic dimensionality.

Pancakes under Pressure: A Case Study on Isostructural Dithia- and Diselenadiazolyl Radical Dimers.

The isostructural dimers of the 1,4-phenylene-bridged bis-1,2,3,5-dithia- and bis-1,2,3,5-diselenadiazolyl diradicals 1,4-S/Se are small band gap semiconductors. The response of their molecular and solid state electronic structures to pressure has been explored over the range 0-10 GPa. The crystal structures, which consist of cofacially aligned (pancake) π-dimers packed into herringbone arrays, experience a continuous, near-isotropic compression. While the intramolecular covalent E-E (E = S/Se) bonds remain relatively unchanged with pressurization, the intradimer E···E separations are significantly shortened. Molecular and band electronic structure calculations using density functional theory methods indicate that compression of the π-dimers leads to a widening of the gap Δ E between the highest occupied and lowest unoccupied molecular orbitals of the dimer, an effect that offsets the expected decrease in the valence-to-conduction band gap Eg occasioned by pressure-induced spreading of the valence and conduction bands. Consistent with the predicted consequences of this competition between intra- and interdimer interactions, variable temperature high pressure conductivity measurements reveal at best an order-of-magnitude increase in conductivity with pressure for the two compounds over the pressure range 0-10 GPa. While a small reduction in the thermal activation energy Eact with increasing pressure is observed, extrapolation of the rate of decrease suggests a projected onset of metallization ( Eact ≈ 0) in excess of 20 GPa.

Three-Dimensional Magnetic Exchange Networks in Trigonal Bisdithiazolyl Radicals.

The N-methyl-4-phenyl-pyridine-bridged bisdithiazolyl radical PhBPMe is polymorphic, crystallizing from cold acetonitrile in a trigonal α-phase, space group P3121, and from hot dichloroethane in an orthorhombic ß-phase, space group Pca21. The crystal structures of both phases consist of slipped π-stacks of undimerized radicals aligned laterally into herringbone arrays. In the ß-phase, there are two independent radicals in the asymmetric unit, and the resulting π-stacks form corrugated layers interspersed by methyl and phenyl groups which block the approach of neighboring radicals. In the α-phase, the methyl/phenyl groups and the radical π-stacks separately form spirals about 31 axes, the latter giving rise to a 3D network of close radical/radical contacts. Variable temperature magnetic susceptibility measurements on the ß-phase indicate strong antiferromagnetic coupling. Weaker but predominantly antiferromagnetic interactions (θ = -20.7 K) are observed in the α-phase. A high temperature series expansion analysis of the magnetic data for the α-phase affords antiferromagnetic exchange energies for the one- and two-step radical/radical interactions about the 31 spirals ( J1 = -1.2 K, J2 = -10.9 K, respectively), with weak ferromagnetic interactions along the π-stacks ( Jπ = +1.8 K). Despite the presence of a 3D network based on the dominant J2 interactions, which affords two independent bipartite sublattices, no evidence of bulk antiferromagnetic order has been observed above T = 2 K. The magnetic results are discussed in light of exchange energies calculated using density functional theory broken symmetry methods.

Outcomes of salvage surgery for the oropharynx and larynx: a contemporary experience in a UK Cancer Centre.

INTRODUCTION: The purpose of this study was to review our recent experience of salvage surgery, comparing larynx and oropharynx recurrence patterns. METHODS: A single centre, retrospective review of salvage surgery for recurrent head and neck cancer including patients between 2008 and 2016. RESULTS: 61 patients were identified, 36 underwent salvage laryngectomy and 25 received oropharyngeal resections. The median overall survival of oropharyngeal recurrent tumors was 26 months (95% CI 15-118 months) and for laryngeal tumors was 23 months (95% CI 11-38 months), p = 0.1008. There was a significant overall survival benefit in patients with negative resection margin. The median survival in the negative margin group was 38 months (95% CI 25-108 months) compared to the positive margin group, 9 months (95% CI 5-15 months), p < 0.0001. CONCLUSION: Survival results following surgical salvage in the larynx and oropharynx appear to be similarly poor. Those patients with clear margins appear to have a significantly better prognosis.

Magnetic Bistability in Naphtho-1,3,2-dithiazolyl: Solid State Interconversion of a Thiazyl π-Radical and Its N-N σ-Bonded Dimer.

Crystals of the heterocyclic radical naphtho-1,3,2-dithiazolyl NDTA display magnetic bistability with a well-defined hysteretic phase transition at Tc↓ = 128(2) K and Tc↑ = 188(2) K. The magnetic signature arises from a radical/dimer interconversion involving one of the two independent π-radicals in the P1̅ unit cell. Variable temperature X-ray crystallography has established that while all the radicals in HT-NDTA serve as paramagnetic ( S = 1/2) centers, half of the radicals in LT-NDTA form closed-shell N-N σ-bonded dimers ( S = 0) and half retain their S = 1/2 spin state. The wide window of bistability (60 K) may be attributed to the large structural changes that accompany the phase transition.

Non-Innocent Base Properties of 3- and 4-Pyridyl-dithia- and Diselenadiazolyl Radicals: The Effect of N-Methylation.

Condensation of persilylated nicotinimideamide and isonicotinimideamide with sulfur monochloride affords double salts of the 3-, 4-pyridyl-substituted 1,2,3,5-dithiadiazolylium DTDA cations of the general formula [3-, 4-pyDTDA][Cl][HCl] in which the pyridyl nitrogen serves as a noninnocent base. Reduction of these salts with triphenylantimony followed by deprotonation of the intermediate-protonated radical affords the free base radicals [3-, 4-pyDTDA], the crystal structures of which, along with those of their diselenadiazolyl analogues [3-, 4-pyDSDA], have been characterized by powder or single-crystal X-ray diffraction. The crystal structures consist of "pancake" π-dimers linked head-to-tail into ribbonlike arrays by η2-S2---N(py) intermolecular secondary bonding interactions. Methylation of the persilylated (iso)nicotinimide-amides prior to condensation with sulfur monochloride leads to N-methylated double chloride salts Me[3-, 4-pyDTDA][Cl]2, which can be converted by metathesis into the corresponding triflates Me[3-, 4-pyDTDA][OTf]2 and then reduced to the N-methylated radical triflates Me[3-, 4-pyDTDA][OTf]. The crystal structures of both the N-methylated double triflate and radical triflate salts have been determined by single-crystal X-ray diffraction. The latter consist of trans-cofacial π-dimers strongly ion-paired with triflate anions. Variable temperature magnetic susceptibility measurements on both the neutral and radical ion dimers indicate that they are diamagnetic over the temperature range 2-300 K.

Benzoquinone-Bridged Heterocyclic Zwitterions as Building Blocks for Molecular Semiconductors and Metals.

In pursuit of closed-shell building blocks for single-component organic semiconductors and metals, we have prepared benzoquino-bis-1,2,3-thiaselenazole QS, a heterocyclic selenium-based zwitterion with a small gap (λmax = 729 nm) between its highest occupied and lowest unoccupied molecular orbitals. In the solid state, QS exists in two crystalline phases and one nanocrystalline phase. The structures of the crystalline phases (space groups R3 c and P21/ c) have been determined by high-resolution powder X-ray diffraction methods at ambient and elevated pressures (0-15 GPa), and their crystal packing patterns have been compared with that of the related all-sulfur zwitterion benzoquino-bis-1,2,3-dithiazole QT (space group Cmc21). Structural differences between the S- and Se-based materials are interpreted in terms of local intermolecular S/Se···N'/O' secondary bonding interactions, the strength of which varies with the nature of the chalcogen (S vs Se). While the perfectly two-dimensional "brick-wall" packing pattern associated with the Cmc21 phase of QT is not found for QS, all three phases of QS are nonetheless small band gap semiconductors, with σRT ranging from 10-5 S cm-1 for the P21/ c phase to 10-3 S cm-1 for the R3 c phase. The bandwidths of the valence and conduction bands increase with applied pressure, leading to an increase in conductivity and a decrease in thermal activation energy Eact. For the R3 c phase, band gap closure to yield an organic molecular metal with a σRT of ∼102 S cm-1 occurs at 6 GPa. Band gaps estimated from density functional theory band structure calculations on the ambient- and high-pressure crystal structures of QT and QS correlate well with those obtained experimentally.

The Power of Packing: Metallization of an Organic Semiconductor.

Benzoquino-bis-1,2,3-dithiazole 5 is a closed shell, antiaromatic 16π-electron zwitterion with a small HOMO-LUMO gap. Its crystal structure consists of planar ribbon-like molecular arrays packed into offset layers to generate a "brick-wall" motif with strong 2D interlayer electronic interactions. The spread of the valence and conduction bands, coupled with the narrow HOMO-LUMO gap, affords a small band gap semiconductor with σRT = 1 × 10-3 S cm-1 and Eact = 0.14 eV for transport within the brick-wall arrays. Closure of the band gap to form an all-organic molecular metal with σRT > 101 S cm-1 can be achieved by the application of pressure to 8 GPa.

Fine Tuning the Performance of Multiorbital Radical Conductors by Substituent Effects.

A critical feature of the electronic structure of oxobenzene-bridged bisdithiazolyl radicals 2 is the presence of a low-lying LUMO which, in the solid state, improves charge transport by providing additional degrees of freedom for electron transfer. The magnitude of this multiorbital effect can be fine-tuned by variations in the π-electron releasing/accepting nature of the basal ligand. Here we demonstrate that incorporation of a nitro group significantly stabilizes the LUMO, and hence lowers Ueff, the effective Coulombic barrier to charge transfer. The effect is echoed, at the molecular level, in the observed trend in Ecell, the electrochemical cell potential for 2 with R = F, H and NO2. The crystal structures of the MeCN and EtCN solvates of 2 with R = NO2 have been determined. In the EtCN solvate the radicals are dimerized, but in the MeCN solvate the radicals form superimposed and evenly spaced π-stacked arrays. This highly 1D material displays Pauli-like temperature independent paramagnetic behavior, with χTIP = 6 × 10-4 emu mol-1, but its charge transport behavior, with σRT near 0.04 S cm-1 and Eact = 0.05 eV, is more consistent with a Mott insulating ground state. High pressure crystallographic measurements confirm uniform compression of the π-stacked architecture with no phase change apparent up to 8 GPa. High pressure conductivity measurements indicate that the charge gap between the Mott insulator and metallic states can be closed near 6 GPa. These results are discussed in the light of DFT band structure calculations.

Spin Frustration in an Organic Radical Ion Salt Based on a Kagome-Coupled Chain Structure.

Electro-oxidation of the quinoidal bisdithiazole BT in dichloroethane in the presence of [Bu4N][GaBr4] affords the 1:1 radical ion salt [BT][GaBr4], crystals of which belong to the trigonal space group P3. The packing pattern of the radical cations provides a rare example of an organic kagome basket structure, with S = 1/2 radical ion chains located at the triangular corners of a trihexagonal lattice. Magnetic measurements over a wide temperature range from 30 mK to 300 K suggest strongly frustrated AFM interactions on the scale of J/kb ∼ 30 K, but reveal no anomalies that would be associated with magnetic order. These observations are discussed in terms of the symmetry allowed magnetic interactions within and between the frustrated layers.

(18)F-FDG PET/CT to assess response and guide risk-stratified follow-up after chemoradiotherapy for oropharyngeal squamous cell carcinoma.

PURPOSE: To evaluate the use of (18)F-FDG PET/CT as the principal investigation to assess tumour response, to determine the need for further surgery and to guide follow-up following radical chemoradiotherapy for stage III/IV oropharyngeal squamous cell carcinoma (OPSCC). METHODS: A retrospective analysis was undertaken in 146 patients treated at our centre with radical chemoradiotherapy for OPSCC and who had a PET/CT scan to assess response. According to the PET/CT findings, patients were divided into four groups and recommendations: (1) complete metabolic response (enter clinical follow-up); (2) low-level uptake only (follow-up PET/CT scan in 12 weeks); (3) residual uptake suspicious for residual disease (further investigation with or without neck dissection); and (4) new diagnosis of distant metastatic disease (palliative treatment options). RESULTS: The initial PET/CT scan was performed at a median of 12.4 weeks (range 4.3 - 21.7 weeks) following treatment. Overall sensitivity and specificity rates were 92.0 % (74.0 - 99.0 %) and 85 % (77.5 - 90.9 %). Of the 146 patients, 90 (62 %) had a complete response and had estimated 3-year overall and disease-free survival rates of 91.9 % (85.6 - 98.2 %) and 85.6 % (78.0 - 93.2 %), respectively, 17 (12 %) had residual low-level uptake only (with two having confirmed residual disease on subsequent PET/CT, both surgically salvaged), 30 (21 %) had suspicious residual uptake (12 proceeded to neck dissection; true positive rate at surgery 33 %). HPV-positive patients with reassuring PET/CT findings had an estimated 3-year progression-free survival rate of 91.7 % (85.2 - 98.2 %), compared with 66.2 % (41.5 - 90.9 %) of HPV-negative patients. CONCLUSION: A strategy of using PET/CT results alongside clinical examination to help select patients for salvage surgery appears successful. Despite a complete response on the 12-week PET/CT scan, HPV-negative patients have a significant risk of disease relapse in the following 2 years and further studies to assess whether surveillance imaging in this group could improve outcomes are warranted.

Quantification of lymph nodes in the central compartment of the neck: a cadaveric study.

Differentiated thyroid cancer (DTC) accounts for over 90 % of thyroid malignancies, and is frequently associated with central neck compartment nodal metastasis that requires a therapeutic central compartment neck dissection (CCND) for clinically evident nodes. Current knowledge on the expected lymph node yield from a CCND is limited, compared with data on the lateral neck. The aim of our study was to accurately quantify nodal yield from the cadaveric central neck compartment. Twenty-eight cadaveric necks were dissected and the central neck compartment was subdivided into four regions: pre-laryngeal (delphian), pre-tracheal, right and left para-tracheal regions. Each cadaver had a thyroid gland, which was also removed, and the CCND tissue in each compartment was processed and examined by a consultant histopathologist. Only lymphoid tissue with a defined microscopic fibrous capsule and subcapsular sinus was included in the node count. The median total lymph node count per cadaver was four (range 1-16), with a median of one node detectable in each para-tracheal region (range 0-7) and the pre-tracheal region (range 0-8). The median pre-laryngeal node count was 0 (range 0- 2). The average lymph node size across all compartments was 2.9 mm. This is the first European study to assess cadaveric central neck lymph nodes and establish baseline counts for nodal yield. If a prophylactic or therapeutic CCND is required during thyroid surgery, those involved in DTC management must recognise that there is a wide range, and low median yield of central neck compartment lymph nodes.