Dosimetric impact of contour editing on CT and MRI deep-learning autosegmentation for brain OARs.

PURPOSE: To establish the clinical applicability of deep-learning organ-at-risk autocontouring models (DL-AC) for brain radiotherapy. The dosimetric impact of contour editing, prior to model training, on performance was evaluated for both CT and MRI-based models. The correlation between geometric and dosimetric measures was also investigated to establish whether dosimetric assessment is required for clinical validation. METHOD: CT and MRI-based deep learning autosegmentation models were trained using edited and unedited clinical contours. Autosegmentations were dosimetrically compared to gold standard contours for a test cohort. D1%, D5%, D50%, and maximum dose were used as clinically relevant dosimetric measures. The statistical significance of dosimetric differences between the gold standard and autocontours was established using paired Student's t-tests. Clinically significant cases were identified via dosimetric headroom to the OAR tolerance. Pearson's Correlations were used to investigate the relationship between geometric measures and absolute percentage dose changes for each autosegmentation model. RESULTS: Except for the right orbit, when delineated using MRI models, the dosimetric statistical analysis revealed no superior model in terms of the dosimetric accuracy between the CT DL-AC models or between the MRI DL-AC for any investigated brain OARs. The number of patients where the clinical significance threshold was exceeded was higher for the optic chiasm D1% than other OARs, for all autosegmentation models. A weak correlation was consistently observed between the outcomes of dosimetric and geometric evaluations. CONCLUSIONS: Editing contours before training the DL-AC model had no significant impact on dosimetry. The geometric test metrics were inadequate to estimate the impact of contour inaccuracies on dose. Accordingly, dosimetric analysis is needed to evaluate the clinical applicability of DL-AC models in the brain.

The benefit of MR-only radiotherapy treatment planning for anal and rectal cancers: A planning study.

INTRODUCTION: Limited evidence exists showing the benefit of magnetic resonance (MR)-only radiotherapy treatment planning for anal and rectal cancers. This study aims to assess the impact of MR-only planning on target volumes (TVs) and treatment plan doses to organs at risks (OARs) for anal and rectal cancers versus a computed tomography (CT)-only pathway. MATERIALS AND METHODS: Forty-six patients (29 rectum and 17 anus) undergoing preoperative or radical external beam radiotherapy received CT and T2 MR simulation. TV and OARs were delineated on CT and MR, and volumetric arc therapy treatment plans were optimized independently (53.2 Gy/28 fractions for anus, 45 Gy/25 fractions for rectum). Further treatment plans assessed gross tumor volume (GTV) dose escalation. Differences in TV volumes and OAR doses, in terms of Vx Gy (organ volume (%) receiving x dose (Gy)), were assessed. RESULTS: MR GTV and primary planning TV (PTV) volumes systematically reduced by 13 cc and 98 cc (anus) and 44 cc and 109 cc (rectum) respectively compared to CT volumes. Statistically significant OAR dose reductions versus CT were found for bladder and uterus (rectum) and bladder, penile bulb, and genitalia (anus). With GTV boosting, statistically significant dose reductions were found for sigmoid, small bowel, vagina, and penile bulb (rectum) and vagina (anus). CONCLUSION: Our findings provide evidence that the introduction of MR (whether through MR-only or CT-MR pathways) to radiotherapy treatment planning for anal and rectal cancers has the potential to improve treatments. MR-related OAR dose reductions may translate into less treatment-related toxicity for patients or greater ability to dose escalate.

4D-Precise: Learning-based 3D motion estimation and high temporal resolution 4DCT reconstruction from treatment 2D+t X-ray projections.

BACKGROUND AND OBJECTIVE: In radiotherapy treatment planning, respiration-induced motion introduces uncertainty that, if not appropriately considered, could result in dose delivery problems. 4D cone-beam computed tomography (4D-CBCT) has been developed to provide imaging guidance by reconstructing a pseudo-motion sequence of CBCT volumes through binning projection data into breathing phases. However, it suffers from artefacts and erroneously characterizes the averaged breathing motion. Furthermore, conventional 4D-CBCT can only be generated post-hoc using the full sequence of kV projections after the treatment is complete, limiting its utility. Hence, our purpose is to develop a deep-learning motion model for estimating 3D+t CT images from treatment kV projection series. METHODS: We propose an end-to-end learning-based 3D motion modelling and 4DCT reconstruction model named 4D-Precise, abbreviated from Probabilistic reconstruction of image sequences from CBCT kV projections. The model estimates voxel-wise motion fields and simultaneously reconstructs a 3DCT volume at any arbitrary time point of the input projections by transforming a reference CT volume. Developing a Torch-DRR module, it enables end-to-end training by computing Digitally Reconstructed Radiographs (DRRs) in PyTorch. During training, DRRs with matching projection angles to the input kVs are automatically extracted from reconstructed volumes and their structural dissimilarity to inputs is penalised. We introduced a novel loss function to regulate spatio-temporal motion field variations across the CT scan, leveraging planning 4DCT for prior motion distribution estimation. RESULTS: The model is trained patient-specifically using three kV scan series, each including over 1200 angular/temporal projections, and tested on three other scan series. Imaging data from five patients are analysed here. Also, the model is validated on a simulated paired 4DCT-DRR dataset created using the Surrogate Parametrised Respiratory Motion Modelling (SuPReMo). The results demonstrate that the reconstructed volumes by 4D-Precise closely resemble the ground-truth volumes in terms of Dice, volume similarity, mean contour distance, and Hausdorff distance, whereas 4D-Precise achieves smoother deformations and fewer negative Jacobian determinants compared to SuPReMo. CONCLUSIONS: Unlike conventional 4DCT reconstruction techniques that ignore breath inter-cycle motion variations, the proposed model computes both intra-cycle and inter-cycle motions. It represents motion over an extended timeframe, covering several minutes of kV scan series.

Simulation of ultrafast photodynamics of pyrrole with a multiconfigurational Ehrenfest method.

We report the first results of ab initio multiconfigurational Ehrenfest simulations of pyrrole photodynamics. We note that, in addition to the two intersections of 1(1)A2 and 1(1)B1 states with the ground state 1(1)A1, which are known to be responsible for N-H bond fission, another intersection between the 1(2)A2 and 1(2)B1 states of the resulting molecular radical becomes important after the departure of the H atom. This intersection, which is effectively between the two lowest electronic states of the pyrrolyl radical, may play a significant role in explaining the branching ratio between the two states observed experimentally. The exchange of population between the two states of pyrrolyl occurs on a longer scale than that of N-H bond fission.

DragNet: Learning-based deformable registration for realistic cardiac MR sequence generation from a single frame.

Deformable image registration (DIR) can be used to track cardiac motion. Conventional DIR algorithms aim to establish a dense and non-linear correspondence between independent pairs of images. They are, nevertheless, computationally intensive and do not consider temporal dependencies to regulate the estimated motion in a cardiac cycle. In this paper, leveraging deep learning methods, we formulate a novel hierarchical probabilistic model, termed DragNet, for fast and reliable spatio-temporal registration in cine cardiac magnetic resonance (CMR) images and for generating synthetic heart motion sequences. DragNet is a variational inference framework, which takes an image from the sequence in combination with the hidden states of a recurrent neural network (RNN) as inputs to an inference network per time step. As part of this framework, we condition the prior probability of the latent variables on the hidden states of the RNN utilised to capture temporal dependencies. We further condition the posterior of the motion field on a latent variable from hierarchy and features from the moving image. Subsequently, the RNN updates the hidden state variables based on the feature maps of the fixed image and the latent variables. Different from traditional methods, DragNet performs registration on unseen sequences in a forward pass, which significantly expedites the registration process. Besides, DragNet enables generating a large number of realistic synthetic image sequences given only one frame, where the corresponding deformations are also retrieved. The probabilistic framework allows for computing spatio-temporal uncertainties in the estimated motion fields. Our results show that DragNet performance is comparable with state-of-the-art methods in terms of registration accuracy, with the advantage of offering analytical pixel-wise motion uncertainty estimation across a cardiac cycle and being a motion generator. We will make our code publicly available.

Collision-induced dissociation of halide ion-arginine complexes: evidence for anion-induced zwitterion formation in gas-phase arginine.

We report the first low-energy collisional-induced dissociation studies of the X(-)·arginine (X(-) = F(-), Cl(-), Br(-), I(-), NO(3)(-), ClO(3)(-)) series of clusters to investigate the novel phenomenom of anion-induced zwitterion formation in a gas-phase amino acid. Fragmentation of the small halide ion clusters (F(-)·arginine and Cl(-)·arginine) is dominated by deprotonation of the arginine, whereas the major fragmentation channel for the largest ion clusters (I(-)·arginine and ClO(3)(-)·arginine) corresponds to simple cluster fission into the ion and neutral molecule. However, the fragmentation profiles of Br(-)·arginine and NO(3)(-)·arginine, display distinctive features that are consistent with the presence of the zwitterionic form of the amino acid in these clusters. The various dissociation pathways have been studied as a function of % collision energy and are discussed in comparison to the fragmentation profiles of protonated and deprotonated arginine. Electronic structure calculations are presented for Br(-)·arginine to support the presence of the zwitterionic amino acid in this complex. The results obtained in this work provide important information on the low-energy potential energy surfaces of these anion-amino acid clusters and reveal the presence of several overlapping surfaces in the low-energy region for the Br(-)·arginine and NO(3)(-)·arginine systems.

Dose-Response Analysis Describes Particularly Rapid Repopulation of Non-Small Cell Lung Cancer during Concurrent Chemoradiotherapy.

(1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low α/ß ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction ≤3 Gy over 16-60 days. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and α/ß to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour α/ß ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low α/ß ratio suggests hypofractionation should be efficacious.

Conformer-independent ureidoimidazole motifs--tools to probe conformational and tautomeric effects on the molecular recognition of triply hydrogen-bonded heterodimers.

Linear arrays of hydrogen bonds are useful for the reversible assembly of "stimuli-responsive" supramolecular materials. There is thus an ongoing requirement for easy-to-synthesise motifs that are capable of presenting hydrogen-bonding functionality in a predictable manner, such that high-affinity and high-fidelity recognition occurs. The design of linear arrays is made challenging as a consequence of their ability to adopt multiple conformational and tautomeric configurations; with each additional hydrogen-bonding heteroatom added to an array, the available tautomeric and conformational space increases and it can be difficult to anticipate where unproductive conformers/tautomers will arise. This paper describes a detailed study on the complementary ureidoimidazole donor-donor-acceptor (DDA) array (1) and amidoisocytosine donor-acceptor-acceptor (DAA) array (2). A specific feature of 1 is that two degenerate, intramolecular hydrogen-bonded conformations are postulated, both of which present a DDA array that is complementary to appropriate DAA partners. 1D and 2D (1)H NMR spectroscopy, isothermal titration calorimetry, and ab initio structure calculations confirm 1 interacts with 2 (K(a) ≈ 33,000 M(-1) in CDCl(3)) in a conformer-independent fashion driven by enthalpy. Comparison of the binding behaviour of 1 with hexylamidocytosine (4) and amidonaphthyridine (5) provides insight on the role that intramolecular hydrogen-bonding plays in mediating affinity towards DAA partners.

Evidence for hydrogen bond network formation in microsolvated clusters of Pt(CN)4(2-): collision induced dissociation studies of Pt(CN)4(2-)·(H2O)(n) n = 1-4, and Pt(CN)4(2-)·(MeCN)(m) m = 1, 2 cluster ions.

Low-energy collision induced dissociation has been used to investigate the structure and stability of microsolvated clusters of the prototypical, aprotic multiply charged anion, Pt(CN)(4)(2-), i.e. Pt(CN)(4)(2-)·(H(2)O)(n) n = 1-4, Pt(CN)(4)(2-)·(MeCN)(m) m =1, 2, and Pt(CN)(4)(2-)·(H(2)O)(3)·MeCN. For all of the systems studied, the lowest energy fragmentation pathway was found to correspond to decay of the cluster with loss of the entire solvent ensemble. No sequential solvent evaporation was observed. These observations suggest that the Pt(CN)(4)(2-) solvent clusters studied here form hydrogen-bonded "surface solvated" structures. Electronic structure calculations are presented to support the experimental results. In addition, the detailed fragmentation patterns observed are interpreted with reference to the differential solvation of the ionic fragmentation and electron detachment potential energy surfaces of the core Pt(CN)(4)(2-) dianion. The results described represent some of the first experiments to probe the microsolvation of this important class of multiply charged anions.

Exploring nuclear motion through conical intersections in the UV photodissociation of phenols and thiophenol.

High-resolution time-of-flight measurements of H atom products from photolysis of phenol, 4-methylphenol, 4-fluorophenol, and thiophenol, at many UV wavelengths (lambda(phot)), have allowed systematic study of the influence of ring substituents and the heteroatom on the fragmentation dynamics. All dissociate by X-H (X = O, S) bond fission after excitation at their respective S(1)((1)pipi*)-S(0) origins and at all shorter wavelengths. The achieved kinetic energy resolution reveals population of selected vibrational levels of the various phenoxyl and thiophenoxyl coproducts, providing uniquely detailed insights into the fragmentation dynamics. Dissociation in all cases is deduced to involve nuclear motion on the (1)pisigma* potential energy surface (PES). The route to accessing this PES, and the subsequent dynamics, is seen to be very sensitive to lambda(phot) and substitution of the heteroatom. In the case of the phenols, dissociation after excitation at long lambda(phot) is rationalized in terms of radiationless transfer from S(1) to S(0) levels carrying sufficient O-H stretch vibrational energy to allow coupling via the conical intersection between the S(0) and (1)pisigma* PESs at longer O-H bond lengths. In contrast, H + C(6)H(5)O(X(2)B(1)) products formed after excitation at short lambda(phot) exhibit anisotropic recoil-velocity distributions, consistent with prompt dissociation induced by coupling between the photoprepared (1)pipi* excited state and the (1)pisigma* PES. The fragmentation dynamics of thiophenol at all lambda(phot) matches the latter behavior more closely, reflecting the different relative dispositions of the (1)pipi* and (1)pisigma* PESs. Additional insights are provided by the observed branching into the ground (X(2)B(1)) and first excited ((2)B(2)) states of the resulting C(6)H(5)S radicals.

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

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

Multicentre, deep learning, synthetic-CT generation for ano-rectal MR-only radiotherapy treatment planning.

BACKGROUND AND PURPOSE: Comprehensive dosimetric analysis is required prior to the clinical implementation of pelvic MR-only sites, other than prostate, due to the limited number of site specific synthetic-CT (sCT) dosimetric assessments in the literature. This study aims to provide a comprehensive assessment of a deep learning-based, conditional generative adversarial network (cGAN) model for a large ano-rectal cancer cohort. The following challenges were investigated; T2-SPACE MR sequences, patient data from multiple centres and the impact of sex and cancer site on sCT quality. METHOD: RT treatment position CT and T2-SPACE MR scans, from two centres, were collected for 90 ano-rectal patients. A cGAN model trained using a focal loss function, was trained and tested on 46 and 44 CT-MR ano-rectal datasets, paired using deformable registration, respectively. VMAT plans were created on CT and recalculated on sCT. Dose differences and gamma indices assessed sCT dosimetric accuracy. A linear mixed effect (LME) model assessed the impact of centre, sex and cancer site. RESULTS: A mean PTV D95% dose difference of 0.1% (range: -0.5% to 0.7%) was found between CT and sCT. All gamma index (1%/1 mm threshold) measurements were >99.0%. The LME model found the impact of modality, cancer site, sex and centre was clinically insignificant (effect ranges: -0.4% and 0.3%). The mean dose difference for all OAR constraints was 0.1%. CONCLUSION: Focal loss cGAN models using T2-SPACE MR sequences from multiple centres can produce generalisable, dosimetrically accurate sCTs for ano-rectal cancers.

Pi sigma* excited states in molecular photochemistry.

The last few years have seen a surge in interest (both theoretical and experimental) in the photochemistry of heteroaromatic molecules (e.g. azoles, phenols), which has served to highlight the importance of dissociative excited states formed by electron promotion to sigma* molecular orbitals. Such excited states--which, for brevity, are termed pi sigma* states in this Perspective article--may be populated by direct photo-excitation (though the transition cross-sections are intrinsically small), or indirectly, by non-adiabatic coupling from an optically 'bright' excited state (e.g. an excited state resulting from pi* <--pi excitation). The analogous pi sigma* excited states in prototypical hydride molecules like H(2)O and NH(3) have long been recognised. They have served as test-beds for developing concepts like Rydbergisation, conical intersections (CIs) between potential energy surfaces, and for investigating the ways in which non-adiabatic couplings at such CIs influence the eventual photofragmentation dynamics. This Perspective article seeks to highlight the continuity of behaviour revealed by the earlier small molecule studies and by the more recent studies of heteroaromatic systems, and to illustrate the photochemical importance of pi sigma* excited states in many broad families of molecules. Furthermore, the dynamical influence of such excited states is not restricted to closed shell species; the Article concludes with a brief consideration of the consequences of populating sigma* orbitals in free radical species, in molecular cations, and in dissociative electron attachment processes.

Noncovalent interactions in the gas-phase conformers of anionic iduronate (methyl 2-o-sulfo-α-L-iduronate): variation of subconformer versus ring conformer energetics for a prototypical anionic monosaccharide studied using computational methods.

The conformational preferences of the prototypical anionic monosaccharide (methyl 2-O-sulfo-α-L-iduronate) have been studied at various computational levels to investigate the energetic variation of 17 subconformers associated with the (4)C(1), (2)S(0), (5)S(1), and (1)C(4) ring conformers. These calculations include the first fully optimized MP2 calculations that have been performed for an anionic sugar system, and therefore allow an assessment of the performance of a group of DFT functionals (B3LYP, PW91PW91, and M05-2X) for treating the noncovalent dispersion and anomeric effects that are present in this system. We find that the recently developed M05-2X functional of Truhlar and co-workers [Y. Zhao, N. E. Schultz, D. G. Truhlar, J. Chem. Theory Comput., 2006, 2, 364] reproduces the MP2 results most closely, thus indicating that it may well be suitable for computational studies of larger ionic saccharides. Most importantly, the results presented indicate that it is crucial to consider the subconformers (which correspond to rearrangements of the sugar-ring side-chains) of the main ring-conformers in order to obtain a reliable overview of the potential energy surface of such systems. We find that the lowest isolated (gas-phase) conformer corresponds to a (4)C(1) chair conformer, which displays a pair of strong C(3)-OH···SO(3)(-) and OMe···SO(3)(-) electrostatic hydrogen-bonding interactions, coupled with a looser C(4)-OH···SO(3)(-) interaction. Overall, the relative energies of the subconformers appear to be straightforwardly related to the number of hydrogen-bonding interactions that each conformer displays among its pendant functional groups.

Ultraviolet photodissociation dynamics of 2-methyl, 3-furanthiol: tuning pi-conjugation in sulfur substituted heterocycles.

H atom loss following ultraviolet photoexcitation of 2-methyl, 3-furanthiol (2M,3FT) at many wavelengths in the range 269 nm > or = lambda(phot) > or = 210 nm and at 193 nm has been investigated by H (Rydberg) atom photofragment translational spectroscopy. The photodissociation dynamics of this SH decorated aromatic ring system are contrasted with that of thiophenol (Devine et al. J. Phys. Chem. A 2008, 112, 9563), the excited electronic states of which show a different energetic ordering. Ab initio theory and experiment find that the first excited state of 2M,3FT is formed by electron promotion from an orbital comprised of an admixture of the S lone pair and the furan pi system (n/pi) to a sigma* orbital centered on the S-H bond. Photoexcitation at long wavelengths results in population of the (1)(n/pi)sigma* excited state, prompt S-H bond fission, H atoms displaying a (nonlimiting) perpendicular recoil velocity distribution, and partner radicals formed in selected low vibrational levels of the ground state. This energy disposal can be rationalized by considering the forces acting as the excited molecules evolve on the (1)(n/pi)sigma* potential energy surface (PES). Energy conservation arguments, together with the product vibrational state analysis, yield a value of 31320 +/- 100 cm(-1) for the S-H bond strength in 2M,3FT. Excitation at shorter wavelengths (lambda(phot) < or = 230 nm) is deduced to populate one or more (diabatically bound) (1)(n/pi)pi* excited states which decay by coupling to the (1)(n/pi)sigma* PES and/or to high vibrational levels of the electronic ground state.

Exploring the mechanisms of H atom loss in simple azoles: Ultraviolet photolysis of pyrazole and triazole.

The photophysics of gas phase pyrazole (C(3)N(2)H(4)) and 2H-1,2,3-triazole (C(2)N(3)H(3)) molecules following excitation at wavelengths in the range 230 nm>or=lambda(phot)>or=193.3 nm has been investigated using the experimental technique of H (Rydberg) atom photofragment translational spectroscopy. The findings are compared with previous studies of pyrrole (C(4)N(1)H(5)) and imidazole (C(3)N(2)H(4)), providing a guide to H atom loss dynamics in simple N-containing heterocycles. CASPT2 theoretical methods have been employed to validate these findings. Photoexcitation of pyrazole at the longest wavelengths studied is deduced to involve pi( *)<--pi excitation, but photolysis at lambda(phot)or=193.3 nm. The N-H bond strength of pyrazole is determined as 37 680+/-40 cm(-1), significantly greater than that of the N-H bonds in pyrrole and imidazole. The correlation between the photochemistry of azoles and the number and position of nitrogen atoms within the ring framework is discussed in terms of molecular symmetry and orbital electron density. A photodissociation channel yielding H atoms with low kinetic energies is also clearly evident in both pyrazole and 2H-1,2,3-triazole. Companion studies of pyrazole-d(1) suggest that these slow H atoms arise primarily from the N-H site, following pi( *)<--pi excitation, and subsequent internal conversion and/or unintended multiphoton absorption processes.

Chemoradiotherapy of locally-advanced non-small cell lung cancer: Analysis of radiation dose-response, chemotherapy and survival-limiting toxicity effects indicates a low α/ß ratio.

PURPOSE: To analyse changes in 2-year overall survival (OS2yr) with radiotherapy (RT) dose, dose-per-fraction, treatment duration and chemotherapy use, in data compiled from prospective trials of RT and chemo-RT (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC). MATERIAL AND METHODS: OS2yr data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0 Gy. An initial model considering dose, dose-per-fraction and RT duration was fitted using maximum-likelihood techniques. Model extensions describing chemotherapy effects and survival-limiting toxicity at high doses were assessed using likelihood-ratio testing, the Akaike Information Criterion (AIC) and cross-validation. RESULTS: A model including chemotherapy effects and survival-limiting toxicity described the data significantly better than simpler models (p < 10-14), and had better AIC and cross-validation scores. The fitted α/ß ratio for LA-NSCLC was 4.0 Gy (95%CI: 2.8-6.0 Gy), repopulation negated 0.38 (95%CI: 0.31-0.47) Gy EQD2/day beyond day 12 of RT, and concurrent CRT increased the effective tumour EQD2 by 23% (95%CI: 16-31%). For schedules delivered in 2 Gy fractions over 40 days, maximum modelled OS2yr for RT was 52% and 38% for stages IIIA and IIIB NSCLC respectively, rising to 59% and 42% for CRT. These survival rates required 80 and 87 Gy (RT or sequential CRT) and 67 and 73 Gy (concurrent CRT). Modelled OS2yr rates fell at higher doses. CONCLUSIONS: Fitted dose-response curves indicate that gains of ~10% in OS2yr can be made by escalating RT and sequential CRT beyond 64 Gy, with smaller gains for concurrent CRT. Schedule acceleration achieved via hypofractionation potentially offers an additional 5-10% improvement in OS2yr. Further 10-20% OS2yr gains might be made, according to the model fit, if critical normal structures in which survival-limiting toxicities arise can be identified and selectively spared.

Intramolecular amide stacking and its competition with hydrogen bonding in a small foldamer.

Attractive interactions between two carboxamide groups in a "stacked" geometry are explored under isolated molecule conditions. Infrared spectra of single conformations of a small gamma-peptide, Ac-gamma(2)-hPhe-NHMe, reveal the presence of a conformation in which the two amide planes are approximately parallel with the amide dipoles in an antialigned orientation. This stacked conformation is energetically comparable to conformations that contain an intramolecular amide-amide H-bond. Amide stacking interactions can compete with H-bonding in circumstances where the amide groups can be brought into a stacking configuration with minimal strain, opening the way for its use in the design of future foldamer structures.

Exploring the time-scales of H-atom detachment from photoexcited phenol-h(6) and phenol-d(5): statistical vs nonstatistical decay.

The prevalence of (1)pi sigma* states in the photochemistry of heteroaromatics is becoming increasingly clear from the recent literature. Photodissociation measurements have shown that following excitation of phenol molecules above the S(1)/S(2) conical intersection, H-atoms are eliminated with two distinct ranges of kinetic energy release. Those with high kinetic energy are attributed to direct dissociation while those with low kinetic energy are traditionally attributed to indirect dissociation or statistical unimolecular decay, both pathways giving electronic ground-state phenoxyl fragments. Using a combination of femtosecond pump/probe spectroscopy and velocity map ion imaging techniques, the time and energy resolved H-atom elimination in phenol-h(6) and phenol-d(5), following excitation at 200 nm has been measured. At the lowest kinetic energies, the H-atom elimination from phenol-d(5) occurs in <150 fs, in sharp contrast to what one expects from a statistical decay process. This implies that these H-atoms are formed through a direct dissociation process yielding electronically excited phenoxyl fragments.

High-resolution and dispersed fluorescence examination of vibronic bands of tryptamine: spectroscopic signatures for L(a)/L(b) mixing near a conical intersection.

The vibronic spectrum of tryptamine has been studied in a molecular beam up to an energy of 930 cm(-1) above the S(0)-S(1) electronic origin. Rotationally resolved electronic spectra reveal a rotation of the transition dipole moment direction from (1)L(b) to (1)L(a) beginning about 400 cm(-1) above the (1)L(b) origin. In this region, vibronic bands which appear as single bands at low resolution contain rotational structure from more than one vibronic transition. The number of these transitions closely tracks the total vibrational state density in the (1)L(b) electronic state as a function of internal energy. Dispersed fluorescence spectra show distinct spectroscopic signatures attributable to the (1)L(b) and (1)L(a) character of the mixed excited-state wave functions. The data set is used to extrapolate to a (1)L(a) origin about 400 cm(-1) above the (1)L(b) origin. DFT-MRCI calculations locate a conical intersection between these two states at about 900 cm(-1) above the L(a) origin, whose structure is located along a tuning coordinate which is close to a linear interpolation between the two excited-state geometries. Along the branching coordinate, there is no barrier from (1)L(a) to (1)L(b). A two-tier model for the vibronic coupling is proposed.