Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism.

BACKGROUND: PET imaging of 18F-fluorodeoxygucose (FDG) is used widely for tumour staging and assessment of treatment response, but the biology associated with FDG uptake is still not fully elucidated. We therefore carried out gene set enrichment analyses (GSEA) of RNA sequencing data to find KEGG pathways associated with FDG uptake in primary breast cancers. METHODS: Pre-treatment data were analysed from a window-of-opportunity study in which 30 patients underwent static and dynamic FDG-PET and tumour biopsy. Kinetic models were fitted to dynamic images, and GSEA was performed for enrichment scores reflecting Pearson and Spearman coefficients of correlations between gene expression and imaging. RESULTS: A total of 38 pathways were associated with kinetic model flux-constants or static measures of FDG uptake, all positively. The associated pathways included glycolysis/gluconeogenesis ('GLYC-GLUC') which mediates FDG uptake and was associated with model flux-constants but not with static uptake measures, and 28 pathways related to immune-response or inflammation. More pathways, 32, were associated with the flux-constant K of the simple Patlak model than with any other imaging index. Numbers of pathways categorised as being associated with individual micro-parameters of the kinetic models were substantially fewer than numbers associated with flux-constants, and lay around levels expected by chance. CONCLUSIONS: In pre-treatment images GLYC-GLUC was associated with FDG kinetic flux-constants including Patlak K, but not with static uptake measures. Immune-related pathways were associated with flux-constants and static uptake. Patlak K was associated with more pathways than were the flux-constants of more complex kinetic models. On the basis of these results Patlak analysis of dynamic FDG-PET scans is advantageous, compared to other kinetic analyses or static imaging, in studies seeking to infer tumour-to-tumour differences in biology from differences in imaging. Trial registration NCT01266486, December 24th 2010.

Reduced Fractionation in Lung Cancer Patients Treated with Curative-intent Radiotherapy during the COVID-19 Pandemic.

Patients treated with curative-intent lung radiotherapy are in the group at highest risk of severe complications and death from COVID-19. There is therefore an urgent need to reduce the risks associated with multiple hospital visits and their anti-cancer treatment. One recommendation is to consider alternative dose-fractionation schedules or radiotherapy techniques. This would also increase radiotherapy service capacity for operable patients with stage I-III lung cancer, who might be unable to have surgery during the pandemic. Here we identify reduced-fractionation for curative-intent radiotherapy regimes in lung cancer, from a literature search carried out between 20/03/2020 and 30/03/2020 as well as published and unpublished audits of hypofractionated regimes from UK centres. Evidence, practical considerations and limitations are discussed for early-stage NSCLC, stage III NSCLC, early-stage and locally advanced SCLC. We recommend discussion of this guidance document with other specialist lung MDT members to disseminate the potential changes to radiotherapy practices that could be made to reduce pressure on other departments such as thoracic surgery. It is also a crucial part of the consent process to ensure that the risks and benefits of undergoing cancer treatment during the COVID-19 pandemic and the uncertainties surrounding toxicity from reduced fractionation have been adequately discussed with patients. Furthermore, centres should document all deviations from standard protocols, and we urge all colleagues, where possible, to join national/international data collection initiatives (such as COVID-RT Lung) aimed at recording the impact of the COVID-19 pandemic on lung cancer treatment and outcomes.

The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer.

PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients.

Validation of a prototype DiodeAir for small field dosimetry.

Standard commercial diode detectors over-respond within small radiation fields, an effect largely attributable to the relatively high mass-density of silicon. However, Monte Carlo studies can be used to optimise dosimeter designs and have demonstrated that 'mass-density compensation'-for example, introducing a low-density air-gap upstream of a diode's high-density silicon volume-can substantially improve instrument response. In this work we used egs_chamber Monte Carlo simulations to predict the ideal air-gap thickness for a PTW 60017 unshielded diode detector. We then developed a prototype instrument incorporating that air-gap and, for a 6 MV linac, tested it experimentally against EBT3 film. We also tested a further three prototypes with different air-gap thicknesses. Our results demonstrate that for a 10 × 10 cm(2) reference field the DiodeAir, a PTW 60017 diode with a built-in air-gap of 1 mm, has on-axis correction factors near unity. Laterally the DiodeAir performs very well off-axis and reports FWHM and penumbra values consistent with those measured using EBT3. For PDD measurement, the performance of the DiodeAir matches that of the original PTW 60017. The experimental focus of this work was 6 MV but we also simulated the on-axis response of the DiodeAir within 15 MV beams and found that our modification proved robust to this substantial increase in beam energy. However, the original diode 60017 does exhibit low energy scatter dependencies and may over-respond to high linac dose-rates such that applying the mass-density compensation method to an alternative instrument (particularly a diamond detector) could ultimately take us even closer to the small-field ideal.

Mass-density compensation can improve the performance of a range of different detectors under non-equilibrium conditions.

Dosimeters often consist of several components whose mass densities differ substantially from water. These components cause small-field correction factors to vary significantly as lateral electronic equilibrium breaks down. Even amongst instruments designed for small-field dosimetry, inter-detector variation in the correction factors associated with very small (∼0.5 cm) fields can amount to tens of per cent. For a given dosimeter, small-field correction factors vary not only with field size but also with detector azimuthal angle and position within the field. Furthermore the accurate determination of these factors typically requires time-intensive Monte Carlo simulations. Thus, if achievable, 'correction factor free' small-field dosimetry would be highly desirable. This study demonstrates that a new generation of mass-density compensated detectors could take us towards this goal. Using a 6 MV beam model, it shows that 'mass-density compensation' can be utilized to improve the performance of a range of different detectors under small-field conditions. Non-sensitive material of appropriate mass-density is incorporated into detector designs in order to make the instruments behave as if consisting only of water. The dosimeter perturbative effects are then reduced to those associated with volume averaging. An even better solution-which modifies detectors to obtain profiles that look like those measured by a point-like water structure-is also considered. Provided that adequate sensitivity can be achieved for a small measurement volume, this study shows that it may be possible to use mass-density compensation (and Monte Carlo-driven design) to produce a solid-state dosimeter/ionization chamber with a near-perfect non-equilibrium response.

Detector density and small field dosimetry: integral versus point dose measurement schemes.

PURPOSE: The Alfonso et al. [Med. Phys. 35, 5179-5186 (2008)] formalism for small field dosimetry proposes a set of correction factors (kQclin,Qmsrfclin,fmsr) which account for differences between the detector response in nonstandard (clinical) and machine-specific-reference fields. In this study, the Monte Carlo method was used to investigate the viability of such small field correction factors for four different detectors irradiated under a variety of conditions. Because kQclin,Qmsrfclin,fmsr values for single detector position measurements are influenced by several factors, a new theoretical formalism for integrated-detector-position [dose area product (DAP)] measurements is also presented and was tested using Monte Carlo simulations. METHODS: A BEAMnrc linac model was built and validated for a Varian Clinac iX accelerator. Using the egs++ geometry package, detailed virtual models were built for four different detectors: a PTW 60012 unshielded diode, a PTW 60003 Diamond detector, a PTW 31006 PinPoint (ionization chamber), and a PTW 31018 MicroLion (liquid-filled ionization chamber). The egs_chamber code was used to investigate the variation of kQclin,Qmsrfclin,fmsr with detector type, detector construction, field size, off-axis position, and the azimuthal angle between the detector and beam axis. Simulations were also used to consider the DAP obtained by each detector: virtual detectors and water voxels were scanned through high resolution grids of positions extending far beyond the boundaries of the fields under consideration. RESULTS: For each detector, the correction factor (kQclin,Qmsrfclin,fmsr) was shown to depend strongly on detector off-axis position and detector azimuthal angle in addition to field size. In line with previous studies, substantial interdetector variation was also observed. However, it was demonstrated that by considering DAPs rather than single-detector-position dose measurements the high level of interdetector variation could be eliminated. Under small field conditions, mass density was found to be the principal determinant of water equivalence. Additionally, the mass densities of components outside the sensitive volumes were found to influence the detector response. CONCLUSIONS: kQclin,Qmsrfclin,fmsr values for existing detector designs depend on a host of variables and their calculation typically relies on the use of time-intensive Monte Carlo methods. Future moves toward density-compensated detector designs or DAP based protocols may simplify the methodology of small field dosimetry.

Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement.

In this overview we review and model how radiotherapy tumour control and complication rates vary with dose, fractionation, schedule duration, irradiated volume and use of chemotherapy for stage III non-small cell lung cancer (NSCLC), and use the modelling to study the effectiveness of different NSCLC dose-escalation approaches being developed in the UK. Data have been collated for pneumonitis, lung fibrosis, early and late oesophagitis, cord and cardiac complications, and local progression-free survival at 30 months. Dependences of the various end points on treatment-related factors are catalogued and analysed using the linear-quadratic incomplete repair model to account for dose and fractionation effects, making linear corrections for differences in schedule duration, and loosely characterising volume effects using parallel- and series-type concepts. Tolerance limits are calculated for the different end points and distilled into ranges of prescribed dose likely to be tolerable when delivered in 2.5 and 4 week radiation and 6 week chemoirradiation schedules using conformal techniques. Worthwhile ( approximately 20%) gains in 30 month local progression-free survival should be achievable at safely deliverable levels of dose escalation. The analysis suggests that longer schedules may be more beneficial than shorter ones, but this finding is governed by the relative rates of tumour and oesophageal accelerated proliferation, which are quite imprecisely known. Consequently escalated 2.5, 4 and 6 week schedules are being developed; each should lead to useful improvements in local control but it is not yet known which schedule will be most effective.

Cerebellopontine angle meningioma resulting in middle-ear polyp.

Extracranial spread of meningiomas to involve the middle ear is very rare. We present the case of a 43-year-old woman with a known cerebellopontine angle meningioma who subsequently presented with left-sided otalgia and a middle-ear mass extruding through the tympanic membrane due to local invasion of the meningioma. The tumour was excised surgically. A discussion of the relevant literature is also presented.

Quality assurance of a helical tomotherapy machine.

Helical tomotherapy has been developed at the University of Wisconsin, and 'Hi-Art II' clinical machines are now commercially manufactured. At the core of each machine lies a ring-gantry-mounted short linear accelerator which generates x-rays that are collimated into a fan beam of intensity-modulated radiation by a binary multileaf, the modulation being variable with gantry angle. Patients are treated lying on a couch which is translated continuously through the bore of the machine as the gantry rotates. Highly conformal dose-distributions can be delivered using this technique, which is the therapy equivalent of spiral computed tomography. The approach requires synchrony of gantry rotation, couch translation, accelerator pulsing and the opening and closing of the leaves of the binary multileaf collimator used to modulate the radiation beam. In the course of clinically implementing helical tomotherapy, we have developed a quality assurance (QA) system for our machine. The system is analogous to that recommended for conventional clinical linear accelerator QA by AAPM Task Group 40 but contains some novel components, reflecting differences between the Hi-Art devices and conventional clinical accelerators. Here the design and dosimetric characteristics of Hi-Art machines are summarized and the QA system is set out along with experimental details of its implementation. Connections between this machine-based QA work, pre-treatment patient-specific delivery QA and fraction-by-fraction dose verification are discussed.

Geometric leaf placement strategies.

Geometric leaf placement strategies for multileaf collimators (MLCs) typically involve the expansion of the beam's-eye-view contour of a target by a uniform MLC margin, followed by movement of the leaves until some point on each leaf end touches the expanded contour. Film-based dose-distribution measurements have been made to determine appropriate MLC margins--characterized through an index d90--for multileaves set using one particular strategy to straight lines lying at various angles to the direction of leaf travel. Simple trigonometric relationships exist between different geometric leaf placement strategies and are used to generalize the results of the film work into d90 values for several different strategies. Measured d90 values vary both with angle and leaf placement strategy. A model has been derived that explains and describes quite well the observed variations of d90 with angle. The d90 angular variations of the strategies studied differ substantially, and geometric and dosimetric reasoning suggests that the best strategy is the one with the least angular variation. Using this criterion, the best straightforwardly implementable strategy studied is a 'touch circle' approach for which semicircles are imagined to be inscribed within leaf ends, the leaves being moved until the semicircles just touch the expanded target outline.

The impact of clinical guidelines on surgical management in patients with thyroid cancer.

AIMS: Thyroid cancer is an uncommon but highly curable disease if treated optimally. The aim of this study was to determine whether clinical guidelines introduced locally at the beginning of 1999 were associated with better surgical outcome, using radioiodine uptake as a surrogate measure of completeness of thyroidectomy. MATERIALS AND METHODS: We reviewed the medical records of all patients with thyroid cancer referred to a cancer centre (n=176) 3 years before and 3 years after the introduction of guidelines. The uptake of radioiodine in the thyroid bed after thyroidectomy and before radioiodine ablation was used to assess the completeness of primary surgical treatment. RESULTS: The number of new cases referred to our centre increased from 80 in the 1996-1998 period to 94 during 1999-2001. This was largely because of an excess of papillary thyroid cancers. Documentation in the medical records of the pathological primary tumour size improved from 47.5% to 80.8% following the introduction of guidelines. A significant reduction in radioiodine uptake in the thyroid bed was observed following the introduction of guidelines (5.03% +/- 6.82 (SD) vs 2.75% +/- 5.10 (SD); P=0.005). Linear regression analysis of clinical variables indicated that the year of surgery was the only significant factor influencing radioiodine uptake in the thyroid bed (P=0.014). Twelve hospitals within the Northern Cancer Network carried out thyroid surgery for thyroid cancer in the pre-guideline era compared with seven hospitals in the post-guideline era. Surgeons who were members of the regional multidisciplinary thyroid cancer team operated on 35% of cases in the 1996-1998 period and 56.4% in the 1999-2001 period (P<0.01). CONCLUSIONS: The introduction of clinical guidelines in 1999 was associated with a reduction in the size of thyroid remnant after primary surgical treatment. This was accompanied by fewer hospitals undertaking thyroid surgery and more patients being operated on by surgeons who were members of the thyroid cancer multidisciplinary team.

Inflammatory myositis: a rare differential diagnosis of a neck lump.

Inflammatory myositis is an extremely rare benign inflammatory condition of skeletal muscle. It usually affects the extremities, and there are only 10 cases reported in the head and neck region. Its significance is that in this region it can be clinically mistaken for a neoplasm. We describe a case and review the literature.

Series model volume effects in a population of non-identical patients: how low is low?

Working with several mechanisms of critical local tissue damage, formulae are analytically derived that describe normal tissue complication probabilities (ntcps) for series-type radiotherapy complications arising in heterogeneous patient populations. Using the formulae, values are calculated for deltaD50(10)-the increase in dose leading to a 50% series-type complication rate (D50) when irradiated organ volume is reduced tenfold. From the structure of the ntcp formulae derived, it follows that dose-levels leading to clinically relevant serious complication rates (less than 5%) will change less with irradiated volume than will D50. Calculated values of deltaD50(10) for the heterogeneous series model are low-generally less than 6 Gy; such values are much lower than those calculated for the non-heterogeneous series model (27-37 Gy). These results suggest that if the dose-limiting toxicity of a radiotherapy treatment is a series-type complication with a local damage mechanism similar to any of those studied in this work, then even very substantial improvements in technique-leading to large reductions in highly dosed normal tissue volumes-would be unlikely to allow a useful degree of escalation of the dose delivered to the tumour, unless highly dosed normal tissue volumes can be reduced below the length-scale of a functional subunit.

Impact of dose-distribution uncertainties on rectal ntcp modeling. I: Uncertainty estimates.

A trial of nonescalated conformal versus conventional radiotherapy treatment of prostate cancer has been carried out at the Royal Marsden NHS Trust (RMH) and Institute of Cancer Research (ICR), demonstrating a significant reduction in the rate of rectal bleeding reported for patients treated using the conformal technique. The relationship between planned rectal dose-distributions and incidences of bleeding has been analyzed, showing that the rate of bleeding falls significantly as the extent of the rectal wall receiving a planned dose-level of more than 57 Gy is reduced. Dose-distributions delivered to the rectal wall over the course of radiotherapy treatment inevitably differ from planned distributions, due to sources of uncertainty such as patient setup error, rectal wall movement and variation in the absolute rectal wall surface area. In this paper estimates of the differences between planned and treated rectal dose-distribution parameters are obtained for the RMH/ICR nonescalated conformal technique, working from a distribution of setup errors observed during the RMH/ICR trial, movement data supplied by Lebesque and colleagues derived from repeat CT scans, and estimates of rectal circumference variations extracted from the literature. Setup errors and wall movement are found to cause only limited systematic differences between mean treated and planned rectal dose-distribution parameter values, but introduce considerable uncertainties into the treated values of some dose-distribution parameters: setup errors lead to 22% and 9% relative uncertainties in the highly dosed fraction of the rectal wall and the wall average dose, respectively, with wall movement leading to 21% and 9% relative uncertainties. Estimates obtained from the literature of the uncertainty in the absolute surface area of the distensible rectal wall are of the order of 13%-18%. In a subsequent paper the impact of these uncertainties on analyses of the relationship between incidences of bleeding and planned rectal dose-distributions is explored.

Impact of dose-distribution uncertainties on rectal ntcp modeling. II: Uncertainty implications.

A trial of nonescalated conformal versus conventional radiotherapy treatment of prostate cancer has been carried out at the Royal Marsden NHS Trust (RMH) and Institute of Cancer Research (ICR), demonstrating a significant reduction in the rate of rectal bleeding reported for patients treated using the conformal technique. The rate of bleeding has been shown to fall significantly as the extent of rectal wall receiving a planned dose-level in excess of 57 Gy is reduced. Dose-distributions delivered to the rectal wall over the course of radiotherapy treatment inevitably differ from planned distributions. In a previous paper estimates were obtained of the uncertainties in some planned rectal dose-distribution parameters generated by patient setup error, rectal wall movement and the variable degree of rectal wall distension. Here these uncertainties are combined to obtain estimates of the total planning uncertainties in rectal dose-distribution parameters thought likely, on the basis of mechanistic biological modeling, to correlate strongly with the complication rate. Working from these totaled uncertainty values, together with values of patient-to-patient and technique-to-technique differences in planned dose-distribution parameters, it can be inferred that the rectal dose-distribution uncertainties: (i) Have only a marginal impact on fits of a normal tissue complication probability (ntcp) model to RMH/ICR dose-distribution and grade 1, 2, 3 bleeding data (slightly flattening observed volume-response curves); (ii) only slightly reduce the power of a 2 x 100 patient trial of conformal versus conventional prostate radiotherapy to detect a significantly lower rate of grade 1,2,3 rectal bleeding amongst conformally treated patients; (iii) do not diminish the information content of individual planned patient dose-distribution data to the point where the fitting of technique-averaged data would provide as sensitive a test of the existence of a volume effect as the fitting of individual patient data.

An ntcp formula for the series model with a Yaes-type functional subunit mechanism.

Yaes and Kalend have noted that if functional subunit size is determined by factors such as cell migration lengths or biochemical diffusion lengths, rather than by fixed anatomical boundaries, then the conventional series normal tissue complication probability (ntcp) model should be conceptually modified. Here a von Mises-type formula describing the ntcp for such a modified model is derived, using a methodology based on that of Feller.

Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD.

OBJECTIVE: To compare regional cerebral blood flow (rCBF) changes using 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT in subjects with dementia with Lewy bodies (DLB) and AD and in normal age-matched control subjects; to examine the utility of SPECT changes in the differential diagnosis of AD and DLB. METHOD: Whole-brain SPECT scans were acquired using a single-headed rotating gamma camera (IGE CamStar XR/T) in elderly subjects with consensus criteria DLB (n = 23; mean age = 79.4 years), National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association AD (n = 50; 81.9 years), and normal control subjects (n = 20; 78.1 years) after injection with 500 MBq of 99mTc-HMPAO. Region-of-interest analysis was performed using a SPECT template registered in Talairach space, with rCBF normalized to cerebellum. RESULTS: Both DLB and AD subjects had significantly reduced rCBF in parietal and temporal regions compared with the control subjects. The AD group also showed a significant reduction in rCBF in the frontal and medial temporal regions and the DLB in the occipital areas compared with control subjects. AD and DLB groups differed only in occipital perfusion (p < 0.01). SPECT measures (occipital and medial temporal) correctly classified 69% of all subjects, with a 65% sensitivity and 87% specificity for DLB against AD and control subjects. CONCLUSION: Temporoparietal hypoperfusion on SPECT is common to both AD and DLB. Occipital hypoperfusion is more frequently seen in DLB. Although not diagnostically specific in individual cases, occipital hypoperfusion on SPECT should raise suspicion that DLB may be the cause of dementia, prompting careful search for other features of the disorder.