Technical Radiotherapy Advances - The Role of Magnetic Resonance Imaging-Guided Radiation in the Delivery of Hypofractionation.

Safe delivery of hypofractionated radiotherapy requires high levels of accuracy due to the high doses of radiation delivered per fraction. Magnetic resonance guided radiotherapy (MRgRT) represents a new treatment paradigm which allows improved visualisation of targets and organs at risk, alongside the capability to adapt the treatment plan in real time prior to treatment delivery. There are challenges to delivering hypofractionated radiotherapy with conventional image-guided radiotherapy (IGRT) techniques and MRgRT may help to improve accuracy in radiation delivery in a number of clinical and anatomical scenarios. Specifically, there is an emerging role of MRgRT in delivering stereotactic body radiotherapy (SBRT) for locally advanced pancreatic cancer (LAPC) due to the superior soft tissue contrast provided by Magnetic Resonance Imaging combined with the ability to accommodate variation in anatomical appearances during treatment delivery. Reported data on the use of MRgRT in LAPC and it's role in enabling dose escalation are discussed in this article. There are further potential benefits to the use of MRgRT, for example the use of functional imaging during treatment delivery and generation of synthetic computed tomography, which have previously been impractical or unachievable. The overall aim of this article is to demonstrate the utility of MRgRT in facilitating safe delivery of hypofractionated radiotherapy and to highlight ways in which it may help to overcome challenges posed by current IGRT techniques.

UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy.

The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.

Cost-Effectiveness Analysis of Stereotactic Ablative Body Radiation Therapy Compared With Surgery and Radiofrequency Ablation in Two Patient Cohorts: Metastatic Liver Cancer and Hepatocellular Carcinoma.

AIMS: To compare the cost-effectiveness of stereotactic ablative body radiation therapy (SABR) with radiofrequency ablation and surgery in adult patients with metastatic liver cancer and hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Two patient cohorts were assessed: liver oligometastases and HCC. For each patient cohort, a decision analytic model was constructed to assess the cost-effectiveness of interventions over a 5-year horizon. A Markov process was embedded in the decision model to simulate the possible prognosis of cancer. Data on transition probabilities, survival, side-effects, quality of life and costs were obtained from published sources and the SABR Commissioning through Evaluation (CtE) scheme. The primary outcome was the incremental cost-effectiveness ratio with respect to quality-adjusted life-years. The robustness of the results was examined in a sensitivity analysis. Analyses were conducted from a National Health Service and Personal Social Services perspective. RESULTS: In the base case analysis, which assumed that all three interventions were associated with the same cancer progression rates and mortality rates, SABR was the most cost-effective intervention for both patient cohorts. This conclusion was sensitive to the cancer progression rate, mortality rate and cost of interventions. Assuming a willingness-to-pay threshold of £20 000 per quality-adjusted life-year, the probability that SABR is cost-effective was 57% and 50% in liver oligometastases and HCC, respectively. CONCLUSIONS: Our results indicate a potential for SABR to be cost-effective for patients with liver oligometastases and HCC. This finding supports further investigation in clinical trials directly comparing SABR with surgery and radiofrequency ablation.

Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer.

AIMS: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.

Passive Ballistic Microbunching of Nonultrarelativistic Electron Bunches Using Electromagnetic Wakefields in Dielectric-Lined Waveguides.

Temporally modulated electron beams have a wide array of applications ranging from the generation of coherently enhanced electromagnetic radiation to the resonant excitation of electromagnetic wakefields in advanced-accelerator concepts. Likewise producing low-energy ultrashort microbunches could be useful for ultrafast electron diffraction and new accelerator-based light-source concepts. In this Letter we propose and experimentally demonstrate a passive microbunching technique capable of forming a picosecond bunch train at ∼6 MeV. The method relies on the excitation of electromagnetic wakefields as the beam propagates through a dielectric-lined waveguide. Owing to the nonultrarelativistic nature of the beam, the induced energy modulation eventually converts into a density modulation as the beam travels in a following free-space drift. The modulated beam is further accelerated to ∼20 MeV while preserving the imparted density modulation.

Cascading speciation among mutualists and antagonists in a tree-beetle-fungi interaction.

Cascading speciation is predicted to occur when multiple interacting species diverge in parallel as a result of divergence in one species promoting adaptive differentiation in other species. However, there are few examples where ecological interactions among taxa have been shown to result in speciation that cascades across multiple trophic levels. Here, we test for cascading speciation occurring among the western pine beetle (Dendroctonus brevicomis), its primary host tree (Pinus ponderosa), and the beetle's fungal mutualists (Ceratocystiopsis brevicomi and Entomocorticium sp. B). We assembled genomes for the beetle and a fungal symbiont and then generated reduced representation genomic data (RADseq) from range-wide samples of these three interacting species. Combined with published data for the host tree, we present clear evidence that the tree, the beetle, and the fungal symbionts are all genetically structured into at least two distinct groups that have strongly codiverged with geographical isolation. We then combine our genomic results with diverse population and laboratory-based data to show evidence for reproductive isolation at each level of the cascade and for coevolution of both antagonistic and mutualistic species interactions within this complex network.

Observation of the Self-Modulation Instability via Time-Resolved Measurements.

Self-modulation of an electron beam in a plasma has been observed. The propagation of a long (several plasma wavelengths) electron bunch in an overdense plasma resulted in the production of multiple bunches via the self-modulation instability. Using a combination of a radio-frequency deflector and a dipole spectrometer, the time and energy structure of the self-modulated beam was measured. The longitudinal phase space measurement showed the modulation of a long electron bunch into three bunches with an approximately 200 keV/c amplitude momentum modulation. Demonstrating this effect is a breakthrough for proton-driven plasma accelerator schemes aiming to utilize the same physical effect.

Implementing Head and Neck Contouring Peer Review without Pathway Delay: The On-demand Approach.

AIMS: Peer review of contour volume is a priority in the radiotherapy treatment quality assurance process for head and neck cancer. It is essential that incorporation of peer review activity does not introduce additional delays. An on-demand peer review process was piloted to assess the feasibility and efficiency of this approach, as compared with a historic scheduled weekly approach. MATERIALS AND METHODS: Between November 2016 and April 2017 four head and neck clinicians in one centre took part in an on-demand peer review process. Cases were of radical or adjuvant intent of any histology and submitted on a voluntary basis. The outcome of contour peer review would be one of unchanged (UC), unchanged with variation or discretion noted (UV), minor change (M) or significant change (S). The time difference between the completion of the on-demand peer review was compared with the time difference to a hypothetical next Monday or Tuesday weekly peer review meeting. The time taken to review each case was also documented in the latter period of the pilot project. RESULTS: In total, 62 cases underwent peer review. Peer review on-demand provided dosimetrists with an average of an extra two working days available per case to meet treatment start dates. The proportion of cases with outcomes UC, UV, M and S were 45%, 16%, 26% and 13%, respectively. The mean peer review time spent per case was 17 min (12 cases). The main reason for S was discrepancy in imaging interpretation (4/8 cases). A lower proportion of oropharyngeal cases were submitted and had S outcomes. A higher proportion of complex cases, e.g. sinonasal/nasopharynx location or previous downstaging chemotherapy had S outcomes. The distribution of S outcomes appears to be similar regardless of clinician experience. The level of peer review activity among individuals differed by workload and job timetable. CONCLUSION: On-demand peer review of the head and neck contour volume is feasible, reduces delay to the start of dosimetry planning and bypasses the logistical barriers of weekly meetings. An audit of participation will be required to ensure successful implementation.

A prospective comparison of common toxicity criteria adverse events Version 3 and 4 in assessing oral mucositis for oral and oropharyngeal carcinoma.

BACKGROUND AND PURPOSE: Oral mucositis is an expected complication of radiotherapy in the management of carcinoma of the head and neck. The Common Terminology Criteria for Adverse Events (CTCAE) Version 3 (V3) and related systems based on mucosal appearance have been used in clinical trials historically. More recently, Version 4 (V4) which is based on patient symptoms has been employed. This study compares the use of V3 and V4 in the grading of mucositis in patients undergoing radiotherapy with or without concurrent systemic therapy for carcinoma of the oral cavity and oropharynx. METHODS: Oral mucositis was graded prospectively in patients receiving radiotherapy with or without concurrent systemic therapy using both V3 and V4. Grading was recorded during and after completion of therapy. RESULTS: Between November 2014 and November 2015, 555 measurements were taken from 73 patients. Mucositis scores were equal in both versions in 327 (59%) measurements. Significant differences between V3 and V4 were seen in patients receiving cetuximab-based concurrent therapy (p < 0.001) and beyond 8 weeks from the start of radiotherapy (p = 0.004). CONCLUSION: Differences in grading of mucositis scored by V3 and V4 are frequent. Relationships between biologically effective dose and rates of grade 3 mucositis have historically been based on mucosal appearances. It is not known whether the same relationships apply when mucositis is graded based on symptomatic grading systems. Both V3 and V4 should be used in clinical trials to improve understanding of mucositis and its relationship to quality of life and late mucosal toxicity.

Hypopharyngeal cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. With an age standardised incidence rate of 0.63 per 100 000 population, hypopharynx cancers account for a small proportion of the head and neck cancer workload in the UK, and thus suffer from the lack of high level evidence. This paper discusses the evidence base pertaining to the management of hypopharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care. Recommendations • Cross-sectional imaging with computed tomography of the head, neck and chest is necessary for all patients; magnetic resonance imaging of the primary site is useful particularly in advanced disease; and computed tomography and positron emission tomography to look for distant disease. (R) • Careful evaluation of the upper and lower extents of the disease is necessary, which may require contrast swallow or computed tomography and positron emission tomography imaging. (R) • Formal rigid endoscopic assessment under general anaesthetic should be performed. (R) • Nutritional status should be proactively managed. (R) • Full and unbiased discussion of treatment options should take place to allow informed patient choice. (G) • Early stage disease can be treated equally effectively with surgery or radiotherapy. (R) • Endoscopic resection can be considered for early well localised lesions. (R) • Bulky advanced tumours require circumferential or non-circumferential resection with wide margins to account for submucosal spread. (R) • Offer primary surgical treatment in the setting of a compromised larynx or significant dysphagia. (R) • Midline lesions require bilateral neck dissections. (R) • Consider management of silent nodal areas usually not addressed for other primary sites. (G) • Reconstruction needs to be individualised to the patients' needs and based on the experience of the unit with different reconstructive techniques. (G) • Consider tumour bulk reduction with induction chemotherapy prior to definitive radiotherapy. (R) • Consider intensity modulated radiation therapy where possible to limit the consequences of wide field irradiation to a large volume. (R) • Use concomitant chemotherapy in patients who are fit enough and consider epidermal growth factor receptor blockers for those who are less fit. (R).

Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system.

Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.

Population Pharmacokinetics and Pharmacodynamics of Lampalizumab Administered Intravitreally to Patients With Geographic Atrophy.

Intravitreally administered lampalizumab is an investigational complement inhibitor directed against complement factor D (CFD) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. We sought to develop an integrated ocular and systemic pharmacokinetic/pharmacodynamic model for lampalizumab in patients with GA using the data from the clinical phase I and II studies. The kinetics of lampalizumab and CFD disposition were well described by the combined ocular/serum target-mediated drug disposition model using a quasi-steady-state approximation. This model takes into account the drug, target, and drug-target complex clearance, their transfer rates between ocular and serum compartments, and turnover kinetics of CFD. The constructed model provided a prediction of target occupancy in ocular tissues and supported that the two dosing regimens (10 mg q4w and 10 mg q6w) selected for the phase III studies are expected to be efficacious and able to achieve near-complete target engagement in the vitreous humor.

Genetic and phenotypic influences on copulatory plug survival in mice.

Across a diversity of animals, male seminal fluid coagulates upon ejaculation to form a hardened structure known as a copulatory plug. Previous studies suggest that copulatory plugs evolved as a mechanism for males to impede remating by females, but detailed investigations into the time course over which plugs survive in the female's reproductive tract are lacking. Here, we cross males from eight inbred strains to females from two inbred strains of house mice (Mus musculus domesticus). Plug survival was significantly affected by male genotype. Against intuition, plug survival time was negatively correlated with plug size: long-lasting plugs were small and relatively more susceptible to proteolysis. Plug size was associated with divergence in major protein composition of seminal vesicle fluid, suggesting that changes in gene expression may play an important role in plug dynamics. In contrast, we found no correlation to genetic variation in the protein-coding regions of five genes thought to be important in copulatory plug formation (Tgm4, Svs1, Svs2, Svs4 and Svs5). Our study demonstrates a complex relationship between copulatory plug characteristics and survival. We discuss several models to explain unexpected variation in plug phenotypes.

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.

BACKGROUND: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. METHODS: Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. RESULTS: Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). CONCLUSION: Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.

Divergence with gene flow within the recent chipmunk radiation (Tamias).

Increasing data have supported the importance of divergence with gene flow (DGF) in the generation of biological diversity. In such cases, lineage divergence occurs on a shorter timescale than does the completion of reproductive isolation. Although it is critical to explore the mechanisms driving divergence and preventing homogenization by hybridization, it is equally important to document cases of DGF in nature. Here we synthesize data that have accumulated over the last dozen or so years on DGF in the chipmunk (Tamias) radiation with new data that quantify very high rates of mitochondrial DNA (mtDNA) introgression among para- and sympatric species in the T. quadrivittatus group in the central and southern Rocky Mountains. These new data (188 cytochrome b sequences) bring the total number of sequences up to 1871; roughly 16% (298) of the chipmunks we have sequenced exhibit introgressed mtDNA. This includes ongoing introgression between subspecies and between both closely related and distantly related taxa. In addition, we have identified several taxa that are apparently fixed for ancient introgressions and in which there is no evidence of ongoing introgression. A recurrent observation is that these introgressions occur between ecologically and morphologically diverged, sometimes non-sister taxa that engage in well-documented niche partitioning. Thus, the chipmunk radiation in western North America represents an excellent mammalian example of speciation in the face of recurrent gene flow among lineages and where biogeography, habitat differentiation and mating systems suggest important roles for both ecological and sexual selection.

Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy.

Despite tremendous advances in radiotherapy techniques, allowing dose escalation to tumour tissues and sparing of organs at risk, cure rates from radiotherapy or chemoradiotherapy remain suboptimal for most cancers. In tandem with our growing understanding of tumour biology, we are beginning to appreciate that targeting the molecular response to radiation-induced DNA damage holds great promise for selective tumour radiosensitisation. In particular, approaches that inhibit cell cycle checkpoint controls offer a means of exploiting molecular differences between tumour and normal cells, thereby inducing so-called cancer-specific synthetic lethality. In this overview, we discuss cellular responses to radiation-induced damage and discuss the potential of using G2/M cell cycle checkpoint inhibitors as a means of enhancing tumour control rates.