A Multicentre UK Study of Outcomes for Locally Advanced Sinonasal Squamous Cell Carcinoma Treated with Adjuvant or Definitive Intensity-modulated Radiotherapy.

AIMS: Sinonasal malignancies are rare; the most common histological subtype is squamous cell carcinoma (SCC). No randomised trial data exist to guide treatment decisions, with options including surgery, radiotherapy and chemotherapy. The role and sequence of a primary non-surgical approach in this disease remains uncertain. The aim of this study was to present treatment outcomes for a multicentre population of patients with locally advanced, stage IVa/b sinonasal SCC treated with radical-intent intensity-modulated radiotherapy, either definitively or postoperatively. MATERIALS AND METHODS: Consecutively treated patients with locally advanced, stage IVa/b sinonasal SCC at four UK oncology centres between January 2012 and December 2017 were retrospectively identified. Descriptive statistics and survival analyses were carried out. Univariable Cox regression analysis was carried out to evaluate the relationship between patient, disease and treatment factors and survival outcomes. RESULTS: In total, 56 patients with sinonasal SCC were included (70% maxillary sinus, 21% nasal cavity, 9% ethmoid/frontal sinus). Forty-one patients (73%) were treated by surgery/adjuvant (chemo)radiotherapy and 15 (27%) by definitive (chemo)radiotherapy. The median duration of follow-up was 3.8 years (interquartile range 2.0-4.7 years). Estimates for 5-year overall survival and progression-free survival were 30.2% and 24.2%, respectively. Local, regional and distant treatment failures were seen in 33%, 33% and 16% of patients, respectively. Univariable analysis revealed inferior progression-free survival for patients treated with neck dissection (hazard ratio 2.6, 95% confidence interval 1.2-6.1, P = 0.022) but no other significant association between the studied factors and survival outcomes. CONCLUSION: We show poor survival outcomes and high rates of locoregional treatment failure for patients with locally advanced stage IVa/b sinonasal SCC. There is a need to investigate improved treatments for this group of patients.

Radiogenomics in the Era of Advanced Radiotherapy.

Most radiogenomics studies investigate how genetic variation can help to explain the differences in early and late radiotherapy toxicity between individuals. The field of radiogenomics in photon beam therapy has grown rapidly in recent years, carving out a unique translational discipline, which has progressed from candidate gene studies to larger scale genome-wide association studies, meta-analyses and now prospective validation studies. Genotyping is increasingly sophisticated and affordable, and whole-genome sequencing may soon become readily available as a diagnostic tool in the clinic. The ultimate aim of radiogenomics research is to tailor treatment to the individual with a test based on a combination of treatment, clinical and genetic factors. This personalisation would allow the greatest tumour control while minimising acute and long-term toxicity. Here we discuss the evolution of the field of radiogenomics with reference to the most recent developments and challenges.

Effects of injectable trace minerals administered concurrently with a modified live virus vaccine on long-term protection against bovine viral diarrhea virus acute infection in dairy calves.

The objective was to evaluate the effects of injectable trace minerals (ITM) concurrent with modified-live virus (MLV) vaccination on protection from bovine viral diarrhea virus (BVDV) infection in dairy calves. In a previous study (Palomares et al., 2016), thirty dairy calves received two doses of a MLV vaccine subcutaneously (SC), concurrently with ITM (n = 15) or saline (n = 15), SC. Five months later, 20 of these calves received ITM (G1, n = 10) or saline (G2, n = 10) according to their previous groups and were challenged intranasally with BVDV2. Five unvaccinated calves were also challenged with BVDV2 (G3). Blood samples were collected on days 0 (BVDV challenge), 3, 5, 6, 7, 8, 9, 11, 14, 18, 21, 32 and 61 for leukocyte count, virus isolation and BVDV serum neutralizing antibodies (SNA). Mild-moderate clinical signs were observed in G3 after BVDV challenge. Group 1 showed lower sum health score and nasal score on d5 and fecal score on d8 compared to G2. Rectal temperature and leukocyte counts were not different between G1 and G2. In contrast, G3 calves had significant leukopenia and lymphopenia from d3 to d7 (P < .05) and higher rectal temperatures on d6 to d8, compared to values on d0 (P < .05). All unvaccinated calves became viremic, while viremia was not detected in G1 or G2. Average daily gain was not different between vaccinated groups, however, only G1 calves had significantly greater (P = .04) ADG compared to non-vaccinated calves during the first 14 days post challenge. Vaccinated calves treated or not with ITM were protected from BVDV2 infection five months post-vaccination.

Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine.

AIMS: To evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy. MATERIALS AND METHODS: High-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low-grade chondrosarcoma, with a median dose of 65 Gy (range 65-70 Gy). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6 ml (median 124.7 ml). A PTV of 110 ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110 ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (P = 0.019, Fisher's exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose. CONCLUSION: Our results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high-dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma.

Automatic contour propagation using deformable image registration to determine delivered dose to spinal cord in head-and-neck cancer radiotherapy.

To determine delivered dose to the spinal cord, a technique has been developed to propagate manual contours from kilovoltage computed-tomography (kVCT) scans for treatment planning to megavoltage computed-tomography (MVCT) guidance scans. The technique uses the Elastix software to perform intensity-based deformable image registration of each kVCT scan to the associated MVCT scans. The registration transform is then applied to contours of the spinal cord drawn manually on the kVCT scan, to obtain contour positions on the MVCT scans. Different registration strategies have been investigated, with performance evaluated by comparing the resulting auto-contours with manual contours, drawn by oncologists. The comparison metrics include the conformity index (CI), and the distance between centres (DBC). With optimised registration, auto-contours generally agree well with manual contours. Considering all 30 MVCT scans for each of three patients, the median CI is [Formula: see text], and the median DBC is ([Formula: see text]) mm. An intra-observer comparison for the same scans gives a median CI of [Formula: see text] and a DBC of ([Formula: see text]) mm. Good levels of conformity are also obtained when auto-contours are compared with manual contours from one observer for a single MVCT scan for each of 30 patients, and when they are compared with manual contours from six observers for two MVCT scans for each of three patients. Using the auto-contours to estimate organ position at treatment time, a preliminary study of 33 patients who underwent radiotherapy for head-and-neck cancers indicates good agreement between planned and delivered dose to the spinal cord.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: Comparison of Clinician- versus Patient-reported Outcomes.

AIMS: Breast radiotherapy-associated toxicity is often reported using clinical and photographic assessments. The addition of patient-reported outcome measures (PROMs) is becoming more common. This study investigated the concordance between clinician- and patient-reported outcomes. MATERIALS AND METHODS: The Cambridge Breast Intensity-modulated Radiotherapy (IMRT) trial prospectively collected data on clinician assessment and PROMs at 2 and 5 years after breast radiotherapy. Clinician assessment included physical examination and photographic assessment. PROMs included European Organization for Research and Treatment of Cancer (EORTC) BR23 questionnaire and four breast radiotherapy-specific questions. The correlation between patient and clinician scores were analysed on an independent patient basis using percentage agreement, Cohen's kappa coefficient (k) and Bowker's test of symmetry. The analysis was repeated after stratifying patients based on age, baseline Hospital Anxiety and Depression Score (HADS) and baseline body image score. RESULTS: At 2 and 5 years, a weak level of concordance was seen between the clinician-based assessment and PROMS for all the five toxicity end points (k = 0.05-0.21), with individual patient-based agreement of 32.9-78.3% and a highly discordant Bowker's test of symmetry (P < 0.001). The most frequently reported moderate-severe toxicity by patients was change in breast appearance (14% at both 2 and 5 years), whereas it was breast induration (36% and 25% at 2 and 5 years, respectively) by the clinicians. The lack of concordance was not affected by patient's age, baseline HADS and baseline body image score. CONCLUSIONS: This study found that moderate-severe toxicity reported by patients is low and the overall concordance between clinicians and patients is low. This could be due to methodological limitations or alternatively reflects the subjective nature of PROMs. Incorporation of a patient's perception on treatment-related toxicity will have important implications for treatment decisions and follow-up care.

Incorporating Genetic Biomarkers into Predictive Models of Normal Tissue Toxicity.

There is considerable variation in the level of toxicity patients experience for a given dose of radiotherapy, which is associated with differences in underlying individual normal tissue radiosensitivity. A number of syndromes have a large effect on clinical radiosensitivity, but these are rare. Among non-syndromic patients, variation is less extreme, but equivalent to a ±20% variation in dose. Thus, if individual normal tissue radiosensitivity could be measured, it should be possible to optimise schedules for individual patients. Early investigations of in vitro cellular radiosensitivity supported a link with tissue response, but individual studies were equivocal. A lymphocyte apoptosis assay has potential, and is currently under prospective validation. The investigation of underlying genetic variation also has potential. Although early candidate gene studies were inconclusive, more recent genome-wide association studies are revealing definite associations between genotype and toxicity and highlighting the potential for future genetic testing. Genetic testing and individualised dose prescriptions could reduce toxicity in radiosensitive patients, and permit isotoxic dose escalation to increase local control in radioresistant individuals. The approach could improve outcomes for half the patients requiring radical radiotherapy. As a number of patient- and treatment-related factors also affect the risk of toxicity for a given dose, genetic testing data will need to be incorporated into models that combine patient, treatment and genetic data.

Exploiting biological and physical determinants of radiotherapy toxicity to individualize treatment.

The recent advances in radiation delivery can improve tumour control probability (TCP) and reduce treatment-related toxicity. The use of intensity-modulated radiotherapy (IMRT) in particular can reduce normal tissue toxicity, an objective in its own right, and can allow safe dose escalation in selected cases. Ideally, IMRT should be combined with image guidance to verify the position of the target, since patients, target and organs at risk can move day to day. Daily image guidance scans can be used to identify the position of normal tissue structures and potentially to compute the daily delivered dose. Fundamentally, it is still the tolerance of the normal tissues that limits radiotherapy (RT) dose and therefore tumour control. However, the dose-response relationships for both tumour and normal tissues are relatively steep, meaning that small dose differences can translate into clinically relevant improvements. Differences exist between individuals in the severity of toxicity experienced for a given dose of RT. Some of this difference may be the result of differences between the planned dose and the accumulated dose (DA). However, some may be owing to intrinsic differences in radiosensitivity of the normal tissues between individuals. This field has been developing rapidly, with the demonstration of definite associations between genetic polymorphisms and variation in toxicity recently described. It might be possible to identify more resistant patients who would be suitable for dose escalation, as well as more sensitive patients for whom toxicity could be reduced or avoided. Daily differences in delivered dose have been investigated within the VoxTox research programme, using the rectum as an example organ at risk. In patients with prostate cancer receiving curative RT, considerable daily variation in rectal position and dose can be demonstrated, although the median position matches the planning scan well. Overall, in 10 patients, the mean difference between planned and accumulated rectal equivalent uniform doses was -2.7 Gy (5%), and a dose reduction was seen in 7 of the 10 cases. If dose escalation was performed to take rectal dose back to the planned level, this should increase the mean TCP (as biochemical progression-free survival) by 5%. Combining radiogenomics with individual estimates of DA might identify almost half of patients undergoing radical RT who might benefit from either dose escalation, suggesting improved tumour cure or reduced toxicity or both.

Outcome of Adult Brain Tumor Consortium (ABTC) prospective dose-finding trials of I-125 balloon brachytherapy in high-grade gliomas: challenges in clinical trial design and technology development when MRI treatment effect and recurrence appear similar.

OBJECTIVES: The aim of this study is to define the maximal safe radiation dose to guide further study of the GliaSite balloon brachytherapy (GSBT) system in untreated newly diagnosed glioblastoma (NEW-GBM) and recurrent high-grade glioma (REC-HGG). GBST is a balloon placed in the resection cavity and later filled through a subcutaneous port with liquid I-125 Iotrex, providing radiation doses that diminish uniformly with distance from the balloon surface. METHODS: The Adult Brain Tumor Consortium initiated prospective dose-finding studies to determine maximum tolerated dose in NEW-GBM treated before standard RT or after surgery for REC-HGG. Patients were inevaluable if there was progression before the 90-day posttreatment toxicity evaluation point. RESULTS: Ten NEW-GBM patients had the balloon placed, and 2/10 reached the 90 day timepoint. Five REC-HGG enrolled and two were assessable at the 90-day evaluation endpoint. Imaging progression occurred before 90-day evaluation in 7/12 treated patients. The trials were closed as too few patients were assessable to allow dose escalation, although no dose-limiting toxicities (DLTs) were observed. Median survival from treatment was 15.3 months (95 % CI 7.1-23.6) for NEW-GBM and 12.8 months (95 % CI 4.2-20.9) for REC-HGG. CONCLUSION: These trials failed to determine a maximum tolerated dose (MTD) for further testing as early imaging changes, presumed to be progression, were common and interfered with the assessment of treatment-related toxicity. The survival outcomes in these and other related studies, although based on small populations, suggest that GSBT may be worthy of further study using clinical and survival endpoints, rather than standard imaging results. The implications for local therapy development are discussed.

Profile of select hepatic insulin signaling pathway genes in response to 2-aminoanthracene dietary ingestion.

Some genes that regulate various processes such as insulin signaling, glucose metabolism, fatty acid, and lipid biosynthesis were profiled. The objective of the current investigation is to examine the mRNA expression of some genes that mediate insulin signaling due to 2AA toxicity. 2AA is a polycyclic aromatic hydrocarbon (PAH) that has been detected in broiled food and tobacco smoke. Twenty-four post-weaning 3-4-week-old F344 male rats were exposed to 0 mg/kg-diet, 50 mg/kg-diet, 75 mg/kg-diet, and 100 mg/kgdiet 2AA for 2 weeks and 4 weeks. The mRNA expression of AKT1, G6PC, GCK, GLUT4, INSR, IRS1, PP1R3C, PAMPK, SOCS 2, and SREBF1 was determined by qRTPCR followed by the quantification of G6PC and AMPK via ELISA. The results suggest that 2AA modulates these genes depending on the length of exposure. Up-regulation of AMPK and SOCS2 genes in animals treated with 100 mg/kg-diet and 50 mg/kg-diet, respectively, during 14 days of feeding was noted. G6PC expression was inhibited in the 2-week group while being dose-dependently increased in the 4-week group. Hepatic activity of G6PC was enhanced significantly in the livers of rats that ingested 2AA. It appears that 2AA intoxication leads to the activation of irs1 and akt1 genes in the liver. Quantified AMPK amounts increased significantly in the short-term treatment group. Dose-dependent rise of AMPK in animals treated to 2AA showed an increased production of hepatic AMPK in response to the toxicity of 2AA in order to maintain cellular homeostasis. In contrast, the reduction in AMPK concentration in treated animals within the 4-week set indicated an adaptive recovery.

A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy.

BACKGROUND: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. METHODS: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. RESULTS: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98). CONCLUSION: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.

Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial.

AIMS: There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS: Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS: The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION: The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy.

Presence of key findings in the medical record prior to a documented high-risk diagnosis.

BACKGROUND: Failure or delay in diagnosis is a common preventable source of error. The authors sought to determine the frequency with which high-information clinical findings (HIFs) suggestive of a high-risk diagnosis (HRD) appear in the medical record before HRD documentation. METHODS: A knowledge base from a diagnostic decision support system was used to identify HIFs for selected HRDs: lumbar disc disease, myocardial infarction, appendicitis, and colon, breast, lung, ovarian and bladder carcinomas. Two physicians reviewed at least 20 patient records retrieved from a research patient data registry for each of these eight HRDs and for age- and gender-compatible controls. Records were searched for HIFs in visit notes that were created before the HRD was established in the electronic record and in general medical visit notes for controls. RESULTS: 25% of records reviewed (61/243) contained HIFs in notes before the HRD was established. The mean duration between HIFs first occurring in the record and time of diagnosis ranged from 19 days for breast cancer to 2 years for bladder cancer. In three of the eight HRDs, HIFs were much less likely in control patients without the HRD. CONCLUSIONS: In many records of patients with an HRD, HIFs were present before the HRD was established. Reasons for delay include non-compliance with recommended follow-up, unusual presentation of a disease, and system errors (eg, lack of laboratory follow-up). The presence of HIFs in clinical records suggests a potential role for the integration of diagnostic decision support into the clinical workflow to provide reminder alerts to improve the diagnostic focus.

Impact of a computer-based diagnostic decision support tool on the differential diagnoses of medicine residents.

BACKGROUND: Computer-based medical diagnostic decision support systems have been used for decades, initially as stand-alone applications. More recent versions have been tested for their effectiveness in enhancing the diagnostic ability of clinicians. OBJECTIVE: To determine if viewing a rank-ordered list of diagnostic possibilities from a medical diagnostic decision support system improves residents' differential diagnoses or management plans. METHOD: Twenty first-year internal medicine residents at Massachusetts General Hospital viewed 3 deidentified case descriptions of real patients. All residents completed a web-based questionnaire, entering the differential diagnosis and management plan before and after seeing the diagnostic decision support system's suggested list of diseases. In all 3 exercises, the actual case diagnosis was first on the system's list. Each resident served as his or her own control (pretest/posttest). RESULTS: For all 3 cases, a substantial percentage of residents changed their primary considered diagnosis after reviewing the system's suggested diagnoses, and a number of residents who had not initially listed a "further action" (laboratory test, imaging study, or referral) added or changed their management options after using the system. Many residents (20% to 65% depending on the case) improved their differential diagnosis from before to after viewing the system's suggestions. The average time to complete all 3 cases was 15.4 minutes. Most residents thought that viewing the medical diagnostic decision support system's list of suggestions was helpful. CONCLUSION: Viewing a rank-ordered list of diagnostic possibilities from a diagnostic decision support tool had a significant beneficial effect on the quality of first-year medicine residents' differential diagnoses and management plans.

The Cambridge Breast Intensity-modulated Radiotherapy Trial: patient- and treatment-related factors that influence late toxicity.

AIMS: The effect of patient- and treatment-related factors in the development of late normal tissue toxicity after radiotherapy is not yet fully established. The aim of this study was to elucidate the relative importance of such factors in the development of late toxicity after breast-conserving surgery and adjuvant breast radiotherapy. MATERIALS AND METHODS: Patient- and treatment-related factors were analysed in 1014 patients who had received adjuvant radiotherapy to the breast in the Cambridge Breast Intensity-modulated Radiotherapy (IMRT) Trial. Late toxicity data were collected using photographic and clinical assessments and patient-reported questionnaires at 2 years after radiotherapy. RESULTS: On multivariate analysis, a larger breast volume was statistically significantly associated with the development of breast shrinkage assessed by serial photographs (odds ratio per litre increase in breast volume = 1.98, 95% confidence interval 1.41, 2.78; P < 0.0005), telangiectasia (odds ratio = 3.94, 95% confidence interval 2.49, 6.24; P < 0.0005), breast oedema (odds ratio = 3.65, 95% confidence interval 2.54, 5.24; P < 0.0005) and pigmentation (odds ratio = 1.75, 95% confidence interval 1.21, 2.51; P = 0.003). Current smokers had an increased risk of developing pigmentation (odds ratio = 2.09, 95% confidence interval 1.23, 3.54; P = 0.006). Patients with a moderate or poor post-surgical cosmesis had a greatly increased risk of moderate or poor overall cosmesis (odds ratio = 38.19; 95% confidence interval 21.9, 66.7; P < 0.0005). Postoperative infection requiring antibiotics was associated with increased risk of telangiectasia (odds ratio = 3.39, 95% confidence interval 1.94, 5.91; P < 0.0005) and breast oversensitivity (odds ratio = 1.78, 95% confidence interval 1.27, 2.49; P = 0.001). CONCLUSIONS: In this study, the greatest risk factors for the development of late toxicity 2 years after breast-conserving surgery and adjuvant radiotherapy were larger breast volume, baseline pre-radiotherapy surgical cosmesis, postoperative infection and possibly smoking. These factors seem to be more important than relatively small differences in dose inhomogeneity and the addition of boost radiotherapy at 2 years after the completion of radiotherapy. The modification of potentially preventable risk factors, such as postoperative infection and smoking, may limit the development of late toxicity after breast radiotherapy.