Locoregional control and toxicity following high-dose hypofractionated and accelerated palliative radiotherapy regimens in breast cancer.

AIMS: For patients with locally advanced primary/recurrent breast cancer, radiotherapy is an effective treatment for locoregional control. 36 Gy in 6 Gy once-weekly fractions is a commonly used schedule, but there are no data comparing local control and toxicity between 36 Gy delivered once-weekly versus accelerated schedules of multiple 6 Gy fractions per week. This retrospective study compared local control rates and acute and late toxicity in patients undergoing 30-36 Gy in 6 Gy fractions over 6 weeks versus more accelerated schedules over 2-3 weeks for an unresected breast cancer. MATERIALS AND METHODS: Patients who received 30-36 Gy in 6 Gy fractions to an unresected breast cancer ± involved lymph nodes between December 2011 and August 2020 were identified. Patients were grouped into once-weekly versus accelerated fractionation schedules. Response rates, local control and toxicity data were analysed. RESULTS: In total, 109 patients were identified. The median follow-up duration was 46 months. Forty-seven patients (43%) received once-weekly fractions and 62 patients (57%) received accelerated fractionation schedules. There were no significant differences in baseline tumour characteristics between the groups. Eighty-seven per cent of patients had an objective (complete or partial) response (81% in the once-weekly group; 91% in the accelerated group). The median time to local progression was 23.5 months overall (95% confidence interval 17.8-29.2); 23.5 months (95% confidence interval 18.8-28.1) in the once-weekly group and 19.0 months (95% confidence interval 7.0-31.1) in the accelerated group (P = 0.99). Acute toxicity of any grade occurred in 75% of patients (76% in the once-weekly group; 74% in the accelerated group) and grade 3 toxicity occurred in 7% of patients (7% in the once-weekly group; 8% in the accelerated group). There were no associations between the groups and acute or late toxicity grade (P = 0.78 and P = 0.26, respectively), although one grade 4 late toxicity (skin radionecrosis) occurred in a patient who received five fractions a week and therefore this regimen is not recommended. Study limitations included a lack of statistical power analysis, the necessary grouping of all accelerated patients for analysis and a high rate of censored data. CONCLUSION: There were no apparent differences in response rate, time to local progression or toxicity between patients who received 30-36 Gy in 6 Gy fractions once-weekly compared with twice-weekly as palliative treatment for locally advanced breast cancer. This regimen appears to be a safe alternative and may be preferred by patients.

A Comparison of Isotoxic Dose-escalated Radiotherapy in Lung Cancer with Moderate Deep Inspiration Breath Hold, Mid-ventilation and Internal Target Volume Techniques.

AIMS: With interest in normal tissue sparing and dose-escalated radiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer, this study investigated the impact of motion-managed moderate deep inspiration breath hold (mDIBH) on normal tissue sparing and dose-escalation potential and compared this to planning with a four-dimensional motion-encompassing internal target volume or motion-compensating mid-ventilation approach. MATERIALS AND METHODS: Twenty-one patients underwent four-dimensional and mDIBH planning computed tomography scans. Internal and mid-ventilation target volumes were generated on the four-dimensional scan, with mDIBH target volumes generated on the mDIBH scan. Isotoxic target dose-escalation guidelines were used to generate six plans per patient: three with a target dose cap and three without. Target dose-escalation potential, normal tissue complication probability and differences in pre-specified dose-volume metrics were evaluated for the three motion-management techniques. RESULTS: The mean total lung volume was significantly greater with mDIBH compared with four-dimensional scans. Lung dose (mean and V21 Gy) and mean heart dose were significantly reduced with mDIBH in comparison with four-dimensional-based approaches, and this translated to a significant reduction in heart and lung normal tissue complication probability with mDIBH. In 20/21 patients, the trial target prescription dose cap of 79.2 Gy was achievable with all motion-management techniques. CONCLUSION: mDIBH aids lung and heart dose sparing in isotoxic dose-escalated radiotherapy compared with four-dimensional planning techniques. Given concerns about lung and cardiac toxicity, particularly in an era of consolidation immunotherapy, reduced normal tissue doses may be advantageous for treatment tolerance and outcome.

The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice.

BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk.

Implementation of Royal College of Radiologists Consensus Statements and National Institute for Health and Care Excellence Guidance: Breast Radiotherapy Practice in the UK.

AIMS: Breast radiotherapy practice, driven by large randomised controls trials, is increasingly being risk adapted to the biology and stage of the cancer. The aim of this audit was to measure current breast radiotherapy practice in the UK against quality standards from the 2016 Royal College of Radiologists (RCR) consensus statements and the 2018 updated National Institute for Health and Care Excellence (NICE) guidelines. These guidelines include new recommendations for partial breast irradiation for women at lower risk of recurrence and internal mammary chain radiotherapy for those at higher risk. MATERIALS AND METHODS: Radiotherapy departments completed a questionnaire for all patients starting adjuvant radiotherapy for early breast cancer in a 2-week period mid-2019. RESULTS: Eighty-one per cent of centres returned data on 958 patients, including 18 bilateral cancers. Of 976 breast cancers, 23.9% were treated with mastectomy. The dose fractionation schedule for adjuvant radiotherapy was 40 Gy in 15 fractions in 95.7% of cases. Of the 743 cases treated with breast conservation, 29.9% received an additional tumour bed boost. The boost was given sequentially in 91.9% of cases and with eight different dose fractionation schedules. Of 494 left-sided breast cancer cases, 54% (n = 267) received radiotherapy in deep inspiratory breath hold. All centres except one had a deep inspiratory breath hold technique available. Only 12% of patients who met the RCR criteria for partial breast irradiation received it. Overall, 14.7% and 9.9% of patients meeting the RCR and NICE criteria for internal mammary chain radiotherapy, respectively, received it. CONCLUSIONS: Despite established consensus statements and NICE guidelines there persists variation in breast radiotherapy practice in the UK. The results of practice-changing trials showing the benefit of cardiac-sparing radiotherapy techniques, partial breast radiotherapy and internal mammary nodal radiotherapy have not been fully implemented. This audit highlights areas for targeted quality improvement and future consensus statements.

Melanocortin peptide therapy for the treatment of arthritic pathologies.

Arthritic pathologies are a major cause of morbidity within the western world, with rheumatoid arthritis affecting approximately 1% of adults. This review highlights the therapeutic potential of naturally occurring hormones and their peptides, in both arthritic models of disease and patients. The arthritides represent a group of closely related pathologies in which cytokines, joint destruction, and leukocytes play a causal role. Here we discuss the role of naturally occurring pro-opiomelanocortin (POMC)-derived melanocortin peptides (e.g., alpha melanocyte stimulating hormone [alpha-MSH]) and synthetic derivatives in these diseases. Melanocortins exhibit their biological efficacy by modulating proinflammatory cytokines and subsequent leukocyte extravasation. Their biological effects are mediated via seven transmembrane G-protein-coupled receptors, of which five have been cloned, identified, and termed MC1 to MC5. Adrenocorticotrophic hormone represents the parent molecule of the melanocortins; the first 13 amino acids of which (termed alpha-MSH) have been shown to be the most pharmacologically active region of the parent hormone. The melanocortin peptides have been shown to display potent anti-inflammatory effects in both animal models of disease and patients. The potential anti-inflammatory role for endogenous peptides in arthritic pathologies is in its infancy. The ability to inhibit leukocyte migration, release of cytokines, and induction of anti-inflammatory proteins appears to play an important role in affording protection in arthritic injury, and thus may lead to potential therapeutic targets.

Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1.

Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.

Cytotoxicity of clove (Syzygium aromaticum) oil and its major components to human skin cells.

The essential oil extracted from clove (Syzygium aromaticum) is used as a topical application to relieve pain and promote healing in herbal medicine and also finds use in the fragrance and flavouring industries. Clove oil has two major components, eugenol and beta-caryophyllene, which constitute 78% and 13% of the oil, respectively. Clove oil and these components are generally recognized as 'safe', but the in-vitro study here demonstrates cytotoxic properties of both the oil and eugenol, towards human fibroblasts and endothelial cells. Clove oil was found to be highly cytotoxic at concentrations as low as 0.03% (v/v) with up to 73% of this effect attributable to eugenol. beta-caryophyllene did not exhibit any cytotoxic activity, indicating that other cytotoxic components may also exist within the parent oil.

The Royal College of Radiologists' audit of prostate brachytherapy in the year 2012.

AIMS: This audit provides a comprehensive overview of UK prostate brachytherapy practice in the year 2012, measured against existing standards, immediately before the introduction of new Royal College of Radiologists (RCR) guidelines. This audit allows comparison with European and North American brachytherapy practice and for the impact of the RCR 2012 guidelines to be assessed in the future. MATERIALS AND METHODS: A web-based data collection tool was developed by the RCR Clinical Audit Committee and sent to audit leads at all cancer centres in the UK. Standards were developed based on available guidelines in use at the start of 2012 covering case mix and dosimetry. Further questions were included to reflect areas of anticipated change with the implementation of the 2012 guidelines. Audit findings were compared with similar audits of practice in Europe, the USA and Latin America. RESULTS: Forty-nine of 59 cancer centres submitted data. Twenty-nine centres reported carrying out prostate brachytherapy; of these, 25 (86%) provided data regarding the number of implants, staffing, dosimetry, medication and anaesthesia and follow-up. Audit standards achieved excellent compliance in most areas, although were low in post-implant dosimetry and in post-implant scanning at 30 days. CONCLUSION: This audit provides a comprehensive picture of prostate brachytherapy in the UK in 2012. Patterns of care of prostate brachytherapy are similar to practice in the USA and Europe. The number of prostate brachytherapy implants carried out in the UK has grown significantly since a previous RCR audit in 2005 and it is important that centres maintain minimum numbers of cases to ensure that experience can be maintained and compliance to guidelines achieved.

Urocortin--from Parkinson's disease to the skeleton.

Urocortin (Ucn 1), a 40 amino acid long peptide related to corticotropin releasing factor (CRF) was discovered 19 years ago, based on its sequence homology to the parent molecule. Its existence was inferred in the CNS because of anatomical and pharmacological discrepancies between CRF and its two receptor subtypes. Although originally found in the brain, where it has opposing actions to CRF and therefore confers stress-coping mechanisms, Ucn 1 has subsequently been found throughout the periphery including heart, lung, skin, and immune cells. It is now well established that this small peptide is involved in a multitude of physiological and pathophysiological processes, due to its receptor subtype distribution and promiscuity in second messenger signalling pathways. As a result of extensive studies in this field, there are now well over one thousand peer reviewed publications involving Ucn 1. In this review, we intend to highlight some of the less well known actions of Ucn 1 and in particular its role in neuronal cell protection and maintenance of the skeletal system, both by conventional methods of reviewing the literature and using bioinformatics, to highlight further associations between Ucn 1 and disease conditions. Understanding how Ucn 1 works in these tissues, will help to unravel its role in normal and pathophysiological processes. This would ultimately allow the generation of putative medical interventions for the alleviation of important diseases such as Parkinson's disease, arthritis, and osteoporosis.

Cytotoxicity of lavender oil and its major components to human skin cells.

Lavender (Lavandula angustifolia) oil, chiefly composed of linalyl acetate (51%) and linalool (35%), is considered to be one of the mildest of known plant essential oils and has a history in wound healing. Concerns are building about the potential for irritant or allergenic skin reactions with the use of lavender oil. This study has demonstrated that lavender oil is cytotoxic to human skin cells in vitro (endothelial cells and fibroblasts) at a concentration of 0.25% (v/v) in all cell types tested (HMEC-1, HNDF and 153BR). The major components of the oil, linalyl acetate and linalool, were also assayed under similar conditions for their cytotoxicity. The activity of linalool reflected that of the whole oil, indicating that linalool may be the active component of lavender oil. Linalyl acetate cytotoxicity was higher than that of the oil itself, suggesting suppression of its activity by an unknown factor in the oil. Membrane damage is proposed as the possible mechanism of action.

Autoantibodies to neutrophil granule proteins: pathogenic potential in vasculitis?

The discovery of circulating autoantibodies to neutrophil granule proteins (ANCA), which are present in a high proportion of patients with vasculitis, has revitalised both clinical and experimental research in this area. Although their antigen specificities and strong association with vasculitic diseases have now been established, the role of ANCA in the disease process is uncertain. This review is a brief outline of some of the clinical associations of ANCA, and describes interesting new avenues being taken in recent research which may provide an insight into how ANCA may contribute to vascular damage in patients with vasculitis.

Varidase: the science behind the medicament.

Varidase is used throughout the world for the topical treatment of purulent and suppurating wounds. Its efficacy is centred on two enzymes, streptokinase and streptodornase. However, these represent only a small proportion of the bulked solid. This article gives an overview of the preparation and mode of action of Varidase, as well as showing some of the research and development that has gone into improving the assessment of its quality and composition.

A royal college of radiologists national audit of radiotherapy in the treatment of metastatic spinal cord compression and implications for the development of acute oncology services.

AIMS: To audit the current use of radiotherapy in UK cancer centres for the treatment of metastatic spinal cord compression against national standards that seek to optimise functional and quality of life outcomes. MATERIALS AND METHODS: A Royal College of Radiologists prospective national audit of patients treated with radiotherapy in UK cancer centres was carried out over a 3 month period between September and December 2008, with a repeat audit carried out in August 2012. RESULTS: Five hundred and ninety-six cases were received from 42 cancer centres (74%) in 2008, with data from 323 cases received from 52 (90%) centres in 2012. Ninety-three per cent (358) of patients had a diagnostic magnetic resonance imaging scan carried out within 24 h of referral for radiotherapy in 2008 compared with 205 patients (97%) in 2012. One hundred and eleven (32%) good prognosis patients were discussed with spinal surgeons; only 10 good prognosis patients were recorded as proceeding to surgery in 2008. This improved in 2012, with 94 (41% of good prognosis patients recorded as having been discussed with nine proceeding to surgery). Sixty-nine per cent of paraplegic patients in 2008 received multiple fractions of radiotherapy, which was similar to 2012 when 62% received more than a single fraction. A metastatic spinal cord compression co-ordinator was available in just over 50% of cases (164/323) and was involved in patient management in 26% of cases in 2012. CONCLUSION: Despite level 1 evidence of the superior functional outcome and survival benefit for surgery, few good prognosis patients were recorded as having been discussed with surgeons and even fewer proceeded to surgery.

Multileaf collimation cardiac shielding in breast radiotherapy: Cardiac doses are reduced, but at what cost?

AIMS: To measure cardiac tissue doses in left-sided breast cancer patients receiving supine tangential field radiotherapy with multileaf collimation (MLC) cardiac shielding of the heart and to assess the effect on target volume coverage. MATERIALS AND METHODS: Sixty-seven consecutive patients who underwent adjuvant radiotherapy to the left breast (n = 48) or chest wall (n = 19) in 2009/2010 were analysed. The heart, left anterior descending coronary artery (LAD), whole breast and partial breast clinical target volumes (WBCTV and PBCTV) were outlined retrospectively (the latter only in patients who had undergone breast-conserving surgery [BCS]). The mean heart and LAD NTDmean and maximum LAD doses (LADmax) were calculated for all patients (NTDmean is a biologically weighted mean dose normalised to 2 Gy fractions using a standard linear quadratic model). Coverage of WBCTV and PBCTV by the 95% isodose was assessed (BCS patients only). RESULTS: The mean heart NTDmean (standard deviation) was 0.8 (0.3) Gy, the mean LAD NTDmean 6.7 (4.3) Gy and the mean LADmax 40.3 (10.1) Gy. Coverage of the WBCTV by 95% isodose was <90% in one in three patients and PBCTV coverage <95% (range 78-94%) in one in 10 BCS patients. CONCLUSION: The use of MLC cardiac shielding reduces doses to cardiac tissues at the expense of target tissue coverage. Formal target volume delineation in combination with an assessment of the likelihood of local relapse is recommended in order to aid decisions regarding field and MLC placement.

Urocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis?

Osteoarthritis (OA) is characterized by a loss of joint mobility and pain resulting from progressive destruction and loss of articular cartilage secondary to chondrocyte death and/ or senescence. Certain stimuli including nitric oxide (NO) and the pro-inflammatory cytokine tumor necrosis factor α (TNF-α have been implicated in this chondrocyte death and the subsequent accelerated damage to cartilage. In this study, we demonstrate that a corticotrophin releasing factor (CRF) family peptide, urocortin (Ucn), is produced by a human chondrocyte cell line, C-20/A4, and acts both as an endogenous survival signal and as a cytoprotective agent reducing the induction of apoptosis by NO but not TNF-α when added exogenously. Furthermore, treatment with the NO donor S-nitroso-N-acetyl-D-L-penicillamine upregulates chondrocyte Ucn expression, whereas treatment with TNF-α does not. The chondroprotective effects of Ucn are abolished by both specific ligand depletion (with an anti-Ucn antibody) and by CRF receptor blockade with the pan-CRFR antagonist α-helical CRH(9-41). CRFR expression was confirmed by reverse transcription-PCR with subsequent amplicon sequence analysis and demonstrates that C-20/A4 cells express both CRFR1 and CRFR2, specifically CRFR1α and CRFR2ß. Protein expression of these receptors was confirmed by western blotting. The presence of both Ucn and its receptors in these cells, coupled with the induction of Ucn by NO, suggests the existence of an endogenous autocrine/paracrine chondroprotective mechanism against stimuli inducing chondrocyte apoptosis via the intrinsic/mitochondrial pathway.

Variations in radiotherapy delivery in England - evidence from the national radiotherapy dataset.

AIMS, MATERIALS AND METHOD: Data in the national radiotherapy dataset for England for 2009-2011 is based upon downloads of activity from every linear accelerator in the country through its oncology management system linked to the local patient administration system to give a full overview of each patient episode. RESULTS: An analysis of this dataset shows that there is still a considerable variation in radiotherapy activity across the country, with a two-fold variation between the most and least active networks. Lower activity is seen in London and the southeast compared with the rest of the country, but when the data are split between the north and south of the country, no such variation is seen. Activity is higher in smaller centres and non-teaching centres. About half of all treatment is palliative and this proportion does not vary with geography, although there is considerable variation between individual centres in the proportion of radical radiotherapy given. There is a trend towards less use of radiotherapy, both radical and palliative, in the more deprived population groups, although no change in the relative use of palliative and radical treatment. CONCLUSION: It is important to emphasise that these data currently reflect activity patterns only and do not reflect quality of care or treatment outcomes, which will be achieved by linkage with cancer registry data in the future.

Interactions between cell surface protein disulphide isomerase and S-nitrosoglutathione during nitric oxide delivery.

In this study, we investigated the role of protein disulphide isomerase (PDI) in rapid metabolism of S-nitrosoglutathione (GSNO) and S-nitrosoalbumin (albSNO) and in NO delivery from these compounds into cells. Incubation of GSNO or albSNO (1 microM) with the megakaryocyte cell line MEG-01 resulted in a cell-mediated removal of each compound which was inhibited by blocking cell surface thiols with 5,5'-dithiobis 2-nitrobenzoic acid (DTNB) (100 microM) or inhibiting PDI with bacitracin (5mM). GSNO, but not albSNO, rapidly inhibited platelet aggregation and stimulated cyclic GMP (cGMP) accumulation (used as a measure of intracellular NO entry). cGMP accumulation in response to GSNO (1 microM) was inhibited by MEG-01 treatment with bacitracin or DTNB, suggesting a role for PDI and surface thiols in NO delivery. PDI activity was present in MEG-01 conditioned medium, and was inhibited by high concentrations of GSNO (500 microM). A number of cell surface thiol-containing proteins were labelled using the impermeable thiol specific probe 3-(N-maleimido-propionyl) biocytin (MPB). Pretreatment of cells with GSNO resulted in a loss of thiol reactivity on some but not all proteins, suggesting selective cell surface thiol modification. Immunoprecipitation experiments showed that GSNO caused a concentration-dependent loss of thiol reactivity of PDI. Our data indicate that PDI is involved in both rapid metabolism of GSNO and intracellular NO delivery and that during this process PDI is itself altered by thiol modification. In contrast, the relevance of PDI-mediated albSNO metabolism to NO signalling is uncertain.

Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers.

Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.