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Introduction: A wide variety of fractionation schedules have been employed for the treatment of early glottic cancer. The aim is to report our 10-year experience of using hypofractionated radiotherapy with 55Gy in 20 fractions at 2.75Gy per fraction., Methods: Patients treated between 2004 and 2013 with definitive radiotherapy to a dose of 55Gy in 20 fractions over 4 weeks for T1/2 N0 squamous cell carcinoma of the glottis were retrospectively identified. Patients with prior therapeutic minor surgery (eg. laser stripping, cordotomy) were included. The probabilities of local control, ultimate local control (including salvage surgery), regional control, cause specific survival (CSS) and overall survival (OS) were calculated., Results: One hundred thirty-two patients were identified. Median age was 65 years (range 33-89). Median follow up was 72 months (range 7-124). 50 (38 %), 18 (14 %) and 64 (48 %) of patients had T1a, T1b and T2 disease respectively. Five year local control and ultimate local control rates were: overall - 85.6 % and 97.3 % respectively, T1a - 91.8 % and 100 %, T1b - 81.6 and 93.8 %, and T2 - 80.9 % and 95.8 %. Five year regional control, CSS and OS rates were 95.4 %, 95.7 % and 78.8 % respectively. There were no significant associations of covariates (e.g. T-stage, extent of laryngeal extension, histological grade) with local control on univariate analysis. Only increasing age and transglottic extension in T2 disease were significantly associated with overall survival (both p <0.01). Second primary cancers developed in 17 % of patients. 13 (9.8 %) of patients required enteral tube feeding support during radiotherapy; no patients required long term enteral nutrition. One patient required a tracheostomy due to a non-functioning larynx on long term follow up., Conclusions: Hypofractionated radiation therapy with a dose of 55Gy in 20 fractions for early stage glottic cancer provides high rates of local control with acceptable toxicity.

Background: The aim of this study was to evaluate the disease outcomes of patients treated with definitive and adjuvant radiotherapy for squamous cell carcinomas of the nasal cavity and paranasal sinuses in a single institution., Methods: Between 2007-2012 patients were retrospectively identified from electronic databases who had undergone surgery and adjuvant radiotherapy or definitive radiotherapy for sinonasal squamous cell carcinomas with curative intent., Results: Fourty three patients with sinonasal squamous cell carcinoma were identified (22 nasal cavity, 21 paranasal sinuses). 31/43 (72%) had T3 or T4 disease; nodal stage was N0 in 38, N1 in 4, Na/b in 0 and N2c in 1 patient. Median age was 67 years (range 41-86). 18 (42%) received definitive and 25 (58%) adjuvant radiotherapy. Radiotherapy was delivered using either conventional radiotherapy (n = 39) or intensity modulated radiotherapy (n = 4). Elective neck radiotherapy was delivered to two patients. Chemotherapy was delivered to 6/43 (14%) of patients. Two-year local control, regional control, distant metastases free survival, progression free survival, cause specific survival and overall survival were 81%, 90%, 95%, 71%, 84% and 80% respectively. There was no significant difference in outcome comparing patients who underwent surgery and adjuvant radiotherapy with patients receiving definitive radiotherapy (2 year locoregional disease free survival 75% and 70% respectively, p = 0.98). Pooly differentiated tumours were significantly associated with inferior disease outcomes. Local, regional, combined local and regional, and distant failure occurred in 7 (16%), 3 (7%), 1 (2%) and 2 (5%) of patients; all 3 regional recurrences were in patients with nasal cavity squamous cell carcinomas who had not undergone elective neck treatment., Conclusions: Definitive or adjuvant radiotherapy provides an effective treatment for sinonasal malignancies. The main pattern of failure remains local, suggesting the need for investigation of intensified local therapy. Whilst remaining uncommon, the cases of regional failure mean that the merits of elective lymph node treatment should be considered on an individual basis.

INTRODUCTION: The accuracy of response assessment positron emission tomography (PET)-computed tomography (CT) following radiotherapy with or without chemotherapy for laryngeal/hypopharyngeal squamous cell carcinoma is uncertain. METHODS: In all, 35 patients with laryngeal or hypopharyngeal squamous cell carcinoma who were treated between 2009 and 2014 with (chemo)radiotherapy were identified. The accuracy of response assessment PET-CT was made by correlation with clinical follow-up and pathological findings. RESuLTS: Of the 35 patients, 20 (57%) had an overall complete metabolic response. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for response assessment [18Fluorine]-fluoro-2-deoxy-D-glucose (FDG) PET-CT for primary and nodal sites, respectively, were 100%, 73%, 46%, and 100% and 83%, 95%, 83%, and 95%. CONCLUSIONS: Response assessment FDG PET-CT following (chemo)radiotherapy for laryngeal and hypopharyngeal carcinomas has a high NPV for both primary site and lymph nodes and can be used to guide treatment decisions. The PPV of residual FDG uptake at the primary tumour site is limited and requires examination and biopsy confirmation. [ABSTRACT FROM AUTHOR]

Background: This study aimed to quantify the variation in oropharyngeal squamous cell carcinoma gross tumour volume (GTV) delineation between CT, MR and FDG PET-CT imaging.Methods: A prospective, single centre, pilot study was undertaken where 11 patients with locally advanced oropharyngeal cancers (2 tonsil, 9 base of tongue primaries) underwent pre-treatment, contrast enhanced, FDG PET-CT and MR imaging, all performed in a radiotherapy treatment mask. CT, MR and CT-MR GTVs were contoured by 5 clinicians (2 radiologists and 3 radiation oncologists). A semi-automated segmentation algorithm was used to contour PET GTVs. Volume and positional analyses were undertaken, accounting for inter-observer variation, using linear mixed effects models and contour comparison metrics respectively.Results: Significant differences in mean GTV volume were found between CT (11.9 cm(3)) and CT-MR (14.1 cm(3)), p < 0.006, CT-MR and PET (9.5 cm(3)), p < 0.0009, and MR (12.7 cm(3)) and PET, p < 0.016. Substantial differences in GTV position were found between all modalities with the exception of CT-MR and MR GTVs. A mean of 64 %, 74 % and 77 % of the PET GTVs were included within the CT, MR and CT-MR GTVs respectively. A mean of 57 % of the MR GTVs were included within the CT GTV; conversely a mean of 63 % of the CT GTVs were included within the MR GTV. CT inter-observer variability was found to be significantly higher in terms of position and/or volume than both MR and CT-MR (p < 0.05). Significant differences in GTV volume were found between GTV volumes delineated by radiologists (9.7 cm(3)) and oncologists (14.6 cm(3)) for all modalities (p = 0.001).Conclusions: The use of different imaging modalities produced significantly different GTVs, with no single imaging technique encompassing all potential GTV regions. The use of MR reduced inter-observer variability. These data suggest delineation based on multimodality imaging has the potential to improve accuracy of GTV definition.Trial Registration: ISRCTN Registry: ISRCTN34165059 . Registered 2nd February 2015. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the disease outcomes of patients treated with definitive and adjuvant radiotherapy for squamous cell carcinomas of the nasal cavity and paranasal sinuses in a single institution.Methods: Between 2007-2012 patients were retrospectively identified from electronic databases who had undergone surgery and adjuvant radiotherapy or definitive radiotherapy for sinonasal squamous cell carcinomas with curative intent.Results: Fourty three patients with sinonasal squamous cell carcinoma were identified (22 nasal cavity, 21 paranasal sinuses). 31/43 (72%) had T3 or T4 disease; nodal stage was N0 in 38, N1 in 4, Na/b in 0 and N2c in 1 patient. Median age was 67 years (range 41-86). 18 (42%) received definitive and 25 (58%) adjuvant radiotherapy. Radiotherapy was delivered using either conventional radiotherapy (n = 39) or intensity modulated radiotherapy (n = 4). Elective neck radiotherapy was delivered to two patients. Chemotherapy was delivered to 6/43 (14%) of patients. Two-year local control, regional control, distant metastases free survival, progression free survival, cause specific survival and overall survival were 81%, 90%, 95%, 71%, 84% and 80% respectively. There was no significant difference in outcome comparing patients who underwent surgery and adjuvant radiotherapy with patients receiving definitive radiotherapy (2 year locoregional disease free survival 75% and 70% respectively, p = 0.98). Pooly differentiated tumours were significantly associated with inferior disease outcomes. Local, regional, combined local and regional, and distant failure occurred in 7 (16%), 3 (7%), 1 (2%) and 2 (5%) of patients; all 3 regional recurrences were in patients with nasal cavity squamous cell carcinomas who had not undergone elective neck treatment.Conclusions: Definitive or adjuvant radiotherapy provides an effective treatment for sinonasal malignancies. The main pattern of failure remains local, suggesting the need for investigation of intensified local therapy. Whilst remaining uncommon, the cases of regional failure mean that the merits of elective lymph node treatment should be considered on an individual basis. [ABSTRACT FROM AUTHOR]

Background: The aim of the study is to investigate the prognostic role of pre-treatment of markers of the systemic inflammatory response (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and albumin) in patients with oropharyngeal carcinoma treated with chemoradiotherapy. Methods: A total of 251 patients with oropharyngeal squamous cell cancer treated with chemoradiotherapy between 2004 and 2010 were retrospectively identified. NLR, PLR, and albumin were recorded from baseline blood parameters. NLR threshold of 5 and PLR thresholds of 150, 150 and 300, and 300 were used for analysis. Results: Median follow-up was 46 months (range 9–98). The 3 year overall survival, local control, regional control, and distant control were 70%, 85%, 87%, and 87%, respectively. On multivariate analysis, locoregional control was associated with T stage (HR 3.3 (95% CI 1.5–6.9), P = 0.002) and NLR (HR 2.1 (95% CI 1.1–3.9), P = 0.023). Overall survival was associated with T stage (HR 2.47 (95% CI 1.45–4.2), P = 0.001) and grade (HR 0.61 (95% CI 0.38–0.99), P = 0.048). PLR and albumin were not significantly associated with disease outcomes or survival. Conclusions: The NLR is an independent prognostic factor for locoregional control in oropharyngeal cancer treated with chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Background: To establish recurrence patterns among locally advanced head and neck non-nasopharyngeal squamous cell carcinoma (HNSCC) patients treated with radical (chemo-) radiotherapy and to correlate the sites of loco-regional recurrence with radiotherapy doses and target volumes Method: 151 locally advanced HNSCC patients were treated between 2004-2005 using radical three-dimensional conformal radiotherapy. Patients with prior surgery to the primary tumour site were excluded. The sites of locoregional relapses were correlated with radiotherapy plans by the radiologist and a planning dosimetrist. Results: Median age was 59 years (range:34-89). 35 patients had stage III disease, 116 patients had stage IV A/B. 36 patients were treated with radiotherapy alone, 42 with induction chemotherapy, 63 with induction and concomitant chemoradiotherapy and 10 concomitant chemoradiotherapy. Median follow-up was 38 months (range 3-62). 3-year cause specific survival was 66.8%. 125 of 151 (82.8%) achieved a complete response to treatment. Amongst these 125 there were 20 local-regional recurrence, comprising 8 local, 5 regional and 7 simultaneous local and regional; synchronous distant metastases occurred in 7 of the 20. 9 patients developed distant metastases in the absence of locoregional failure. For the 14 local recurrences with planning data available, 12 were in-field, 1 was marginal, and 1 was out-of-field. Of the 11 regional failures with planning data available, 7 were in-field, 1 was marginal and 3 were out-of-field recurrences. Conclusion: The majority of failures following non-surgical treatment for locally advanced HNSCC were locoregional, within the radiotherapy target volume. Improving locoregional control remains a high priority. [ABSTRACT FROM AUTHOR]

Background: Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil. Methods: A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone. Results: Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively. Conclusion: Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer. [ABSTRACT FROM AUTHOR]

Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT). NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m2 daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level. Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P =.35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P =.88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P <.05). Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival. [ABSTRACT FROM AUTHOR]

Background: Aim of study was to assess impact of deformable registration of diagnostic MRI to planning CT upon gross tumour volume (GTV) delineation of oropharyngeal carcinoma in routine practice. Methods: 22 consecutive patients with oropharyngeal squamous cell carcinoma treated with definitive (chemo)radiotherapy between 2015 and 2016, for whom primary GTV delineation had been performed by a single radiation oncologist using deformable registration of diagnostic MRI to planning CT, were identified. Separate GTVs were delineated as part of routine clinical practice (all diagnostic imaging available side-by-side for each delineation) using: CT (GTVCT), MRI (GTVMR), and CT and MRI (GTVCTMR). Volumetric and positional metric analyses were undertaken using contour comparison metrics (Dice conformity index, centre of gravity distance, mean distance to conformity). Results: Median GTV volumes were 13.7 cm3 (range 3.5–41.7), 15.9 cm3 (range 1.6–38.3), 19.9 cm3 (range 5.5–44.5) for GTVCT, GTVMR and GTVCTMR respectively. There was no significant difference in GTVCT and GTVMR volumes; GTVCTMR was found to be significantly larger than both GTVMR and GTVCT. Based on positional metrics, GTVCT and GTVMR were the least similar (mean Dice similarity coefficient (DSC) 0.71, 0.84, 0.82 for GTVCT–GTVMR, GTVCTMR–GTVCT and GTVCTMR–GTVMR respectively). Conclusions: These data suggest a complementary role of MRI to CT to reduce the risk of geographical misses, although they highlight the potential for larger target volumes and hence toxicity. [ABSTRACT FROM AUTHOR]

Summary: To determine the outcomes of patients managed with different routes of enteral feeding during chemoradiotherapy for oropharynx cancer. The hospital and dietetic records of consecutive patients with oropharynx squamous cell carcinoma treated between January 2007 and June 2009 with concurrent chemoradiotherapy were reviewed retrospectively. One hundred and four patients were analysed. Seventy-one received a prophylactic gastrostomy, 21 were managed with a strategy of NG tube as required and 12 received a therapeutic gastrostomy. Patients with a prophylactic gastrostomy commenced enteral feeding a median of 24days after commencing radiotherapy, compared with a median of 41days (p <0.001) for the NG as required group. Comparing prophylactic gastrostomy, NG as required and therapeutic gastrostomy, median number of unplanned inpatient days were 6, 14 and 7, respectively (p <0.01 for prophylactic gastrostomy vs. NG as required). Mean percentage weight loss at the end of treatment (6.1% vs. 7.1% vs. 5.2%, respectively) and at 6months post-radiotherapy (11.7%, 14.3% and 8.9%) were similar in all groups (p =0.23). There was no significant difference in type of diet post-radiotherapy between prophylactic gastrostomy and NG as required groups (p =0.22). Median duration of enteral feeding was 181, 64 and 644days, respectively (p <0.01 for prophylactic gastrostomy vs. NG as required). Use of a prophylactic gastrostomy (p <0.01) and higher T stage (p <0.01) were associated with increased duration of enteral feeding on a multivariate analysis. These data reinforce concerns regarding the detrimental impact of prophylactic gastrostomy placement upon long-term enteral feed dependence. [Copyright &y& Elsevier]

Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5–60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74–1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375. • This phase III RCT does not support dose escalation using accelerated hypofractionation. • No benefit in local tumour control or survival was seen. • Two-year local tumour failure rate was approximately 30% in both treatment groups. • The larynx was preserved in about 90% patients in both treatment groups. [ABSTRACT FROM AUTHOR]

Abstract Background and purpose Limited data are available to inform on long term swallowing outcomes following concurrent chemoradiotherapy for oropharyngeal carcinoma. The aims of this study are to determine long term patient-reported swallowing outcomes across two large UK centres in routine clinical practice and identify associated factors. Material and methods All patients treated for oropharyngeal squamous cell carcinoma with concurrent chemoradiotherapy, and irradiation of the bilateral neck, between 2011 and 2013 were identified. Those requiring therapeutic enteral feeding prior to treatment, or having subsequent disease relapse, were excluded from the study. Patients were sent postal invitations to complete the MD Anderson Dysphagia Inventory (MDADI), at least two years following completion of treatment. Results Completed MDADI were received from 201/242 eligible patients (83%) at a median of 3.4 years (range 2–5) post treatment. Median composite MDADI score was 68.4. 64 (32%) had composite MDADI <60 classed as ‘poor’ function, 76 (38%) scores ≥60–<80 classed as adequate function, and 61 (31%) had scores ≥80 classed as optimal function. Patients with normal and abnormal pre-treatment diet had median composite MDADI scores of 70.5 versus 47.4 respectively. Patients who did not require enteral feeding during treatment and those who did had median composite MDADI scores of 76.3 versus 65.3 respectively. On multivariate analysis poorer performance status, abnormal pre-treatment diet, and use of enteral feeding during radiotherapy were all significantly associated with lower composite, global and subscale MDADI scores. Conclusions Patient reported swallowing dysfunction remains common in the long term post-chemoradiotherapy. Impaired pre-treatment diet and use of enteral feeding during treatment are key factors associated with poorer swallowing outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this matched pair analysis is to assess patient-reported long term swallow function following chemoradiotherapy for locally advanced oropharyngeal cancer in relation to the use of a prophylactic gastrostomy or reactive nasogastric (NG) tube.Materials and Methods: The MD Anderson Dysphagia Inventory (MDADI) was posted to 68 consecutive patients with stage III/IV oropharyngeal squamous cell carcinoma who had completed parotid sparing intensity modulated radiotherapy with concurrent chemotherapy between 2010 and 2012, had not required therapeutic enteral feeding prior to treatment, minimum 2years follow up post treatment, and who were disease free. 59/68 replies were received, and a matched pair analysis (matching for T and N stage) was performed for 52 patients, 26 managed with a prophylactic gastrostomy and 26 with an approach of an NG tube as needed.Results: There were no significant differences in patient demographics, pre-treatment diet and treatment factors between the two groups. Patient-reported swallowing function measured using the MDADI was superior for patients managed with an NG tube as required compared with a prophylactic gastrostomy: overall composite score 68.1 versus 59.4 (p=0.04), global score 67.7 versus 60 (p=0.04), emotional subscale 73.5 versus 60.4 (p<0.01), functional subscale 75.4 versus 61.7 (p<0.01), and physical subscale 59.6 versus 57.1 (p=0.38).Conclusions: Compared with an approach of an NG tube as required, the use of a prophylactic gastrostomy was associated with inferior long term patient-reported long term swallow outcomes. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine thyroid dysfunction in the early phase of radiotherapy to the head and neck region. Forty-seven patients receiving neck irradiation including the thyroid gland were included. Twenty-eight patients had undergone either a functional or radical neck dissection and in 19 patients radiotherapy was the primary treatment. Compared to the pre-treatment values, there was a significant fall in the TSH level at completion of radiotherapy in the non-operated patients and a non-significant fall in the operated patients. The TSH was also significantly lower in the non-operated group at the end of treatment compared to the operated group. There was a significant fall in the FT3 and significant higher in the FT4 at the end of radiotherapy for both groups. This study shows that even during completion of radiotherapy to the head and neck region changes in thyroid function were observed for both previously operated and non-operated patients. [Copyright &y& Elsevier]