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This study quantifies intrafraction motion in surface-guided radiation therapy (SGRT) for breast cancer and considers the need for individualized intrafraction motion measures when calculating planning target volume (PTV) margins. SGRT was used to assess intrafraction motion in consecutive patients according to (1) site irradiated (whole-breast/chest wall vs whole-breast/chest wall + regional lymph nodes) and (2) the use of deep inspiration breath hold versus free breathing. Intrafraction motion variation was evaluated throughout the treatment course for all cases. Associations between intrafraction motion and patient-specific characteristics were explored. The usefulness of individualized intrafraction motion measures for PTV margin determination was considered. One hundred two patients undergoing 1360 fractions were included. On a population level, average intrafraction motion was less than 0.4 mm and 0.2 degrees for translational and rotational directions, respectively, with 95th percentiles <1.2 mm and 0.6 degrees, respectively. No clinically meaningful differences in intrafraction motion were observed according to the site irradiated or the use of deep inspiration breath hold. Consistency in intrafraction motion was noted for all patients throughout the treatment course. No clinically meaningful associations were found between intrafraction motion and patient-specific characteristics such as age, seroma volume, PTV volume, and mean body volume. Intrafractional deviations with SGRT, using manufacturer-recommended regions of interest, are minimal, do not vary substantially for different treatment techniques or patient-specific characteristics, and remain constant throughout the treatment course. A universal intrafraction motion measure may be sufficient for calculating PTV margins. Further validation studies are needed to evaluate the impact of region of interest size and coverage. [ABSTRACT FROM AUTHOR]

Despite the unfavorable outcomes associated with continued smoking, a substantial proportion of patients with cancer continue to smoke after diagnosis. However, limited use of smoking cessation (SC) interventions has been reported. This study explored the perceptions of patients with cancer who continue to smoke/recently quit regarding SC. Semistructured phone/Zoom/Webex interviews were conducted with 25 participants attending four Irish cancer hospitals who were current smokers or had quit at/after their cancer diagnosis. Thematic analysis was used to analyze the data. A total of four key themes emerged: (1) Diagnosis was a shock and a cue to action. (2) Brief and variable SC support: most participants did not feel stigmatized and reported receiving verbal or written information from oncology healthcare providers (HCPs) on SC supports. However, use of SC services was limited and largely ineffective. Some participants reported that SC discussions occurred earlier in their treatment with limited/no discussion later. (3) Facilitators vs barriers: the presence or absence of willpower and motivation was perceived as important. Family and HCP support helped while stress hindered SC. (4) SC support is a "marathon," not a "sprint." Patients with cancer who continue to smoke or recently quit want a sustained, tailored, nonjudgmental approach to SC incorporating pharmacological and behavioral interventions that span hospital-/community-based settings. While consultants have been identified as the key HCP to initiate the SC discussion, oncology nurses can support patients with cancer who smoke/recently quit by advocating for comprehensive SC services and by using positive messaging and encouragement. [ABSTRACT FROM AUTHOR]

Abstract: The radiotherapy conformity index (CI) is a useful tool to quantitatively assess the quality of radiotherapy treatment plans, and represents the relationship between isodose distributions and target volume. A conformity index of unity implies high planning target volume (PTV) coverage and minimal unnecessary irradiation of surrounding tissues. We performed this analysis to describe the CI for lung cancer 3-dimensional conformal radiotherapy (3DCRT) and to identify clinical and technical determinants of CI, as it is not known which factors are associated with good quality 3D conformal radiotherapy treatment planning. Radiotherapy treatment plans from a database of 52 patients with inoperable Stage 1 to 3b lung cancer, on a hypofractionated 3DCRT trial were evaluated. A CI was calculated for all plans using the definition of the ICRU 62:CI = (TV/PTV), which is the quotient of the treated volume (TV) and the PTV. Data on patient, tumor, and planning variables, which could influence CI, were recorded and analyzed. Mean CI was 2.01 (range = 1.06-3.8). On univariate analysis, PTV (p = 0.023), number of beams (p = 0.036), medial vs. lateral tumor location (p = 0.016), and increasing tumor stage (p = 0.041) were associated with improved conformity. On multiple regression analysis, factors found to be associated with CI included central vs. peripheral tumor location (p = 0.041) and PTV size (p = 0.058). The term 3DCRT is used routinely in the literature, without any indication of the degree of conformality. We recommend routine reporting of conformity indices. Conformity indices may be affected by both planning variables and tumor factors. [Copyright &y& Elsevier]

Oropharyngeal squamous cell cancers have a locoregional recurrence rate range of 17.3-32.5% and a distant metastatic rate of 6.5-17% at 3 years (ref1). Structured follow up is of paramount importance to facilitate early diagnosis and salvage treatment. We examined a cohort of patients with oropharyngeal cancer treated radically within a large Irish tertiary referral centre with diagnosed recurrence in order to better understand the clinical presentation and to optimise outpatient follow up following radical treatment. An existing database of 259 new oropharynx cancer patients treated radically between 2012 and 2020 was assessed to identify any patient with established recurrence. For those with recurrence: details of clinical presentation and diagnosis were recorded. Of the 259 patients assessed 70 experienced recurrence: 12 with locoregional failure, 12 with both local and distant failure, 25 with distant only failure and 21 with persistent disease post treatment. Of the 12 locoregional failures- 92% were symptomatic: pain (83%) and neck lump (8%). One recurrence was identified during routine outpatient review, the remainder following patient contact after onset of symptoms. 75% of the patients with locoregional failure had non-HPV related cancers, and 85% of the group were stage 3 or stage 4 at initial presentation. In terms of timeline to presentation, 50% had been identified within 9 months and 80% within 2 years following treatment. Of the 12 local + distant failures- 75% were symptomatic: pain (67%) and neck lump (8%). 2 patient recurrences were identified during routine outpatient review, the remainder following patient contact. 50% of the patients in this group had HPV related tumours and 50% of this group were stage 3 or stage 4 at initial presentation. 80% of these recurrences had been identified within 2 years following treatment. Of the 25 distant failures: 61% were identified on post treatment imaging, 15% presented with respiratory symptoms, 12% presented with pain or palpable lump and 12% were identified on routine imaging. 70% of the patients in this group had HPV related tumours and 57% of this group were stage 3 or 4 at presentation. 80% of these recurrences has been identified within 2 years following treatment. 21 patients were found to have persistent disease following treatment- all were identified on post treatment imaging. Locoregional recurrence of oropharynx cancer is associated with patient symptoms in over 90% of cases, most commonly pain. These symptoms are rarely discovered during routine review. Of the 12 patients found to have locoregional recurrence, 75% of the group were non HPV related tumours, 85% were stage 3 or 4 at initial presentation and 80% of the recurrences were identified within 2 years of treatment. This study highlights the importance of both patient and staff education and the importance of outpatient communication pathways that facilitate prompt review and investigation of new symptoms. [ABSTRACT FROM AUTHOR]

To investigate if tumour volume (primary, nodal and combined) predicts recurrence free (RFS) and overall survival (OS) in p16+ oropharyngeal squamous cell carcinoma. Study design We conducted a retrospective analysis of patients with OPSCC treated with curative radiotherapy in SLRON from 2013 - 2021. TNM 8th edition definition of stage was applied. Participants Eligible participants had OPSCC and received radiotherapy as definitive, radical treatment. Diagnosis was based on clinical assessment, histological sampling and PET imaging. p16 status was available for all patients. Clinical examination and PET imaging were used to assess response to treatment. Treatment Patients received 65-70Gy over 30-35 fractions, delivered using Intensity-Modulated Radiotherapy (IMRT). Endpoints Primary endpoints: 1. To investigate if GTVp predict RFS & OS in p16+ OPSCC 2. To investigate if GTVn predict RFS & OS in p16+ OPSCC 3. To investigate if GTVcomb predict RFS & OS in p16+ OPSCC Secondary endpoints: 1. To investigate if GTVp &/or GTVn predict RFS & OS in p16- OPSCC 2. To investigate if GTVp &/or GTVn predict RFS & OS in OPSCC 3. To investigate if use of concomitant chemotherapy improves outcomes in OPSCC in this cohort 4. To estimate RFS and OS Statistical Analysis All analyses were performed in IBM SPSS Statistics ver 29.0, and involved descriptive statistics, survival analyses by Kaplan-Meier method, and linear regression by Cox Proportional Hazards (univariate & multivariate). OS was evaluated from date of final RT. RFS was evaluated from date of final RT to the date of first local or distant recurrence, death, or last clinical assessment/investigation. Baseline Characteristics From January 2013 to April 2021, 246 patients were eligible for this review. Median age at first RT was 59.6. 187 (76%) were male. 179 (73%) had p16+ disease. 218 (88.6%) received chemotherapy. Median follow up was 25.5 months (0.5 - 96). Disease stage & Tumour volumes Patients with p16+ disease were diagnosed with earlier stage disease (86% stage 1 or 2), in comparison with those with p16- disease (3% stage 3 or 4; p<.001). Treatment Treatment was delivered using IMRT. 235 (95.5%) received 70Gy in 35 fractions and 11 (4.5%) received 65Gy in 30 fractions. Overall Survival 61 out of 246 patients (25%) died. Median survival for the total population was not reached. 3, 4 and 5 year overall survival was 75% (95%CI: 69 to 81%), 69% (95%CI: 61 to 76%) and 64% (95%CI: 55 to 73%) respectively. There was a significant difference in OS between those with P16- and P16+ (p<.001). Median survival for the P16- population was 34.9 months (95%CI 13 to 56 months). Median survival for the P16+ population was not reached. Recurrence Free Survival Median recurrence free survival for the total population was not reached.3, 4 and 5 year RFS survival was 65% (95%CI: 59 to 72%), 63% (95%CI: 56 to 70%) and 58% (95%CI: 49 to 66%) respectively. There was a significant difference in RFS between those with P16- and P16+ (p<.001). Median survival for the P16- population 23.6 months (95%CI 11 to 37 months). Median survival for the P16+ population was not reached. Survival based on Gross Tumour Volume For the total population (p16+ & p16-): • GTVp greater or less than median GTVp (dichotomized) was a statistically significant predictor of OS (p=.004) • GTVp based on Adrian et al volume brackets <6 cm3, 6–12 cm3, 12–24 cm3, 24–48 cm3, 48–96 cm3, and>96cm3 (as suggested by Adrian et al, 2022) was a statistically significant predictor of OS (p<.001) • GTVp greater or less than 40cm3 (as suggested by Adrian et al, 2022) was a statistically significant predictor of OS (p<.001) • GTVcomb based on volume brackets <15cc, 15-70cc, >70cc (as suggested by Panje et al, 2017) was a statistically significant predictor of OS and RFS (p=.001 and p <.001 respectively). When looking only at those with P16+, neither age, gender nor stage 1-2, were predictive of OS. The following variables were predictive of OS: GTVp, GTVp >18.3cc, GTV as per Adrian et al volume brackets, GTVp 15-70cc, GTVp>40cc, GTVn, GTVcomb and total dose. [Display omitted] [Display omitted] We demonstrate that GTV (primary, nodal and combined) predict outcome in p16+ OPSCC. This metric is readily available to the Radiation Oncologist at tumour delineation, and therefore may aid dose de-escalation decision making, without added delay. Future work may investigate cautious dose de-escalation in a cohort with smaller GTVs. [ABSTRACT FROM AUTHOR]

All head and neck cancer (HNC) patients receiving radiotherapy should have access to Speech and Language Therapy (SLT) for management of speech and swallowing(1). A pilot SLT education group programme, was delivered over a 10-week-period in a radiation-oncology (RO) service in 2023 as part of a waiting-list initiative. The purpose was to increase timely access to SLT for HNC patients. We aimed to evaluate the SLT pilot education group and make recommendations for future service delivery models. HNC patients receiving radical radiotherapy (n=22) prioritised as low-risk SLT patients, attending for RO, were identified and invited to attend an SLT education session. High-risk patients requiring intensive SLT intervention e.g. hypo-pharyngeal cancer, advanced laryngeal cancer and T4 tumours were excluded. Topics covered included an introduction to eating, drinking and swallow (ED&S) mechanisms, side-effects of radiotherapy and potential impact on ED&S, management strategies and prophylactic swallowing exercises. Sessions were interactive and patient information leaflets were provided. Invitations to attend additional sessions were extended; individual appointments were available on patient request. Swallowing outcomes (The MDADI global score, EAT-10) and patient satisfaction levels were completed at the time of attendance. Data was collected on patient demographics, treatment plans, attendance rates, admissions, patient self-report of dysphagia and impact on quality of life. Waiting-list times and cost savings were calculated. The results demonstrated that 14 patients attended (64%) the offered education session (9 males; mean age 66.5, range 46-84 years) The majority of patients had disease staging as ≤T2 (57%; 8/14). Attendees were heterogeneous with regard to tumour location (Table 1). No patients requested individual appointments. Of 14 attendees, 5 required inpatient admission (36%), compared to 6 (75%) patients who were invited and did-not-attend the education session. Reason for admission analysis revealed all 5 attendees required admission for symptom control, chiefly pain management, nausea, constipation and weight loss. Requirement for NG feeding was stated in 3/5 (60%) cases. Inpatient NG insertion requirement in the non-attender cohort was 67% (4/6). Treatment for pneumonia was required in 0% of cases. Attendees were admitted later into their treatment (mean fraction at time of admission 32; range 28-35) when compared to non-attendees (mean fraction at time of admission 23.5; range 13-35). The presence of oropharyngeal dysphagia as per self-report was identified in 8 (57%; EAT-10 score ≥3) attendees. However, the majority of attendees did not consider dysphagia as affecting quality-of-life (Mean MDADI global-question score of 3). All attendees reported the education session as helpful, they planned to implement advice given and would recommend attendance to fellow-patients. Seven patients received SLT input within local departmental standards (KPI of by 5 fractions). An additional 7 patients accessed SLT who would not have been seen due to service constraints. A further 8 patients would have received SLT guidance if they had attended the education session offered. When comparing costings for individual versus group interventions, a saving of €482.46 could be made per group programme for a similar patient cohort(2). [Display omitted] This waiting-list group initiative provided access to SLT for a cohort of low-risk HNC patients who would not have received guidance due to departmental service constraints. This pilot study has shown that group interventions can be an effective way to introduce the role of SLT, deliver general patient education and introduce swallowing rehabilitation to this specific client group. Preliminary findings suggest that this pilot waiting-list initiative was an effective medium to enhance patient experience and encourage patient autonomy and empowerment for HNC patients during their radiation-oncology journey. However, this pilot programme was delivered to a low-risk HNC patient cohort and a similar approach may not be appropriate for HNC patients with more extensive disease where an individualised treatment programme is the gold-standard (3). Group intervention can be a necessary solution to address service delivery demands in the existence of resource constraints. Nevertheless, the value, impact and effectiveness of tailored face-to-face SLT interventions with HNC patients who present with acute, chronic and complex ED&S needs cannot be underestimated(4, 5). This initiative will continue and facilitate further analysis regarding admission avoidance, alternative feeding requirement and swallow function outcomes. Further analysis exploring rationale for nonattendance will assist with future programme design. Data will also be used to assist with future service development, resource allocation and staff planning. [ABSTRACT FROM AUTHOR]

The onset of the COVID-19 outbreak caused major interruptions to the entire healthcare network affecting most oncological referral, diagnosis and treatment pathways. Oropharyngeal cancer patients were a particularly vulnerable group during this period as many were reluctant to present to hospital due to their concerns of contracting the virus. This created a potential for delayed presentation in keeping with more advanced disease with potential for worsened outcomes. We designed a retrospective study to analyse differences in patient presenting stage, treatment encountered, delays encountered and treatment outcomes for patients with oropharyngeal cancer treated before and during the COVID pandemic. All patients receiving radical radiotherapy for oropharyngeal cancer pre-COVID (July 17–July 18= GROUP 1) and during COVID (Mar 20–Mar 21= GROUP 2) in a large Irish tertiary referral network were included. Patient and disease characteristics, diagnostic timelines, treatment delays and disease outcomes were extracted from patient records. Patients were excluded if performance status was not suitable for curative treatment, if evidence of metastatic disease or if any history of prior head and neck radiotherapy. [Display omitted] 159 patients were suitable for assessment, 76 in Group 1 and 83 in Group 2. Median follow up was 48 months in Group 1 and 23 months in Group 2. When comparing Group 1 and 2: TNM overall stage were as follows: Stage 1: (25% vs 45.8%), Stage 2: (28.9% vs 18%), Stage 3:(21% vs 15.7%), Stage 4:(25% vs 20.5%). When grouped by stage we found no statistically significant difference in presentation stage between Group 1 and 2 (p=0.268). Use of hypofractionated regimen (65Gy/30fr) increased during the pandemic (2.6% to 10.8%) in keeping with international guidelines. There was no change in numbers of patients experiencing significant treatment delays between groups, with COVID related sepsis accounting for one significant delay and one death during treatment. There was a small but non-significant reduction in the use of concomitant chemotherapy from 93.4% in group 1 to 85.5% in group 2 (p=0.269). Overall survival assessed at 2 years was 77% in Group 1 and 85% in Group 2 (p=0.350). Disease free survival assessed at 2 years was 69% in Group 1 and 76% in Group 2 (p=0.567). [Display omitted] In spite of challenges related to the COVID-19 pandemic, this study has demonstrated that oropharyngeal cancer patients' treatment standards and outcomes were maintained within a large tertiary referral centre in Ireland. This study is one of the largest assessing the impact of the COVID-19 pandemic on head and neck radiotherapy patients. We did not demonstrate any difference in overall survival and disease free survival at 2 years when compared to a similar group prior to the pandemic. Furthermore we did not demonstrate any worsening of presenting stage related to delayed presentations during the pandemic. [ABSTRACT FROM AUTHOR]

Abstract: Background: An unexpected finding from the phase III parotid sparing radiotherapy trial, PARSPORT (ISRCTN48243537, CRUK/03/005), was a statistically significant increase in acute fatigue for those patients who were treated with intensity-modulated radiotherapy (IMRT) compared to standard conventional radiotherapy (CRT). One possible explanation was the difference in dose to central nervous system (CNS) structures due to differing beam portals. Using data from the trial, a dosimetric analysis of individual CNS structures was performed. Method: Dosimetric and toxicity data were available for 67 patients (27 CRT, 40 IMRT). Retrospective delineation of the posterior fossa, brainstem, cerebellum, pituitary gland, pineal gland, hypothalamus, hippocampus and basal ganglia was performed. Dosimetry was reviewed using summary statistics and dose–volume atlases. Results: A statistically significant increase in maximum and mean doses to each structure was observed for patients who received IMRT compared to those who received CRT. Both maximum and mean doses were significantly higher for the posterior fossa, brainstem and cerebellum for the 42 patients who reported acute fatigue of Grade 2 or higher (p ⩽0.01) compared to the 25 who did not. Dose–volume atlases of the same structures indicated that regions representing larger volumes and higher doses to each structure were consistent with a higher incidence of acute fatigue. There was no association between the dose distribution and acute fatigue for the other structures tested. Conclusions: The excess fatigue reported in the IMRT arm of the trial may, at least in part, be attributed to the dose distribution to the posterior fossa, cerebellum and brainstem. Future studies that modify dose delivery to these structures may allow us to test the hypothesis that radiation-induced fatigue is avoidable. [Copyright &y& Elsevier]

This study investigates whether spinal deviations exceeding 5mm from the planned position during Head & Neck cancer radiotherapy, detected using a rigid registration IGRT approach, warrant rescans or replans. Varian's Velocity™ software package was employed to perform Deformable Image Registration (DIR) on ten radical H&N cases which required re-scanning and re-planning when evaluated using a rigid registration approach. The deformation field was used to generate Synthetic CT's (sCT) using Velocity to evaluate the dosimetric impact of the spinal deviations in Eclipse™. Our findings revealed that 6 out of the 10 plans (60%) exhibiting spinal deviations >5mm and evaluated using a rigid registration approach did not necessitate a replan or rescan, maintaining a dosimetric impact of <2% and adhering to institutional Dose Volume Constraint (DVC) tolerances. Conversely, only 4 of the 10 cases required a rescan and replan when deformation was utilised for evaluation. Rigid registration cannot always account for the anatomical deviations in spinal positions noted during Head & Neck Radiothearpy. The substantial workflow implications of unnecessary rescans and replans accentuate the need for effective adaptive workflows like DIR in making informed decisions in Head & Neck radiotherapy. [ABSTRACT FROM AUTHOR]

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website. • A Delphi process achieved global consensus on key variables to use in a H & N cancer database. • Consensus was endorsed by 19 research organizations representing 34 countries. • This study presents a framework for harmonized data collection in Head & Neck cancer research. [ABSTRACT FROM AUTHOR]

One of the key components of training in Radiation Oncology is gaining knowledge in contouring tumour volumes and organs at risk for radiotherapy planning. Trainees rotate through different tumour sites during their training and are expected to acquire competencies in contouring skills in tumour sites appropriate to their year of training. These skills are mostly acquired in an unstructured manner during supervised clinical work. We report on our institutional experience of introducing structured contouring workshops and on the feedback obtained from trainees. Eight contouring workshops in different tumour sites - Head & Neck (n=3), Prostate (n=1), SABR Lung (n=2), Breast (n=1) and Oesophagus (n=1) were conducted between April 2019 and March 2022.Six were in-person workshops pre-COVID. Two were run virtually during the pandemic. The workshops were of 2-hour duration, limited to around 12 trainees each with varying degrees of experience in that particular tumour site. All workshops were similar in format with a tutorial on the tumour site followed by a contouring demonstration on an anonymised index case on the Eclipse planning platform referencing published contouring atlases. The trainees had access to a copy of the same case throughout the workshop. Their contours were reviewed individually and collectively. Feedback on the contouring experience was collected through a questionnaire after the workshop from each trainee. This feedback was incorporated into subsequent workshops where relevant. An average of 12 trainees (range 10 -14) attended the workshops. All trainees, irrespective of year of training, rated the content, format of the workshops highly and felt that they were relevant to their daily practice. Their reported subjective level of confidence in contouring improved significantly from an average score of 5.6 out of 10 (range 4-7) before the workshop to a score of 8.7 (range 8-9) after, over the 8 workshops. There was no cost associated with conducting these workshops as these were done on our existing planning software. Based on the feedback obtained from the trainees, the workshops were of definite educational benefit. They favoured the inclusion of this approach to the teaching of contouring skills in their curriculum. In keeping with this feedback and the recent implementation of the new radiation oncology training curriculum in Ireland efforts are currently underway in incorporating these contouring workshops into the training programme on a structured basis. This will ensure that trainees develop progressive expertise in contouring skills in keeping with highest international standards. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Magnetic resonance imaging (MRI) provides superior diagnostic accuracy over computed tomography (CT) in oropharyngeal tumours. Precise delineation of the gross tumour volume (GTV) is mandatory in radiotherapy planning when a GTV boost is required. CT volume definition in this regard is poor. We studied the feasibility of using flexible surface (flex-L) coils to obtain MR images for MR–CT fusion to assess the benefit of MRI over CT alone in planning base of tongue tumours. Methods: Eight patients underwent CT and MRI radiotherapy planning scans with an immobilisation device. Distortion-corrected T1-weighted post-contrast MR scans were fused to contrast-enhanced planning CT scans. GTV, clinical target and planning target volumes (CTV, PTV) and organs at risk (OAR) were delineated on CT, then on MRI with blinding to the CT images. The volumetric and spatial differences between MRI and CT volumes for GTV, CTV, PTV and OAR were compared. MR image distortions due to field inhomogeneity and non-linear gradients were corrected and the need for such correction was evaluated. Results: The mean primary GTV was larger on MRI (22.2 vs. 9.5cm3, p =0.05) than CT. The mean primary and nodal GTV (i.e. BOT and macroscopic nodes) was significantly larger on MRI (27.2 vs. 14.4cm3, p =0.05). The volume overlap index (VOI) between MRI and CT for the primary was 0.34 suggesting that MRI depicts parts of the primary tumour not detected by CT. There was no significant difference in volume delineation between MR and CT for CTV, PTV, nodal CTV and nodal PTV. MRI volumes for brainstem and spinal cord were significantly smaller due to improved organ definition (p =0.002). Susceptibility and gradient-related distortions were not found to be clinically significant. Conclusion: MRI improves the definition of tongue base tumours and neurological structures. The use of MRI is recommended for GTV dose-escalation techniques to provide precise depiction of GTV and improved sparing of spinal cord and brainstem. [Copyright &y& Elsevier]