Corrigendum to 'Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomised clinical trial'.

[This corrects the article DOI: 10.1016/j.eclinm.2022.101809.].

Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial.

Background: Psilocybin has been suggested as a novel, rapid-acting treatment for depression. Two consecutive doses have been shown to markedly decrease symptom severity in an open-label setting or when compared to a waiting list group. To date, to our knowledge, no other trial compared a single, moderate dose of psilocybin to a placebo condition. Methods: In this double-blind, randomised clinical trial, 52 participants diagnosed with major depressive disorder and no unstable somatic conditions were allocated to receive either a single, moderate dose (0.215 mg/kg body weight) of psilocybin or placebo in conjunction with psychological support. MADRS and BDI scores were assessed to estimate depression severity, while changes from baseline to 14 days after the intervention were defined as primary endpoints. The trial took place between April 11th, 2019 and October 12th, 2021 at the psychiatric university hospital in Zürich, Switzerland and was registered with clinicaltrials.gov (NCT03715127). Findings: The psilocybin condition showed an absolute decrease in symptom severity of -13.0 points compared to baseline and were significantly larger than those in the placebo condition (95% CI -15.0 to -1.3; Cohens' d = 0.97; P = 0.0011; MADRS) and -13.2 points (95% CI; -13.4 to -1.3; Cohens' d = 0.67; P = 0.019; BDI) 14 days after the intervention. 14/26 (54%) participants met the MADRS remission criteria in the psilocybin condition. Interpretation: These results suggest that a single, moderate dose of psilocybin significantly reduces depressive symptoms compared to a placebo condition for at least two weeks. No serious adverse events were recorded. Larger, multi-centric trials with longer follow-up periods are needed to inform further optimisation of this novel treatment paradigm. Funding: The study was funded by the Swiss National Science Foundation, Crowdfunding, the Swiss Neuromatrix Foundation, and the Heffter Research Institute.

The HLS19-COM-P, a New Instrument for Measuring Communicative Health Literacy in Interaction with Physicians: Development and Validation in Nine European Countries.

BACKGROUND: Sufficient communicative health literacy (COM-HL) is important for patients actively participating in dialogue with physicians, expressing their needs and desires for treatment, and asking clarifying questions. There is a lack of instruments combining communication and HL proficiency. Hence, the aim was to establish an instrument with sufficient psychometric properties for measuring COM-HL. METHODS: The HLS19-COM-P instrument was developed based on a conceptual framework integrating HL with central communicative tasks. Data were collected using different data collection modes in nine countries from December 2019 to January 2021 (n = 18,674). Psychometric properties were assessed using Rasch analysis and confirmatory factor analysis. Cronbach's alpha and Person separation index were considered for reliability. RESULTS: The 11-item version (HLS19-COM-P-Q11) and its short version of six items (HLS19-COM-P-Q6) fit sufficiently the unidimensional partial credit Rasch model, obtained acceptable goodness-of-fit indices and high reliability. Two items tend to under-discriminate. Few items displayed differential item functioning (DIF) across person factors, and there was no consistent pattern in DIF across countries. All items had ordered response categories. CONCLUSIONS: The HLS19-COM-P instrument was well accepted in nine countries, in different data collection modes, and could be used to measure COM-HL.

Challenges in Navigating the Health Care System: Development of an Instrument Measuring Navigation Health Literacy.

Due to their rapid expansion and complexity, it is increasingly difficult for patients to orient themselves in health care systems. Therefore, patients require a high degree of health literacy, or more precisely, navigation health literacy (HL-NAV). The actual extent of HL-NAV of patients and citizens is still largely unknown due to the lack of adequate measurement instruments. Thus, within the new international Health Literacy Population Survey 2019 (HLS19), one aim was to develop a suitable instrument for measuring HL-NAV in the HLS19 the HL-NAV-HLS19. The item development was conducted by an international working group within the HLS19 Consortium led by the first and last authors. Methodologically, it is based on a scoping literature review, development of a conceptual framework for HL-NAV, and first item formation, as well as an evaluation by experts, stakeholders, focus groups, pre-test interviews, and continuously feedback from the HLS19 Consortium. HL-NAV was defined as the ability to access, understand, appraise, and apply information on navigational issues, drawing on ten selected publications and the health literacy definition of the HLS-EU Consortium. Main tasks of HL-NAV at the system, organization, and interaction level were identified, to which first related items were assigned. Based on the feedback from experts, the focus group discussions, and the HLS19 Consortium, the instrument was slightly revised. Finally, twelve items proved to be feasible in the pre-test. The instrument will be used for the first time in the HLS19 survey and will provide first data on HL-NAV in general populations for the countries participating in HLS19. It is suited for cross-country comparisons and monitoring, as well as for intervention development. However, the instrument should be translated into and validated in further languages and countries for population samples.

Health Literacy in Austria: Interventions and Research.

This report provides an overview of Austria's approaches to improve population health literacy (HL). The report suggests: a) research can trigger health policy responses to improve HL; b) linking HL improvement to other reform agendas can boost effectiveness, and c) coordination is required for continuously and systematically working towards better HL. Examples of strategic thematic approaches and interventions - especially in the fields of communication in healthcare, health information products, and organizational HL responsiveness - are provided, and Austria's role in preparing the next European HL survey, HLS19, is briefly described.

[Hemochromatosis related Arthropathy]. / Hämochromatose assoziierte Arthropathie.

Hemochromatosis related Arthropathy Abstract. Hemochromatosis is an autosomal recessive disease that is caused by an HFE gene mutation (High Iron Fe) in most patients. Pathophysiologically, the effect of the mutation is an increased iron absorption in the gut. It is a systemic disorder which, in addition to the involvement of the musculoskeletal system (MSK), can lead to a diabetic metabolic state, liver cirrhosis and skin discoloration, as well as other organ manifestations such as cardiopathy or hypogonadism in the late stages. MSK complications include arthropathy in the form of osteoarthritis, typically of the MCP 2 and 3 joints, and calcium pyrophosphate-associated (CPPD) arthritis. Osteoporosis, as a further complication, is multifactorial. The therapy of hemochromatosis consists of phlebotomy, oral therapy with iron chelators is also possible. Although, these measures have a positive effect on the development of organ complications such as liver cirrhosis, they show little effect on the MSK manifestations, which are treated in analogy to the idiopathic osteoarthritis or pseudogout. The same is true for osteoporosis.

Strengthening patient and family engagement in healthcare - The New Haven Recommendations.

OBJECTIVE: Present and discuss the development and basic structure of a multilevel approach to strengthen patient and family engaged care, "The New Haven Recommendations on partnering with patients, families and citizens to enhance performance and quality in health promoting hospitals and health services". METHODS: A generic literature review was conducted followed by a Delphi procedure to prepare the New Haven Recommendations. From systems theory perspective, three conceptual levels are used to map action areas to enhance patient and family engaged care. RESULTS: The recommendations propose a multilevel approach to enable patient, family, (and citizen representatives') involvement (a) within direct service provision; (b) among hospitals and health services; (c) in planning healthcare delivery systems and policy. CONCLUSION: The New Haven Recommendations provide a strategic tool and practical recommendations, which can be used for reflection on current practices or generating new ways of thinking about patient and family engaged care. They support the development of patient and family engaged care as core aspect of high quality healthcare, and can contribute to achieving the Ottawa Charter's claim of reorienting health services. PRACTICE IMPLICATIONS: The potential benefit of the multilevel approach is to reorient the basic culture of healthcare towards patient- and health-centered care.

Impact of coronal and sagittal views on lung gross tumor volume delineation.

BACKGROUND AND PURPOSE: To study the impact of coronal and sagittal views (CSV) on the gross tumor volume (GTV) delineation on CT and matched PET/CT scans in non-small cell lung cancer. MATERIAL AND METHODS: GTV delineations were performed by 11 experienced radiation oncologists on CT and PET/CT in 22 patients. Two tumor groups were defined: Group I: Primary tumors surrounded by lung or visceral pleura, without venous invasion, and without large extensions to the chest wall or the mediastinum. Group II: Tumors invading the hilar region, heart, large vessels, pericardium, and the mediastinum and/or associated with atelectasis. Tumor volumes and inter-observers variations (SD) were calculated and compared according to the use of axial view only (AW), axial/coronal/sagittal views (ACSW) and ACSW/PET (ACSWP). RESULTS: CSV were not frequently used (57.4% out of 242 delineations on CT). For group I, ACSW didn't improve significantly mean GTVs. SDs were small on CT and on PET (SD=0.3cm). For group II, ACSW had 27-46% smaller observer variation (mean SD=0.7cm) than AW (mean SD=1.1cm). The smaller observer variation of ACSW users was associated with, on average, a 40% smaller delineated volume (p=0.038). Mean GTV of ACSWP was 21% larger than mean GTV of ACSW on CT. CONCLUSIONS: For smaller lung tumors surrounded by healthy lung tissue the effect of multiple axis delineation is limited. However, application of coronal and sagittal windows is highly beneficial for delineation of more complex tumors, with atelectasis and/or pathological lymph nodes even if PET is used.

Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis.

PURPOSE: Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. METHODS AND MATERIALS: Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for ≤3 months, ≥2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. RESULTS: With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. CONCLUSIONS: For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.

Fractionated stereotactic radiotherapy for uveal melanoma, late clinical results.

PURPOSE: To determine local control, late toxicity and metastatic free survival (MFS) of patients treated with fractionated stereotactic radiation therapy (fSRT) for uveal melanoma (UM). METHODS AND MATERIALS: Between 1999 and 2007, 102 UM patients were included in a prospective study of a single institution (median follow-up (FU) 32 months; median tumor thickness 6 mm); five fractions of 10 Gy were given. Primary endpoints were local tumor control and late toxicity (including visual outcome and eye preservation). Secondary endpoint was MFS. RESULTS: Local tumor control was achieved in 96% of the patients. Fifteen enucleations were performed, 2-85 months after radiation. Four eyes were enucleated because of local tumor progression. Nine patients developed grade 3 or 4 neovascular glaucoma (NVG), 19 developed severe retinopathy, 13 developed opticoneuropathy grade 3 or 4, 10 developed cataract grade 3, and 10 patients suffered from keratitis sicca. Best corrected visual acuity (BCVA) decreased from a mean of 0.26 at diagnosis to 0.16, 3 months after radiation and it gradually declined to 0.03, 4 years after therapy. The 5-year actuarial MFS was 75% (95% CIs: 62-84%). CONCLUSIONS: fSRT is an effective treatment modality for uveal melanoma with a good local control. With that, fSRT is a serious eye sparing treatment modality. However, our FU is relatively short. Also, the number of secondary enucleations is substantial, mainly caused by NVG.

Comparison of macroscopic pathology measurements with magnetic resonance imaging and assessment of microscopic pathology extension for colorectal liver metastases.

PURPOSE: To compare pathology macroscopic tumor dimensions with magnetic resonance imaging (MRI) measurements and to establish the microscopic tumor extension of colorectal liver metastases. METHODS AND MATERIALS: In a prospective pilot study we included patients with colorectal liver metastases planned for surgery and eligible for MRI. A liver MRI was performed within 48 hours before surgery. Directly after surgery, an MRI of the specimen was acquired to measure the degree of tumor shrinkage. The specimen was fixed in formalin for 48 hours, and another MRI was performed to assess the specimen/tumor shrinkage. All MRI sequences were imported into our radiotherapy treatment planning system, where the tumor and the specimen were delineated. For the macroscopic pathology analyses, photographs of the sliced specimens were used to delineate and reconstruct the tumor and the specimen volumes. Microscopic pathology analyses were conducted to assess the infiltration depth of tumor cell nests. RESULTS: Between February 2009 and January 2010 we included 13 patients for analysis with 21 colorectal liver metastases. Specimen and tumor shrinkage after resection and fixation was negligible. The best tumor volume correlations between MRI and pathology were found for T1-weighted (w) echo gradient sequence (r(s) = 0.99, slope = 1.06), and the T2-w fast spin echo (FSE) single-shot sequence (r(s) = 0.99, slope = 1.08), followed by the T2-w FSE fat saturation sequence (r(s) = 0.99, slope = 1.23), and the T1-w gadolinium-enhanced sequence (r(s) = 0.98, slope = 1.24). We observed 39 tumor cell nests beyond the tumor border in 12 metastases. Microscopic extension was found between 0.2 and 10 mm from the main tumor, with 90% of the cases within 6 mm. CONCLUSIONS: MRI tumor dimensions showed a good agreement with the macroscopic pathology suggesting that MRI can be used for accurate tumor delineation. However, microscopic extensions found beyond the tumor border indicate that caution is needed in selecting appropriate tumor margins.

Consumer participation and organizational development in health care: a systematic review.

OBJECTIVE: To provide an overview of published data on user participation in Health Care. BACKGROUND: Active and passive involvement of consumers into agendas associated with Health Care is still an exception. Data on the success of user participation projects in various areas of Health Care are lacking. DESIGN: Systematic literature review using public databases. RESULTS: We identified 467 studies including five systematic reviews describing various participation projects, among them workshops, citizens' panels, focus groups, citizens' juries, and consultation meetings. A general trend favoring a specific method was not observed. The categorization of evaluable studies according to Health Care area (n = 331) yielded the following results: general medicine/preventive medicine (n = 5), internal medicine/oncology (n = 132), obstetrics and gynecology (n = 2), surgery (n = 1), neurology/psychiatry (n = 2), social medicine (n = 16), health worker training (n = 38), and research agenda setting (n = 135). Predefined qualitative parameters were extracted from 69/467 (15%) studies. Sixty one of 69 studies (88%) were retrospective analyses without control groups and without outcome assessment. Six studies had outcome assessment, three judged the outcome as successful, two as negative, and one multi-project study reported 'very successful' project assessments in 24% of the projects. In 18 studies, the level of consumer participation was described as 'informed' in 2/18, 'advisory' in 14/18, and 'decision-making' in 2/18. The following factors associated with project success were identified: adequate financing, partnerships with well institutionalized consumer organizations, advanced project logistics, small-scale projects, and adequate internal and external communication. CONCLUSIONS: Most consumer participation projects were performed in research agenda setting, internal medicine/oncology, and health worker training. Various methods have been used in the projects, the level of consumer participation was low, and the success rate of the investigated projects was moderate. Potential factors associated with project success and future areas of research are discussed.

Synthesis of qualitative linguistic research--a pilot review integrating and generalizing findings on doctor-patient interaction.

OBJECTIVE: There is a broad range qualitative linguistic research (sequential analysis) on doctor-patient interaction that had only a marginal impact on clinical research and practice. At least in parts this is due to the lack of qualitative research synthesis in the field. Available research summaries are not systematic in their methodology. This paper proposes a synthesis methodology for qualitative, sequential analytic research on doctor-patient interaction. METHODS: The presented methodology is not new but specifies standard methodology of qualitative research synthesis for sequential analytic research. RESULTS: This pilot review synthesizes twelve studies on German-speaking doctor-patient interactions, identifies 45 verbal actions of doctors and structures them in a systematics of eight interaction components. Three interaction components ("Listening", "Asking for information", and "Giving information") seem to be central and cover two thirds of the identified action types. CONCLUSIONS: This pilot review demonstrates that sequential analytic research can be synthesized in a consistent and meaningful way, thus providing a more comprehensive and unbiased integration of research. Future synthesis of qualitative research in the area of health communication research is very much needed. PRACTICE IMPLICATIONS: Qualitative research synthesis can support the development of quantitative research and of educational materials in medical training and patient training.

Clinical validation of atlas-based auto-segmentation of multiple target volumes and normal tissue (swallowing/mastication) structures in the head and neck.

PURPOSE: To validate and clinically evaluate autocontouring using atlas-based autosegmentation (ABAS) of computed tomography images. METHODS AND MATERIALS: The data from 10 head-and-neck patients were selected as input for ABAS, and neck levels I-V and 20 organs at risk were manually contoured according to published guidelines. The total contouring times were recorded. Two different ABAS strategies, multiple and single subject, were evaluated, and the similarity of the autocontours with the atlas contours was assessed using Dice coefficients and the mean distances, using the leave-one-out method. For 12 clinically treated patients, 5 experienced observers edited the autosegmented contours. The editing times were recorded. The Dice coefficients and mean distances were calculated among the clinically used contours, autocontours, and edited autocontours. Finally, an expert panel scored all autocontours and the edited autocontours regarding their adequacy relative to the published atlas. RESULTS: The time to autosegment all the structures using ABAS was 7 min/patient. No significant differences were observed in the autosegmentation accuracy for stage N0 and N+ patients. The multisubject atlas performed best, with a Dice coefficient and mean distance of 0.74 and 2 mm, 0.67 and 3 mm, 0.71 and 2 mm, 0.50 and 2 mm, and 0.78 and 2 mm for the salivary glands, neck levels, chewing muscles, swallowing muscles, and spinal cord-brainstem, respectively. The mean Dice coefficient and mean distance of the autocontours vs. the clinical contours was 0.8 and 2.4 mm for the neck levels and salivary glands, respectively. For the autocontours vs. the edited autocontours, the mean Dice coefficient and mean distance was 0.9 and 1.6 mm, respectively. The expert panel scored 100% of the autocontours as a "minor deviation, editable" or better. The expert panel scored 88% of the edited contours as good compared with 83% of the clinical contours. The total editing time was 66 min. CONCLUSION: Multiple-subject ABAS of computed tomography images proved to be a useful novel tool in the rapid delineation of target and normal tissues. Although editing of the autocontours is inevitable, a substantial time reduction was achieved using editing, instead of manual contouring (180 vs. 66 min).

A microcosting study of microsurgery, LINAC radiosurgery, and gamma knife radiosurgery in meningioma patients.

The aim of the present study is to determine and compare initial treatment costs of microsurgery, linear accelerator (LINAC) radiosurgery, and gamma knife radiosurgery in meningioma patients. Additionally, the follow-up costs in the first year after initial treatment were assessed. Cost analyses were performed at two neurosurgical departments in The Netherlands from the healthcare providers' perspective. A total of 59 patients were included, of whom 18 underwent microsurgery, 15 underwent LINAC radiosurgery, and 26 underwent gamma knife radiosurgery. A standardized microcosting methodology was employed to ensure that the identified cost differences would reflect only actual cost differences. Initial treatment costs, using equipment costs per fraction, were 12,288 for microsurgery, 1,547 for LINAC radiosurgery, and 2,412 for gamma knife radiosurgery. Higher initial treatment costs for microsurgery were predominantly due to inpatient stay (5,321) and indirect costs (4,350). LINAC and gamma knife radiosurgery were equally expensive when equipment was valued per treatment (2,198 and 2,412, respectively). Follow-up costs were slightly, but not significantly, higher for microsurgery compared with LINAC and gamma knife radiosurgery. Even though initial treatment costs were over five times higher for microsurgery compared with both radiosurgical treatments, our study gives indications that the relative cost difference may decrease when follow-up costs occurring during the first year after initial treatment are incorporated. This reinforces the need to consider follow-up costs after initial treatment when examining the relative costs of alternative treatments.

Primary radiotherapy in progressive optic nerve sheath meningiomas: a long-term follow-up study.

BACKGROUND/AIMS To report the outcome of primary radiotherapy in patients with progressive optic nerve sheath meningioma (ONSM). METHODS The clinical records of all patients were reviewed in a retrospective, observational, multicentre study. RESULTS Thirty-four consecutive patients were included. Twenty-six women and eight men received conventional or stereotactic fractionated radiotherapy, and were followed for a median 58 (range 51-156) months. Fourteen eyes (41%) showed improved visual acuity of at least two lines on the Snellen chart. In 17 (50%) eyes, the vision stabilised, while deterioration was noted in three eyes (9%). The visual outcome was not associated with age at the time of radiotherapy (p=0.83), sex (p=0.43), visual acuity at the time of presentation (p=0.22) or type of radiotherapy (p=0.35). Optic disc swelling was associated with improved visual acuity (p<0.01) and 4/11 patients with optic atrophy also showed improvement. Long-term complications were dry eyes in five patients, cataracts in three, and mild radiation retinopathy in four. CONCLUSION Primary radiotherapy for patients with ONSM is associated with long-term improvement of visual acuity and few adverse effects.

Decreased 3D observer variation with matched CT-MRI, for target delineation in Nasopharynx cancer.

PURPOSE: To determine the variation in target delineation of nasopharyngeal carcinoma and the impact of measures to minimize this variation. MATERIALS AND METHODS: For ten nasopharyngeal cancer patients, ten observers each delineated the Clinical Target Volume (CTV) and the CTV elective. After 3D analysis of the delineated volumes, a second delineation was performed. This implied improved delineation instructions, a combined delineation on CT and co-registered MRI, forced use of sagittal reconstructions, and an on-line anatomical atlas. RESULTS: Both for the CTV and the CTV elective delineations, the 3D SD decreased from Phase 1 to Phase 2, from 4.4 to 3.3 mm for the CTV and from 5.9 to 4.9 mm for the elective. There was an increase agreement, where the observers intended to delineate the same structure, from 36 to 64 surface % (p = 0.003) for the CTV and from 17 to 59% (p = 0.004) for the elective. The largest variations were at the caudal border of the delineations but these were smaller when an observer utilized the sagittal window. Hence, the use of sagittal side windows was enforced in the second phase and resulted in a decreased standard deviation for this area from 7.7 to 3.3 mm (p = 0.001) for the CTV and 7.9 to 5.6 mm (p = 0.03) for the CTV elective. DISCUSSION: Attempts to decrease the variation need to be tailored to the specific causes of the variation. Use of delineation instructions multimodality imaging, the use of sagittal windows and an on-line atlas result in a higher agreement on the intended target.

Stereotactic body radiation therapy for liver tumors: impact of daily setup corrections and day-to-day anatomic variations on dose in target and organs at risk.

PURPOSE: To assess day-to-day differences between planned and delivered target volume (TV) and organ-at-risk (OAR) dose distributions in liver stereotactic body radiation therapy (SBRT), and to investigate the dosimetric impact of setup corrections. METHODS AND MATERIALS: For 14 patients previously treated with SBRT, the planning CT scan and three treatment scans (one for each fraction) were included in this study. For each treatment scan, two dose distributions were calculated: one using the planned setup for the body frame (no correction), and one using the clinically applied (corrected) setup derived from measured tumor displacements. Per scan, the two dose distributions were mutually compared, and the clinically delivered distribution was compared with planning. Doses were recalculated in equivalent 2-Gy fraction doses. Statistical analysis was performed with the linear mixed model. RESULTS: With setup corrections, the mean loss in TV coverage relative to planning was 1.7%, compared with 6.8% without corrections. For calculated equivalent uniform doses, these figures were 2.3% and 15.5%, respectively. As for the TV, mean deviations of delivered OAR doses from planning were small (between -0.4 and +0.3 Gy), but the spread was much larger for the OARs. In contrast to the TV, the mean impact of setup corrections on realized OAR doses was close to zero, with large positive and negative exceptions. CONCLUSIONS: Daily correction of the treatment setup is required to obtain adequate TV coverage. Because of day-to-day patient anatomy changes, large deviations in OAR doses from planning did occur. On average, setup corrections had no impact on these doses. Development of new procedures for image guidance and adaptive protocols is warranted.