The ultimate local failure rate after the watch-and-wait strategy for rectal cancer: a systematic review of literature and meta-analysis.

BACKGROUND: We hypothesise that a high rate of tumour regrowth after the watch-and-wait (w&w) strategy may lead, despite salvage surgery, to a significant impairment of ultimate local control compared with immediate surgery. MATERIALS AND METHODS: To test this hypothesis, we conducted meta-analyses of studies on the w&w strategy (both opportunistic and planned) with an ultimate local failure rate as an endpoint in three patient groups: (1) in all starting radio(chemo)therapy as potential w&w candidates, (2) in a subgroup starting w&w, and (3) in a subgroup with regrowth. RESULTS: We identified eight studies for evaluation of local failure in group 1 (N = 837) and 36 studies in group 2 (N = 1914) and in group 3 (N = 439). The meta-analysis revealed an ultimate local failure rate of 8.0% (95% CI 4.8%-12.1%) in group 1 and 5.4% (95% CI 3.9%-7.1) in group 2. These rates are similar to those reported in the literature following preoperative chemoradiation and surgery. However, in the most unfavourable group 3 (with regrowth), the rate of ultimate local failure was 24.1% (95% CI 17.9%-30.9%), with the most common causes being patients' refusal of salvage total mesorectal excision (TME) (9.1%), recurrence after salvage TME (7.8%), distant metastases (4.1%), frailty (2.4%), and pelvic tumour unresectability (1.7%). CONCLUSION: Nearly 25% of patients with regrowth (unfavourable subgroup) experienced ultimate local failure, primarily due to refusing salvage TME. The risk of ultimate local failure in patients initiating radio(chemo)therapy as potential w&w candidates, or in patients starting w&w, appears comparable to that reported after preoperative chemoradiation and surgery. However, this comparison may be biased, because w&w studies included more early tumours compared with surgical studies.

Involvement of matrix metalloproteinases (MMP-2, -7, -9) and their tissue inhibitors (TIMP-2, -3) in the regression of chicken postovulatory follicles.

The study was undertaken to examine mRNA expression and localization of selected matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), and the activity of MMPs in chicken postovulatory follicles (POFs) during their apoptotic regression. Apoptotic cells and apoptosis-related caspase expression and activity were examined as well. Chickens were sacrificed 2 h and 21 h after ovulation, and five POFs (POF1 to POF5) were isolated from the ovaries. It was found that the number of apoptotic cells (TUNEL-positive) increased along with follicle regression. The relative expression (RQ) of caspase-2, -3, -8 and -9 mRNA increased (P < 0.05) in POF5, while the activity of all examined caspases elevated gradually (approximately 80-150%) reaching the highest level in POF3, and then slowly decreased to the value noted in POF1 (P < 0.05 - P < 0.001). Real-time polymerase chain reaction revealed different expression of MMP-2, -7, -9 and TIMP-2 and -3 on mRNA levels, and activity assay showed the changes in activity of MMP-2 and -9 in the POFs. Regression of the follicles was accompanied predominantly by an increase in the relative expression of MMP-2, and a decrease in TIMP-2 and -3 mRNAs (P < 0.05 - P < 0.001). The activity levels of MMP-2 and -9 showed pronounced changes during the examined period. During follicle regression elevated activity of MMP-2 and -9 was found (P < 0.05 - P < 0.001). Immunohistochemistry demonstrated tissue- and follicle-dependent immunoreactivity of the examined members of the MMP system. In summary, the results showing the apoptotic regression-related changes as well as tissue-dependent differences in the expression of selected MMPs and TIMPs, and activity of MMP-2 and MMP-9, point to the significance that these molecules might participate in the complex orchestration of chicken POF regression.

Expression of aquaporin 4 in the chicken oviduct following tamoxifen treatment.

This study was designed to examine whether aquaporin 4 (AQP4) is present in the chicken oviduct, and if so, whether its expression changes during pause in laying induced by tamoxifen (TMX; oestrogen receptor modulator) treatment. The control chickens were injected with a vehicle (ethanol) and the experimental ones with TMX at a dose of 6 mg/kg of body weight. Birds were treated daily until complete cessation of egg laying. The oviductal parts, that is the infundibulum, magnum, isthmus, shell gland and vagina were isolated from hens on day 8 of the experiment, and subsequently, the gene and protein expressions of AQP4 in tissues were examined by real-time PCR and Western blot, respectively. Immunohistochemical localization of AQP4 in the wall of the chicken oviduct was also investigated. Both mRNA and protein of AQP4 were found in all segments of the chicken oviduct. The relative expression [RQ] of AQP4 was the highest in the infundibulum and the vagina and the lowest, less detectable, in the magnum and isthmus. The pattern of AQP4 protein expression was similar to that of mRNA. Treatment of hens with TMX decreased the mRNA and protein levels of AQP4 in the oviduct. Immunohistochemistry demonstrated tissue and cell-dependent localization of AQP4 protein in the oviductal wall. The intensity of the immunopositive reaction was as follows: the infundibulum > vagina > shell gland ≥ isthmus >˃ magnum. In the control chickens, the immunoreactivity for AQP4 in all oviductal segments was stronger compared with the TMX-treated hens. The results obtained indicate that AQP4 takes part in the regulation of water transport required for the formation of egg in the chicken oviduct. Moreover, a relationship between oestrogen action and AQP4 gene and protein expression is suggested.

Outcome of treatment of recurrent glioblastoma multiforme in elderly and/or frail patients.

Optimal treatment of recurrent glioblastoma multiforme (rGBM) in elderly and/or frail patients remains virtually unexplored, the best supportive care (BSC) only is routinely administered due to the fatal prognosis. We evaluated the impact of different treatment methods on post-progression survival (PPS) and overall survival (OS) of such patients. Data from 98 elderly and/or frail rGBM patients, treated initially with 1-week or 3-week radiotherapy (RT) within the phase III IAEA study (2010-2013), were analyzed. KPS at relapse and salvage treatment methods were recorded. Kaplan-Meier method was used to estimate PPS and OS for different treatment modalities. Eighty-four patients experienced recurrence: 47 (56%) received BSC, 21 (25%)-chemotherapy (CHT), 8 (9.5%)-surgery, 3 (3.5%)-RT, for 5 (6%) the data was unavailable. Median OS from randomization for all 84 patients was 35 weeks: 55 versus 30 weeks for any treatment versus BSC, p < 0.0001. Median PPS was 15 weeks: 23 weeks with any treatment versus 9 weeks with BSC, p < 0.0001. For local treatment (surgery and/or RT) median PPS was 51 versus 21 weeks for CHT, p = 0.36. In patients with poor KPS (≤60) at relapse median PPS was 9 weeks with BSC versus 21 weeks with any treatment, p = 0.014. In poor KPS patients median PPS for local treatment was 14 weeks versus 21 weeks with CHT, p = 0.88. An active therapeutic approach may be beneficial for selected elderly and/or frail rGBM patients. Poor KPS patients may also benefit from active treatment, but there is no benefit of local treatment over CHT.

Accelerated hypofractionated thoracic radiotherapy in limited disease small cell lung cancer : comparison with the results of conventionally fractionated radiotherapy.

PURPOSE: To compare accelerated hypofractionated (A-HYPO) radiotherapy (RT) with conventionally fractionated (CF) thoracic RT in patients with limited-disease small-cell lung cancer (LD-SCLC). METHODS: Out of 217 consecutive LD-SCLC patients, treated between 1997 and 2012, 82 received CF-RT (44-60 Gy, 2 Gy/ fraction) sequentially to 4-6 cycles of platinum-based chemotherapy (CHT), and 100 received A-HYPO-RT (42 Gy, 2.8 Gy/ fraction). Forty-two patients (42%) received "early" (before the 3rd cycle of CHT) A-HYPO-RT, and 58 (58%) patients received "late" A-HYPO-RT. Overall survival (OS), locoregional failure risk (LRFR) and toxicities were retrospectively evaluated and compared between CF-RT and A-HYPO-RT groups (also separately for "early" and "late" A-HYPO-RT). RESULTS: Median survival times (MST) for CF-RT and A-HYPO-RT were 18 and 24 months, respectively; 3-year OS were 19.1 and 39.4%, respectively (p=0.004). Three-year LRFR in CF-RT was 47.3% and 34.0% in the A-HYPO- RT group (p=0.12). Statistically significant difference in OS (p=0.007) and LRFR (p=0.03) was observed, favoring "early" A-HYPO-RT (MST=27 months, 3-year OS=40.0%, 3-year LRFR=28.4%) over CF-RT. Use of CF-RT (relative risk/RR=1.65, p=0.02) and poor CHT compliance (RR=1.69, p=0.03) were independent prognostic factors for poor OS; "early" start of RT was a favorable although non-significant prognostic factor for LRFR (RR=0.42, p=0.05). No difference in toxicities was observed between the groups. CONCLUSIONS: A-HYPO-RT results in better outcomes than CF-RT. "Early" A-HYPO-RT provides additional benefit in locoregional control and survival, without increased toxicity. These results indicate the need for a randomized study on the efficacy of A-HYPO-RT.

Hypofractionated conformal radiotherapy in combination with chemotherapy in limited disease small cell lung cancer patients.

AIM: To evaluate the results of hypofractionated conformal radiotherapy (RT) in limited disease small cell lung cancer (LD-SCLC) patients, with particular interest in the value of "early" RT, i.e. given before the 3rd chemotherapy (CHT) cycle. MATERIAL AND METHODS: Outcome of hypofractionated RT (42 Gy, 2.8 Gy/fraction, given over 19-21 days, using "concomitant boost" technique - elective volume [39 Gy, 2.6 Gy/fraction] and tumour volumes treated during the same fraction) combined with CHT in 100 consecutive LD-SCLC patients, was retrospectively assessed. The outcomes were compared with a previously published series of 117 LD-SCLC patients treated in the same institution with hyperfractionated or conventionally fractionated RT. RESULTS: Forty-two patients (42%) received "early" RT. Grade 3 NCI CTC acute oesophageal toxicity appeared in 5% of patients. There were three treatment-related deaths. Three-year overall survival (OS) rate was 39.4%, median - 24 months in the examined group vs. 26.0%, and 18 months in historical control, P = 0.02. Three-year OS for 78 patients with completed CHT was 42.2%, median - 28 months vs. 30%, and 14 months for 22 patients who received ≤ 3 CHT cycles, (P = 0.03). The actuarial 3-year locoregional failure risk (LRFR) was 34.0% in the examined group vs. 51.0% in the historical control, P = 0.04. Multivariate analysis showed a marginally significant correlation between the "early" use of RT and LRFR: RR = 0.43 (95% CI: 0.17-1.04), P = 0.06, with no significant impact on OS. CONCLUSIONS: Shorter duration of RT using hypofractionation results in encouraging outcomes and acceptable toxicity. Completion of all planned CHT cycles is the most important factor for OS.

Which tumour factors preclude organ preservation in patients with rectal cancer?

BACKGROUND: cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes, extramural vascular invasion (EMVI) and mesorectal fascia threatening (MRF+) have been utilized as exclusion criteria in several studies on the watch-and-wait (w&w) strategy. Here, our aim was to validate these criteria through a post hoc analysis of two pooled prospective studies on w&w following routine radio(chemo)therapy. METHODS: A review of baseline magnetic resonance imaging was performed in a subgroup of 223 patients treated at a single institution. Of these, 17.9 % started w&w, 12.6 % achieved clinical complete response (cCR) and 9.0 % sustained cCR during median follow-up of 54 months. RESULTS: The multivariable logistic analysis showed that the proportion of circumferential bowel involvement and EMVI significantly influenced the chance of sustained cCR; odds ratios were 0.063 (95 % confidence interval [CI] 0.008-0.489, p = 0.008), and 0.109 (95 % CI 0.014-0.850, p = 0.034), respectively. Sustained cCR was observed in none of the 57 patients with 90 %-100 % circumferential bowel involvement and in only one of the 89 patients with EMVI. In contrast, cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes or MRF+ were not independently associated with sustained cCR. Among the subgroups of patients with these features but without (near-)circular tumour or EMVI+, sustained cCR was observed in 12 %-25 % of patients. CONCLUSION: Sustained cCR after routine preoperative radio(chemo)therapy is unlikely in patients with (near-)circular tumour or EMVI, whereas patients with cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes and MRF+ should not be denied w&w.

The potential of virtual triage AI to improve early detection, care acuity alignment, and emergent care referral of life-threatening conditions.

Objective: To evaluate the extent to which patient-users reporting symptoms of five severe/acute conditions requiring emergency care to an AI-based virtual triage (VT) engine had no intention to get such care, and whose acuity perception was misaligned or decoupled from actual risk of life-threatening symptoms. Methods: A dataset of 3,022,882 VT interviews conducted over 16 months was evaluated to quantify and describe patient-users reporting symptoms of five potentially life-threatening conditions whose pre-triage healthcare intention was other than seeking urgent care, including myocardial infarction, stroke, asthma exacerbation, pneumonia, and pulmonary embolism. Results: Healthcare intent data was obtained for 12,101 VT patient-user interviews. Across all five conditions a weighted mean of 38.5% of individuals whose VT indicated a condition requiring emergency care had no pre-triage intent to consult a physician. Furthermore, 61.5% intending to possibly consult a physician had no intent to seek emergency medical care. After adjustment for 13% VT safety over-triage/referral to ED, a weighted mean of 33.5% of patient-users had no intent to seek professional care, and 53.5% had no intent to seek emergency care. Conclusion: AI-based VT may offer a vehicle for early detection and care acuity alignment of severe evolving pathology by engaging patients who believe their symptoms are not serious, and for accelerating care referral and delivery for life-threatening conditions where patient misunderstanding of risk, or indecision, causes care delay. A next step will be clinical confirmation that when decoupling of patient care intent from emergent care need occurs, VT can influence patient behavior to accelerate care engagement and/or emergency care dispatch and treatment to improve clinical outcomes.

[Outcome after PET-CT based radiotherapy for non-small cell lung cancer]. / Wyniki radioterapii planowanej na podstawie badania PET-CTu chorych na niedrobnokomórkowego raka pluca

INTRODUCTION: The value of PET-CT in radiotherapy for non-small cell lung cancer (NSCLC) with regard to determination of target volumes is established. It is less clear whether its use can improve clinical outcomes of irradiated NSCLC patients compared to conventional staging. The outcome of NSCLC patients included in a previously published prospective study of the value of PET-CT in curative radiotherapy candidates was assessed. MATERIALS AND METHODS: Patients were treated according to the PET-CT findings. The survival data were compared between 67 patients treated curatively and 22 patients with palliative treatment given after upstaging based on the PET-CT findings. Survival of curatively treated stage III patients was compared with a previously published outcome of 173 stage III patients treated in the same institution with the same radiation schedule but without PET-CT. RESULTS: The 3-year overall survival was 42% and 0% (median: 21 months and 7 months), for curatively and palliatively managed patients, respectively (p 〈 0.0001). However, the median overall survival of 17 months for 50 stage III patients was the same as that in a previously published series of stage III patients treated with the same radiation schedule but without PET-CT. Three-year overall survival rates were 33% for the PET-CT group and 19% for historical group, p = 0.1. Twenty-one local recurrences and 21 distant metastases were reported. Three of 50 patients (6%) treated without elective nodal irradiation developed isolated nodal failure (without local recurrence). CONCLUSIONS: The high early mortality rate in the patients disqualified from curative radiotherapy after PET-CT suggests the potential value of PET-CT for improving the radiotherapy outcome. However, this benefit seems to be limited in stage III patients.

Does the Gain of Total Neoadjuvant Therapy Outweigh the Harm in Rectal Cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) Phenomenon: A Systematic Review.

BACKGROUND: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. METHODS: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. RESULTS: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. CONCLUSION: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM.

Dosimetric comparison of three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, and volumetric-modulated arc therapy for free-breathing whole-breast irradiation: A planning study.

Background: Currently, recommended heart dose constraints are difficult to meet in whole-breast irradiation (WBI) for left-sided breast cancer patients, who cannot be treated with the deep inspiration breath hold. We performed a radiotherapy planning study to establish if the use of intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) allows for better sparing of the heart and its subvolumes than the three-dimensional conformal radiation therapy (3D-CRT), and how these attempts affect the dose delivered to the other organs. Methods: A total of 17 left-sided and 10 right-sided consecutive patients treated with free-breathing WBI were retrospectively included. The 3D-CRT, IMRT, and VMAT plans were generated. Several dose-volume parameters and plan quality indices were compared, separately for the left- and right-sided plans. Results: All the techniques fulfilled the planning objectives. In the left-sided plans, there was no heart or left ventricle dose reduction with IMRT, nor with VMAT; the maximum dose in the left anterior descending coronary artery was reduced with VMAT (P = 0.005); V5 for the contralateral breast, contralateral lung, and total-body increased markedly in VMAT, and for the ipsilateral lung (V5IL) also in IMRT, compared with 3D-CRT (P < 0.001). In the right-sided plans, the V5 values, except for V5IL, did not differ between the three techniques. Conclusions: IMRT and VMAT had a limited heart-sparing benefit in the left-sided free-breathing WBI, at the cost of increased low-dose volumes, measured by V5. The low-dose volumes are not increased by IMRT or VMAT in the right-sided WBI, where heart sparing is not a problem, but the attempts to reduce cardiac doses in the left-sided WBI increase them.

How Virtual Triage Can Improve Patient Experience and Satisfaction: A Narrative Review and Look Forward.

Objective: To complete a review of the literature on patient experience and satisfaction as relates to the potential for virtual triage (VT) or symptom checkers to enhance and enable improvements in these important health care delivery objectives. Methods: Review and synthesis of the literature on patient experience and satisfaction as informed by emerging evidence, indicating potential for VT to favorably impact these clinical care objectives and outcomes. Results/Conclusions: VT enhances potential clinical effectiveness through early detection and referral, can reduce avoidable care delivery due to late clinical presentation, and can divert primary care needs to more clinically appropriate outpatient settings rather than high-acuity emergency departments. Delivery of earlier and faster, more acuity level-appropriate care, as well as patient avoidance of excess care acuity (and associated cost), offer promise as contributors to improved patient experience and satisfaction. The application of digital triage as a front door to health care delivery organizations offers care engagement that can help reduce patient need to visit a medical facility for low-acuity conditions more suitable for self-care, thus avoiding unpleasant queues and reducing microbiological and other patient risks associated with visits to medical facilities. VT also offers an opportunity for providers to make patient health care experiences more personalized.

The Role of Virtual Triage in Improving Clinician Experience and Satisfaction: A Narrative Review.

Objective: This review examines the literature on improving clinician satisfaction with a focus on what has been most effective in improving experience from the perspective of clinicians, and the potential role that virtual triage (VT) technology can play in delivering positive clinician experiences that improve clinical care, and bring value to health care delivery organizations (HDOs). Methods: Review and synthesis of evidence on clinician satisfaction indicating a potential for VT to favorably impact clinician experience, sense of effectiveness, efficiency, and reduction of administrative task burden. Analysis considers how to conceptualize and the value of improving clinician experience, leading clinician dissatisfiers, and the potential role of VT in improving clinician experience/satisfaction. Results: Contributors to poor clinician experience/satisfaction where VT could have a beneficial impact include better managing resource limitations, administrative workload, lack of care coordination, information overload, and payer interactions. VT can improve clinician experience through the technology's ability to leverage real-time actionable data clinicians can use, streamlining patient-clinician communications, personalizing care delivery, optimizing care coordination, and better aligning digital/virtual services with clinical practice. From an organizational perspective, improvements in clinician experience and satisfaction derive from establishing an effective digital back door, increasing the clinical impact of and satisfaction derived from telemedicine and virtual care, and enhancing clinician centricity. Conclusions: By embracing digital transformation and implementing solutions such as VT that focus on improving patient and clinician experience, HDOs can address barriers to delivery of high-quality, efficient, and cost-effective care. VT is a digital health tool that can create a more streamlined and satisfying experience for clinicians and the patients they care for. VT is a technology solution that can help clinicians make faster more informed decisions, reduces avoidable care, improves communication with patients and within care teams, and lowers their administrative burden so they have more quality time to care for patients.

[Recurrent cervical cancer--therapeutic options]. / Nawrotowy rak szyjki macicy--opcje terapeutyczne.

Cervical cancer is a malignancy associated with high morbidity and mortality in Poland. In a high number of cases the disease is diagnosed at an advanced stage, namely FIGO IB2-IVA. The standard method for radical treatment in these patients is external beam irradiation, together with concurrent chemotherapy based on cisplatin in the first stage, and brachytherapy in the next step. Despite such radical treatment, nearly half of women have relapses within the genital tract and regional lymph nodes. The procedure in these patients is a difficult therapeutic problem in gynecologic oncology There is a small percentage of relapses, which are located exclusively in the genital tract. In these cases appropriate treatment offers a chance for permanent cure, but also a high risk of lower quality of life, which is the consequence of surgery or radiotherapy Therapeutic options available in this strictly selected group of patients are the subject of the present analysis.

The Evaluation of the Periodontal Status of Hemodialysis Patients with End-Stage Renal Disease.

Chronic kidney disease (CKD) is an increasingly common condition observed in developing countries. Similarly, a high prevalence of gingivitis and periodontitis is observed. There are reports in the literature about the interrelationship between chronic kidney disease and periodontitis pathophysiology. This dissertation attempts to: assess the extent of gingivitis and periodontitis in a group of patients with the end-stage renal disease treated with hemodialysis compared to healthy subjects. The study included 200 subjects: 100 hemodialysis patients (HD) and 100 healthy control subjects (K). Periodontal status was assessed by measuring pocket depth (PD) clinical level of connective tissue attachment (CAL). Gingival inflammation indices Gingival Index (GI) and Bleeding on Probing (BOP) were also performed. PD with a depth of more than 6mm was found in 25% of the HD group and 5% of the K group. CAL ≥ 5 mm was found in 55% of HD and 24% of the K group. As defined by Page and Eke, severe periodontitis was found in 21% of HD, and 4% of K. Moderate gingivitis was noted in 55% of HD and 5% of the K group. The mean values of the BOP index in the HD group were 32.08% and in the K group 3.09%. The HD group had a higher incidence and severity of gingivitis and periodontitis than the control group.

Contouring cardiac substructures on average intensity projection 4D-CT for lung cancer radiotherapy: A proposal of a heart valve contouring atlas.

BACKGROUND AND PURPOSE: A detailed contouring atlas of the heart valves is lacking. Existing heart contouring atlases have not been evaluated on average intensity projection four-dimensional non-contrast computed tomography (AVE-4D-CT) scans, routinely used for organ-at-risk delineation in lung cancer radiotherapy. We aimed to develop the heart valve contouring atlas and to assess inter-observer variation in delineation of the heart, its substructures, and coronary arteries on AVE-4D-CT scans, along with its impact on radiotherapy doses. MATERIALS AND METHODS: A heart valve contouring atlas was developed. Five radiation oncologists and four cardiologists delineated the valves according to this atlas, and the remaining heart substructures according to the existing atlases, on AVE-4D-CT scans of ten patients who underwent radio(chemo)therapy for NSCLC. The observer contours were then compared to the collectively defined "reference" contours. Spatial variation was assessed using the Sørensen-Dice similarity coefficient (DSC), directed average Hausdorff distance (DAH), directed Hausdorff distance (HD), and the mean distance to agreement (MDA). The effect of spatial variation on radiotherapy doses was assessed using the patients' treatment plans. RESULTS: Inter-observer contour overlap (mean DSC) was 0.68, 0.49, 0.45 and 0.45, and inter-observer contour separation (mean DAH) was 2.1, 3.4, 2.6 and 2.9 mm for the pulmonic (PV), aortic (AV), mitral (MV) and tricuspid valve (TV), respectively. Mean HD was higher for TV and MV (13.3 and 11.7 mm) than for AV and PV (7.8 and 7 mm). The highest mean MDA of 3.1 mm was found for AV, and the lowest (1.9 mm) for PV. Inter-observer agreement was the lowest for the coronary arteries, but statistically significant dose variation was found mainly in the left ventricular septal and anterior segments. CONCLUSION: Our atlas enables reproducible delineation of the heart valves. Delineation of the heart and its substructures on AVE-4D-CT scans is feasible, with inter-observer variability similar to that reported on conventional non-contrast CT scans.