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Purpose: The administration of dose-escalated radiation for pancreatic adenocarcinoma remains challenging because of the proximity of dose-limiting stomach and bowel, particularly the duodenum for pancreatic head tumors. We explore whether endoscopic injection of a temporary, absorbable hydrogel into the pancreatico-duodenal (PD) groove is safe and feasible for the purpose of increasing spatial separation between pancreatic head tumors and the duodenum., Methods and Materials: Six patients with localized pancreatic adenocarcinoma underwent endoscopic injection of hydrogel into the PD groove. Safety was assessed based on the incidence of procedure-related adverse events resulting in a delay of radiation therapy initiation. Feasibility was defined as the ability to create spatial separation between the pancreas and duodenum, as assessed on simulation CT., Results: All 6 patients were able to undergo endoscopic injection of hydrogel into the PD groove. No device-related events were experienced at any point in follow-up. Presence of hydrogel in the PD groove was apparent on simulation CT in all 6 patients. Mean space created by the hydrogel was 7.7 mm +/- 2.4 mm. In 3 patients who underwent Whipple resection, presence of hydrogel in the PD groove was pathologically confirmed with no evidence of damage to the duodenum., Conclusions: Endoscopic injection of hydrogel into the PD groove is safe and feasible. Characterization of the dosimetric benefit that this technique may offer in the setting of dose-escalated radiation should also be pursued, as should the ability of such dosimetric benefit to translate into clinically improved tumor control., Competing Interests: Disclosures Amol Kumar Narang reports grants or contracts from Boston Scientific, Nanocan, and Flavocure. Theodore S. Hong reports grants or contracts from National Cancer Institute and SU2C. Received consulting fees from Synthetic Biologics, Boston Scientific, Merck, Inviata, GSK, and NextCure. Participated on a Data Safety Monitoring Board or Advisory Board for Novocure and Galera. Has stock or stock options from Panther Therapeutics. Kai Ding reports support for the present manuscript from Augmenix and Boston Scientific. Grants or contracts with NIH. Joseph Herman reports grants or contracts from 1440 Canopy Cancer Collective. Royalties or licenses from Springer Publishing. Consulting fees from Histosonics and Boston Scientific. Support for attending meetings and/or travel from Histosonics and 1440 Canopy Cancer Collective. Patents planned, issued or pending with Oncospace. Has stock or stock options from Histosonics. Jeffrey Meyer reports support for the present manuscript from Boston Scientific. Royalties or licenses from Springer and UpToDate. Manoop S. Bhutani reports support for the manuscript from Boston Scientific. Grants or contracts from Nanobiotix-Research Grant and Trisalis. Consulting fees from Oncosil Inc and Starpax Medical. Kumar Krishnan reports consulting fees from Boston Scientific and Olympus Medical. Euin Ji Shin reports consulting fees from Boston Scientific. Payment for expert testimony from US Dept of Justice. Eugene J, Koay reports support for the present manuscript from Dept of Defense and the NIH. Grants or contracts from Philips Health care, GE Health care, Stand up to Cancer, Project Purple, Elekta, and Dept of Defense. Royalties or licenses from Taylor and Francis LLC. Consulting fees from RenovoRx, AstraZeneca, and Augmenix. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Apollo Cancer Hospitals in Chennai India, Bayer Health care, Philips Health care, and Aptitude Health. Patents planned, issued or pending for the design and fabrication of 3D printed oral stents for head and neck cancer. Leadership of fiduciary role in other board, society, committee or advocacy group, paid or unpaid with International Cholangiocarcinoma Research Network. Has stock or stock options with Quantum Aurea Capital., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Pancreatic cancer is the fourth leading cause of cancer-related death with a 10% 5-year overall survival rate (OS). Radiation therapy (RT) in addition to dose escalation improves the outcome by significantly increasing the OS at 2 and 3 years but is hindered by the toxicity of the duodenum. Our group showed that the insertion of hydrogel spacer reduces duodenal toxicity, but the complex anatomy and the demanding procedure make the benefits highly uncertain. Here, we investigated the feasibility of augmenting the workflow with intraoperative feedback to reduce the adverse effects of the uncertainties., Materials and Methods: We simulated three scenarios of the virtual spacer for four cadavers with two types of gross tumor volume (GTV) (small and large); first, the ideal injection; second, the nonideal injection that incorporates common spacer placement uncertainties; and third, the corrective injection that uses the simulation result from nonideal injection and is designed to compensate for the effect of uncertainties. We considered two common uncertainties: (1) "Narrowing" is defined as the injection of smaller spacer volume than planned. (2) "Missing part" is defined as failure to inject spacer in the ascending section of the duodenum. A total of 32 stereotactic body radiation therapy (SBRT) plans (33 Gy in 5 fractions) were designed, for four cadavers, two GTV sizes, and two types of uncertainties. The preinjection scenario for each case was compared with three scenarios of virtual spacer placement from the dosimetric and geometric points of view., Results: We found that the overlapping PTV space with the duodenum is an informative quantity for determining the effective location of the spacer. The ideal spacer distribution reduced the duodenal V33Gy for small and large GTV to less than 0.3 and 0.1cc, from an average of 3.3cc, and 1.2cc for the preinjection scenario. However, spacer placement uncertainties reduced the efficacy of the spacer in sparing the duodenum (duodenal V33Gy: 1.3 and 0.4cc). The separation between duodenum and GTV decreased by an average of 5.3 and 4.6 mm. The corrective feedback can effectively bring back the expected benefits from the ideal location of the spacer (averaged V33Gy of 0.4 and 0.1cc)., Conclusions: An informative feedback metric was introduced and used to mitigate the effect of spacer placement uncertainties and maximize the benefits of the EUS-guided procedure., (© 2022 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

The aim of this article is to review unrecognized toxicities resulting from radiation therapy of digestive neoplasms. Due to their precocious occurrence, acute toxicities are well-known by radiation oncologist, and their treatment well-established. Thus, acute toxicities will not be described in this review. We will focus on incidence, diagnosis, and management of late and uncommon toxicities occurring in the digestive tract and digestive organs. Prevention, by respecting healthy tissues constraints, is the main tool to reduce incidence of those rare complications. Nonetheless, once installed, late toxicities remain a major burden in terms of quality of life and can even be life threatening. Hence, information and education about their diagnosis and management is important., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

In the event of a radiological attack or accident, it is more likely that the absorbed radiation dose will be heterogeneous, rather than uniformly distributed throughout the body. This type of uneven dose distribution is known as partial-body irradiation (PBI). Partial exposure of the vital organs, specifically the highly radiosensitive intestines, may cause death, if the injury is significant and the post-exposure recovery is considerably compromised. Here we investigated the recovery rate and extent of recovery from PBI-induced intestinal damage in large animals. Rhesus macaques (Macaca mulatta) were randomly divided into four groups: sham-irradiated (0 Gy), 8 Gy PBI, 11 Gy PBI and 14 Gy PBI. A single dose of ionizing radiation was delivered in the abdominal region using a uniform bilateral anteroposterior and posteroanterior technique. Irradiated animals were scheduled for euthanasia on days 10, 28 or 60 postirradiation, and sham-irradiated animals on day 60. Intestinal structural injuries were assessed via crypt depth, villus height, and mucosal surface length in the four different intestinal regions (duodenum, proximal jejunum, distal jejunum and ileum) using H&E staining. Higher radiation doses corresponded with more injury at 10 days post-PBI and a faster recovery rate. However, at 60 days post-PBI, damage was still evident in all regions of the intestine. The proximal and distal ends (duodenum and ileum, respectively) sustained less damage and recovered more fully than the jejunum., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Nanomaterials with antioxidant properties are promising for treating reactive oxygen species (ROS)-related diseases. However, maintaining efficacy at low doses to minimize toxicity is a critical for clinical applications. Tuning the surface strain of metallic nanoparticles can enhance catalytic reactivity, which has rarely been demonstrated in metal oxide nanomaterials. Here, it is shown that inducing surface strains of CeO 2 /Mn 3 O 4 nanocrystals produces highly catalytic antioxidants that can protect tissue-resident stem cells from irradiation-induced ROS damage. Manganese ions deposited on the surface of cerium oxide (CeO 2 ) nanocrystals form strained layers of manganese oxide (Mn 3 O 4 ) islands, increasing the number of oxygen vacancies. CeO 2 /Mn 3 O 4 nanocrystals show better catalytic activity than CeO 2 or Mn 3 O 4 alone and can protect the regenerative capabilities of intestinal stem cells in an organoid model after a lethal dose of irradiation. A small amount of the nanocrystals prevents acute radiation syndrome and increases the survival rate of mice treated with a lethal dose of total body irradiation., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: The duodenum is a critical organ at risk while planning radiation for gastrointestinal cancers or para-aortic nodes from gynaecological cancers due to the close proximity to the target volumes. The aim of this study was to assess the dosimetric parameters of the duodenum received during radiotherapy to upper gastrointestinal and gynaecological malignancies and their correlation with clinical toxicity., Materials and Methods: All adult patients who were treated with radiotherapy for primary upper gastrointestinal cancers (liver, stomach, pancreas, gall bladder) and patients with gynaecological cancers who were treated with extended fields in view of para-aortic nodal involvement from 1 January 2010 to 31 July 2015 were considered for the study. The radiation dose prescription was 45 Gy to the elective clinical target volume and 52.5-60 Gy to the gross nodal volume. The planning computed tomography scan was retrieved and the dose-volume histogram parameters for the duodenum were extracted. The relative volumes of duodenum receiving a dose from 40 to 55 Gy in increments of 5 Gy (V40Gy, V45Gy, V50Gy, V55Gy) were also noted., Results: Of the 258 patients assessed, 30 patients (12.1%) were detected to have grade 2-4 toxicities related to the duodenum as detected on endoscopy. Most had grade 3 toxicity - 18 patients were diagnosed with grade 3 toxicity and four patients had grade 4 toxicity. The most common toxicity noted was duodenal ulceration seen in 16 patients. The other toxicities were duodenal stricture in eight patients, duodenal perforation in five patients and one patient was reported to have duodenal fistula. The patients with duodenum receiving V55Gy ≥ 1 cm 3 (7.7% versus 3.8%, P = 0.014) and V50Gy ≥ 4 cm 3 (7.7% versus 3.8%, P = 0.014) had higher grade ≥2 duodenal toxicity., Conclusion: A threshold level of V55Gy ≥ 1 cm 3 and V50Gy ≥ 4 cm 3 for the duodenum is predictive of clinically significant grade 2 and higher toxicity and could serve as valid dose constraints for the duodenum., (Copyright © 2019. Published by Elsevier Ltd.)

Aim: In this study, we aimed to determine possible mitigation of radiationinduced toxicities in the duodenum, jejunum and colon using post-exposure treatment with resveratrol and alpha-lipoic acid., Background: After the bone marrow, gastrointestinal system toxicity is the second critical cause of death following whole-body exposure to radiation. Its side effects reduce the quality of life of patients who have undergone radiotherapy. Resveratrol has an antioxidant effect and stimulates DNA damage responses (DDRs). Alpha-lipoic acid neutralizes free radicals via the recycling of ascorbic acid and alpha-tocopherol., Objective: This study is a pilot investigation of the mitigation of enteritis using resveratrol and alpha-lipoic acid following histopathological study., Methods: 60 male mice were randomly assigned to six groups; control, resveratrol treatment, alpha-lipoic acid treatment, whole-body irradiation, irradiation plus resveratrol, and irradiation plus alpha-lipoic acid. The mice were irradiated with a single dose of 7 Gy from a cobalt-60 gamma-ray source. Treatment with resveratrol or alpha-lipoic acid started 24 h after irradiation and continued for 4 weeks. All mice were sacrificed after 30 days for histopathological evaluation of radiation-induced toxicities in the duodenum, jejunum and colon., Results and Discussion: Exposure to radiation caused mild to severe damages to vessels, goblet cells and villous. It also led to significant infiltration of macrophages and leukocytes, especially in the colon. Both resveratrol and alpha-lipoic acid were able to mitigate morphological changes. However, they could not mitigate vascular injury., Conclusion: Resveratrol and alpha-lipoic acid could mitigate radiation-induced injuries in the small and large intestine. A comparison between these agents showed that resveratrol may be a more effective mitigator compared to alpha-lipoic acid., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: To compare irradiation dose to the second and third portions of duodenum (Duo2 and Duo3) with a new refined and old delineation method of para-aortic region for patients with locally advanced cervical cancer (LACC) receiving prophylactic extended-field radiotherapy (EFRT)., Methods: Twenty consecutive patients with LACC were treated with prophylactic EFRT from January 2016 to January 2017 at our institute. Two delineation methods of para-aortic region were designed for each patient, the old delineation method ensured a full coverage of aortic and inferior vena cava, while the right paracaval region above L3 was omitted from CTV in the new delineation method. Patients received a dose of 50.4Gy in 28 fractions for PCTV and a dose of 60.2Gy in 28 fractions for PGTV with volumetric-modulated arc therapy (VMRT). The dose delivered to Duo2 and Duo3 with these two delineation methods were compared., Results: All treatment plans achieved excellent target volume coverage with 95% of PCTV receiving 50.4Gy and 95% of PGTV receiving 60.2Gy. There was no difference between delineation methods in low dose level (V5, V10, V15, V20, V25) for Duo2 and Duo3. The V30, V35, V40, V45, V50, Dmax, Dmean and D2cc for Duo2 with the new and old delineation methods were 55.76% vs 80.54% (P = 0.009), 34.72% vs 70.91% (P < 0.001), 18.69% vs 55.46% (P < 0.001), 8.20% vs 41.49% (P < 0.001), 1.86% vs 21.60% (P < 0.001), 49.58Gy vs 52.91Gy (P = 0.002), 30.38Gy vs 39.22Gy (P = 0.001) and 37.90Gy vs 48.64Gy (P < 0.001) respectively. For Duo3, the new delineation method achieved significant advantages in V30, V35, V40, V45, V50 and Dmean over the old one (96.82% vs 99.25%, P = 0.021; 89.65% vs 97.21%, P = 0.001; 79.50% vs 93.18%, P < 0.001; 65.63% vs 82.93%, P < 0.001; 43.39% vs 65.60%, P < 0.001; 46.09Gy vs 49.24Gy, P < 0.001), no deference was observed regarding D2cc and Dmax with these two delineation methods., Conclusion: With the new delineation method of para-aortic area in prophylactic EFRT, significant reduction of irradiation dose to the second and third portions of duodenum in high dose area was obtained. This may further lower the incidence of duodenal toxicity when performing prophylactic EFRT for patients with LACC.

Purpose: Chemotherapy combined with radiation therapy is the most commonly used approach for treating locally advanced pancreatic cancer. The use of curative doses of radiation in this disease setting is constrained because of the close proximity of the head of the pancreas to the duodenum. The purpose of this study was to determine whether fasting protects the duodenum from high-dose radiation, thereby enabling dose escalation for efficient killing of pancreatic tumor cells., Methods and Materials: C57BL/6J mice were either fed or fasted for 24 hours and then exposed to total abdominal radiation at 11.5 Gy. Food intake, body weight, overall health, and survival were monitored. Small intestines were harvested at various time points after radiation, and villi length, crypt depth, and number of crypts per millimeter of intestine were determined. Immunohistochemistry was performed to assess apoptosis and double-strand DNA breaks, and microcolony assays were performed to determine intestinal stem cell regeneration capacity. A syngeneic KPC model of pancreatic cancer was used to determine the effects of fasting on the radiation responses of both pancreatic cancer and host intestinal tissues., Results: We demonstrated that a 24-hour fast in mice improved intestinal stem cell regeneration, as revealed by microcolony assay, and improved host survival of lethal doses of total abdominal irradiation compared with fed controls. Fasting also improved survival of mice with orthotopic pancreatic tumors subjected to lethal abdominal radiation compared with controls with free access to food. Furthermore, fasting did not affect tumor cell killing by radiation therapy and enhanced γ-H2AX staining after radiation therapy, suggesting an additional mild radiosensitizing effect., Conclusions: These results establish proof of concept for fasting as a dose-escalation strategy, enabling ablative radiation in the treatment of unresectable pancreatic cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To test feasibility and safety of hypofractionated intensity modulated radiotherapy (H-IMRT) in pancreatic adenocarcinoma (PAC) treatment., Methods: Patients with unresectable nonmetastatic PAC were prospectively enrolled on a pilot study. Patients received H-IMRT to gross tumor volume to a total dose of 52 Gy (4 Gy/fraction). Toxicity rates, duodenal dosimetric parameters, and clinical outcomes were evaluated., Results: Ten patients received H-IMRT regimen. Objective tumor response was recorded in all patients but one. Gastrointestinal toxicity was the most common acute side effect and its severity moderately correlated with duodenal maximum dose (ρ = 0.46) and percentage of duodenal volume exposed to 5 Gy (ρ = 0.46). The 1-year overall and disease-free survival were 83.3% and 68.6%, respectively., Conclusion: H-IMRT seems to guarantee a high local control rate without severe toxicity. Its use in unresectable nonmetastatic PAC needs to be further investigated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Reirradiation has the potential to provide effective local control of upper abdominal malignancies. This study aimed to evaluate the safety and efficacy of reirradiation for upper abdominal malignancies., Methods: A total of 42 patients with a history of prior radiotherapy (RT) received reirradiation for abdominal malignancies between 2005 and 2017. Each patient's medical records, contours, and dose distribution for both RT courses were reviewed. The median dose of the prior RT was 50.0 Gy (range, 30.0-60.0 Gy) and the median dose of reirradiation was 45.0 Gy (range, 15.0-75.0 Gy)., Results: With a median follow-up of 10.9 months, the median infield-failure-free survival (IFFS) rate was 9.2 months. Gross tumor volume (GTV) significantly related to IFFS in both the univariate (p = 0.009) and multivariate analyses (p = 0.024), and patients with a GTV of <60.0 mL had an improved IFFS (p = 0.001). Four patients experienced ≥grade 3 late toxicities. In the retrospective dose reconstruction analysis in these patients, the cumulative dose to the most exposed 2 cc (D2cc) of the duodenum was >60.0 Gy (range, 60.1-73.7 Gy). In the univariate analysis, the D2cc of the duodenum and a preexisting duodenal ulcer identified using endoscopy prior to reirradiation significantly correlated with late severe toxicity (p = 0.021 and 0.017, respectively)., Conclusions: Reirradiation for upper abdominal malignancies could be safely performed for patients without preexisting gastrointestinal morbidity unless the duodenum received excessive radiation doses. Reirradiation could also provide substantial IFFS, especially for patients with a GTV of <60.0 mL.

Purpose: We previously have shown the feasibility of duodenum sparing using a biodegradable hydrogel spacer in pancreatic cancer radiation therapy. In this study, we propose an overlap volume histogram (OVH) prediction model to select patients who might benefit from hydrogel placement and to predict the hydrogel spacing required to achieve clinical constraints., Methods and Materials: OVH metrics for the duodenum were collected from the stereotactic body radiation therapy plans of 232 patients with unresectable pancreatic cancer (33 Gy in 5 fractions). OVH metrics L 9cc and L 3cc were defined as the tumor volume expansion distance at which 9 cm 3 and 3 cm 3 volumes of the duodenum overlap with tumor. D 9cc and D 3cc of the duodenum were defined as the dose-volume histogram dose to 9 cm 3 and 3 cm 3 , respectively, of the duodenum. Prediction models were established by linear regression between L x and D x , where x = 3 cm 3 and 9 cm 3 . OVH thresholds were obtained for predicting the target spacer thickness. The accuracy of the prediction model was then evaluated using treatment plans on pre-and post-hydrogel injection computed tomography scans from 2 cadaver specimens and 6 patients with previously treated locally advanced pancreatic cancer with simulated spacer., Results: Linear regression analysis showed a significant correlation between L x and D x (r 2  = 0.51 and 0.51 for L 3cc -D 3cc and L 9cc -D 9cc , respectively; both P < .01). The OVH thresholds were Lˆ 3cc  = 7 mm and Lˆ 9cc  = 13 mm. The observed planning doses D 3cc and D 9cc of duodenum from pre-and post-hydrogel injection computed tomography scans of cadaver specimens and clinical patients with simulated spacer using predicted target spacer thickness were within the OVH model prediction range., Conclusion: Our model may predict which patients require placement of a hydrogel spacer before stereotactic body radiation therapy to meet predefined dose constraints. Furthermore, by predicting the required target hydrogel thickness, the spacer injection can be better guided to improve efficacy., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Radiation-induced gastrointestinal syndrome occurs due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of the mucosal barrier, bacterial invasion, inflammation, and sepsis. In this study, we investigated the role of ferulic acid (FA) against ionising radiation-induced duodenal injury and subsequent alterations in redox signalling events in wild type male Swiss albino mice. Mice were administered with FA at a dose of 50 mg/kg body weight for 5 consecutive days prior to exposure of 2.5, 5 and 10 Gy doses of γ-radiation. Histopathological and electron microscopic images revealed marked duodenal injuries in a dose-dependent manner. FA prevented radiation induced damage and loss of cryptic stem cells and the shortening of duodenal villus length. FA pretreatment further suppressed NF-κB-dependent activation of inflammatory pathways and augmented Nrf2 nuclear translocation with higher expression of Mn-SOD and heme-oxygenase one (HO1) activity to combat with radiation induced duodenal stress. The colocalisation of NF-κB and Nrf2 transcription factors in the nuclei of the duodenum indicated their interaction in radiation and the FA combination group. Moreover, FA treatment inhibited phosphatidyl serine (PS) externalisation, and loss of mitochondrial membrane potential in duodenal cells. Animals exposed to 10-Gy irradiation exhibited over activation of p53, p21, caspase 3, poly ADP ribose polymerase (PARP) and DNA double-strand break which were ameliorated by FA treatment. Therefore, this article first uncovers the modulatory effect of FA on radiation-induced ROS/NF-κB/Nrf2/p53-caspase 3-PARP axis in the duodenum and establishing biological function of FA in protecting duodenum from radiation damage with a detailed mechanistic approach.

Radiotherapy of abdominopelvic primary or secondary lesions in conformational or stereotactic techniques is in full development. The small bowel is highly sensitive to irradiation and is the main organ at risk limiting prescription doses. This literature review aims to define the dose constraints to the small bowel and the duodenum in conformational and stereotactic body radiotherapy. The small bowel including the duodenum, jejunum and ileum is delineated on the simulation scanner. The radio-induced intestinal toxicities are acute related to the cellular depopulation of the intestinal mucosa, and late of more complex pathophysiology associating depletion in stem cells, microangiopathy, chronic inflammation and fibrosis. The main predictive factor of intestinal toxicity is the dose-volume ratio. In conformational radiotherapy, the dose constraints to the duodenum are: V25Gy<45% and V35Gy<20%. The jejunum and ileum dose constraints are for delineation by intestinal loop or peritoneal cavity respectively: V15Gy<275mL or V15Gy<830mL and V45Gy<150mL. In stereotactic body radiotherapy, small bowel dose constraints depend on fractionation and are defined on a small volume and on a maximum dose at one point. Intestinal toxicity is also dependent on factors intrinsic to the patient and radiosensitizers such as targeted therapies or chemotherapies. With the development of new techniques allowing dose escalation on the tumour and the development of inverse planning, the definition of dose constraints to the small bowel is essential for current practice., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Background and Purpose: Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data., Material and Methods: A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials., Results: Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n=0.070, m=0.46, TD 50(1) [Gy]=183.8, while the values for the model incorporating the individual patient data were n=0.193, m=0.51, TD 50(1) [Gy]=299.1., Conclusions: LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Prospectively assess relationships between dosimetric parameters and histopathologic/clinical duodenal toxicities in patients on a phase I trial for pancreatic cancer., Methods: Forty-six borderline resectable/unresectable patients were enrolled on a prospective trial testing neoadjuvant gemcitabine/5-fluorouracil followed by SBRT (5 daily fractions of 5-8Gy) and concurrent nelfinavir. Post-SBRT surgery was performed in 13 resectable patients, which constituted the patient population herein. Pathologic duodenal damage was assessed using predetermined criteria: 1, no/minimal; 2, moderate; and 3, marked damage. Clinical toxicities were assessed per the Clinical Terminology Criteria for Adverse Events (CTCAE). Duodenal dosimetric parameters included V5-V40 and mean/maximum doses. Spearman correlation and linear regression evaluated associations between dosimetric parameters and clinical/pathologic duodenal toxicity., Results: The median duodenal mean and maximum doses were 20 and 37Gy. Median duodenal V5-V40 were 64, 62, 52, 39, 27, 14, 5 and 0cc, respectively. The median duodenal damage score was 2 (four 1, eight 2, and one 3). Higher duodenal damage scores correlated with higher duodenal mean doses (r=0.75, p=0.003), V35 (r=0.61, p=0.03), V30 (r=0.67, p=0.01), V25 (r=0.68, p=0.01), V20 (r=0.56, p=0.05), and the planning target volume (PTV) mean (r=0.59, p=0.03) and maximum (r=0.61, p=0.03) doses. Clinical toxicities did not correlate with dosimetric parameters or duodenal pathologic damage., Conclusions: Duodenal histologic damage correlates with mean duodenal dose, V20-V35, and PTV mean/maximum doses., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Toxicity dose-response models describe the correlation between dose delivered to an organ and a given toxic endpoint. Duodenal toxicity is a dose limiting factor in the treatment of pancreatic cancer with radiation but the relationship between dose and toxicity in the duodenum is not well understood. While there have been limited studies into duodenal toxicity through investigations of the volume of the organ receiving dose over a specific threshold, both dose-volume and dose-surface histograms lack spatial information about the dose distribution, which may be important in determining normal tissue response. Due to the complex geometry of the duodenum, previous methods for unwrapping tubular organs for spatial modeling of toxicity are insufficient. A geometrically robust method for producing 2D dose surface maps (DSMs), specifically for the duodenum, has been developed and tested in order to characterize the spatial dose distribution., Methods: The organ contour is defined using Delaunay triangulation. The user selects a start and end coordinate in the structure and a path is found by regulating both length and curvature. This path is discretized and rays are cast from each point on the plane normal to the vector between the previous and the next point on the path and the dose at the closest perimeter point recorded. These angular perimeter slices are "unwrapped" from the edge distal to the pancreas to ensure the high dose region (proximal to the tumor) falls in the centre of the dose map. Gamma analysis is used to quantify the robustness of this method and the effect of overlapping planes., Results: This method was used to extract DSMs for 15 duodena, with one esophagus case to illustrate the application to simpler geometries. Visual comparison indicates that a 30 × 30 map provides sufficient resolution to view gross spatial features of interest. A lookup table is created to store the area (cm 2 ) represented by each pixel in the DSMs in order to allow spatial descriptors in absolute size. The method described in this paper is robust, requires minimal human interaction, has been shown to be generalizable to simpler geometries, and uses readily available commercial software. The difference seen in DSMs due to overlapping planes is large and justifies the need for a solution that removes such planes., Conclusions: This is the first time 2D dose surface maps have been produced for the duodenum and provide spatial dose distribution information which can be explored to create models that may improve toxicity prediction in treatments for locally advanced pancreatic cancer.

The protection of intestinal epithelial cells from the lethal effects induced by high-dose radiation is an important issue in radiotherapy and in the treatment of acute radiation syndrome. However, the effects of middle- and low-dose radiation on intestinal epithelial cells remain unclear. Because the accumulation of DNA damage in intestinal stem cells may be crucial for the development of cancer-initiating cells, it is important to understand the kinetics of DNA repair and tissue response (which are involved in the elimination of damaged cells and tissue injury repair) to middle- to low-dose irradiation. In this study, mice were X-ray irradiated with 0.1, 1 or 4 Gy, after which the small intestine (duodenum and ileum) and colon were harvested from the animals. DNA damage repair and the elimination of damaged cells were quantified by measuring the number of foci of 53BP1, a surrogate marker for DNA double-strand breaks. Tissue-proliferative response was evaluated by determining the number of Ki-67(+) and mitotic cells. Intra-crypt response differed considerably between the small intestine and the colon. In the small intestine, 53BP1 foci were detected immediately after irradiation, but rapidly disappeared thereafter, especially noticeable in Lgr5(+) stem cells. Cellular growth was temporally arrested; however, cell numbers and mitotic cell numbers in the crypt did not change. The kinetics of DNA damage repair in Lgr5(+) stem cells were similar to those in the small intestines, while the colon was more susceptible to radiation-induced damage. Preferential cell loss in the lower crypt was clearly observed in the colon; and after low-dose X-ray irradiation, only the colon exhibited considerably reduced cell numbers and dramatic induction of mitosis. These results suggest that differences in radiation dose response between the small and the large intestine may depend on the growth activity of stem cells after DNA repair.

Pancreatic carcinoma is an aggressive disease and radiotherapy treatment delivery to the primary tumor is constrained by the anatomical close location of the duodenum, stomach, and small bowel. Duodenal dose tolerance for radiosurgery in 2-5 fractions has been largely unknown. The literature was surveyed for quantitative models of risk in 1-5 fractions and we analyzed our own patient population of 44 patients with unresectable pancreatic tumors who received 3 or 5 fractions of stereotactic body radiotherapy (SBRT) between March 2009 and March 2013. A logistic model was constructed in the dose-volume histogram (DVH) Evaluator software for the duodenal D50%, D30cc, D5cc, D1cc, and maximum point dose D0.035cc. Dose tolerance limits from the literature were overlaid onto the clinical duodenal data in the form of a DVH Risk Map, with risk levels of the published limits estimated from the model of clinical data. In 3 fractions, Kopek 2010 found a statistically significant difference in D1cc of patients with no common terminology criteria for adverse events (CTCAE) v3 grade 2 or higher duodenal complications (mean D1cc = 25.3Gy) as compared with patients with grade 2 or higher toxicity (mean D1cc = 37.4Gy). From the logistic model of our duodenal data in 3 fractions, D1cc = 25.3Gy had 4.7% risk of grade 3-4 hemorrhage or stricture and D1cc = 37.4Gy had 20% risk. The 10% risk level was D1cc = 31.4Gy and we were able to keep duodenum dose for all our patients later this level., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated., Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V95% >98%. In addition, the change in PTV size and the changes in V10Gy, V20Gy, V30Gy, V40Gy, Dmean and D2cc for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test., Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D2cc of the duodenum, improved significantly (P≤.002)., Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: There have been conflicting reports regarding the incidence of duodenal toxicity in patients receiving intensity modulated radiation therapy (IMRT) with an extended field covering the para-aortic (PA) lymph nodes for gynecologic cancers. We reviewed our experiences and rates of duodenal toxicity in patients treated with extended field IMRT., Methods and Materials: Patients with either cervical or endometrial cancer who were treated with IMRT to the PA nodes for involved lymph nodes or for prophylactic intent between 2005 and 2013 were included. For prophylactic intent, the radiation dose to the PA nodes was 45 Gy in 25 fractions. For involved lymph nodes, a boost was delivered to the gross disease with a 0.7-cm expansion, with editing for critical structures. The entire duodenum was retrospectively contoured on all patients from the gastric outlet to the jejunal transition., Results: We identified 76 eligible patients with endometrial and cervical cancer. The PA region was treated prophylactically in 46.1% (n = 35) and for involved PA lymph nodes in 53.9% (n = 41). The duodenum was contoured on all patients with a median volume of 83.2 cm(3) (range, 21.2-174.9 cm(3)). The mean volume of duodenum receiving 55 Gy (V55) for those treated prophylactically and for involved PA nodes was 0 cm(3) and 0.8 cm(3) (range, 0-10.6 cm(3)), respectively (P = .014). Specifically, no patient had a V55 >15 cm(3). The mean V40 was 28.3 cm(3) (range, 0-77.3 cm(3)) and 41.4 (range, 0-90.0 cm(3)), respectively (P = .016). The mean dose delivered to 2 cm(3) of the duodenum was 34.9 Gy (range, 0-52.3 Gy) and 50.1 Gy (range, 31.3 - 58.3 Gy), respectively. Grade 3 acute gastrointestinal toxicity was recorded in 3.9% (n = 3) of patients., Conclusions: In our experience, the treatment of PA lymph nodes using an IMRT technique is associated with a low duodenal toxicity profile and there has been no high-grade late duodenal toxicity., (Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Aims and Background: This study was designed to evaluate the prevalence of gastroduodenal complications and factors that contribute to the development of symptomatic GD toxicity in cirrhotic patients with perihilar hepatocellular carcinoma (HCC), after an acceptable dose of radiotherapy., Methods: This was a retrospective study of 40 cirrhotic patients with perihilar HCC treated with radiotherapy from August 2008 to September 2010. Esophagogastroduodenoscopy was performed before and after radiotherapy. The maximum point dose to the gastroduodenum was 35.8 to 44 Gy (2 Gy equivalent, α/β = 10). Gastroduodenal complications were graded using the Common Terminology Criteria for Adverse Events (CTCAE; version 3.0). Child-Pugh score was assessed 3 months after completion of radiotherapy, and compared with the score obtained before radiotherapy., Results: Gastroduodenal complications were observed in 22 patients (55.0%) after radiotherapy. Twelve of these patients (30%) needed medical interventions. Although there were no significant factors that directly correlated with the prevalence of all-grade gastroduodenal complications, symptomatic complications (grade 2 or higher) were significantly related to the degree of Child-Pugh score elevation after radiotherapy (P = 0.002)., Conclusions: Considerable gastroduodenal complications developed in cirrhotic patients with perihilar HCC after an acceptable dose of radiotherapy. The aspects of gastroduodenal toxicities and the maintenance of liver function after radiotherapy may be an important issue in patients who undergo this treatment.

Purpose: Uncontrolled local growth is the cause of death in ∼ 30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk., Methods: The authors compared DS, PBS, and IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test., Results: Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p < 0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6-53.8 and 34.9-52.4 Gy for duodenum using DS and PBS, respectively; p < 0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (<5% and 10%, respectively; p < 0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning., Conclusions: Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.

Purpose: To consolidate duodenum and small bowel toxicity data from clinical studies with different dose fractionation schedules using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose-volume (D,v) parameters to different levels of normal tissue complication probability (NTCP) was presented., Methods and Materials: A set of NTCP model parameters for duodenum toxicity were estimated by the χ(2) fitting method using literature-based tolerance dose and generalized equivalent uniform dose (gEUD) data. These model parameters were then used to convert (D,v) data into the isoeffective dose in 2 Gy per fraction, (D(MLQED2),v) and convert these parameters to an isoeffective dose at another NTCP (D(MLQED2'),v)., Results: The literature search yielded 5 reports useful in making estimates of duodenum and small bowel toxicity. The NTCP model parameters were found to be TD50(1)(model) = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and δ = 0.09 ± 0.03 Gy(-1). Isoeffective dose calculations and toxicity rates associated with hypofractionated radiation therapy reports were found to be consistent with clinical data having different fractionation schedules. Values of (D(MLQED2'),v) between different NTCP levels remain consistent over a range of 5%-20%., Conclusions: MLQ-based isoeffective calculations of dose-response data corresponding to grade ≥2 duodenum toxicity were found to be consistent with one another within the calculation uncertainty. The (D(MLQED2),v) data could be used to determine duodenum and small bowel dose-volume constraints for new dose escalation strategies., (Copyright © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the incidence of duodenal toxicity in patients receiving intensity modulated radiation therapy (IMRT) for treatment of para-aortic nodes and to identify dosimetric parameters predictive of late duodenal toxicity., Methods and Materials: We identified 105 eligible patients with gynecologic malignancies who were treated with IMRT for gross metastatic disease in the para-aortic nodes from January 1, 2005, through December 31, 2009. Patients were treated to a nodal clinical target volume to 45 to 50.4 Gy with a boost to 60 to 66 Gy. The duodenum was contoured, and dosimetric data were exported for analysis. Duodenal toxicity was scored according to Radiation Therapy Oncology Group criteria. Univariate Cox proportional hazards analysis and recursive partitioning analysis were used to determine associations between dosimetric variables and time to toxicity and to identify the optimal threshold that separated patients according to risk of toxicity., Results: Nine of the 105 patients experienced grade 2 to grade 5 duodenal toxicity, confirmed by endoscopy in all cases. The 3-year actuarial rate of any duodenal toxicity was 11.7%. A larger volume of the duodenum receiving 55 Gy (V55) was associated with higher rates of duodenal toxicity. The 3-year actuarial rates of duodenal toxicity with V55 above and below 15 cm(3) were 48.6% and 7.4%, respectively (P<.01). In Cox univariate analysis of dosimetric variables, V55 was associated with duodenal toxicity (P=.029). In recursive partitioning analysis, V55 less than 13.94% segregated all patients with duodenal toxicity., Conclusions: Dose-escalated IMRT can safely and effectively treat para-aortic nodal disease in gynecologic malignancies, provided that care is taken to limit the dose to the duodenum to reduce the risk of late duodenal toxicity. Limiting V55 to below 15 cm(3) may reduce the risk of duodenal complications. In cases where the treatment cannot be delivered within these constraints, consideration should be given to other treatment approaches such as resection or initial chemotherapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs., Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry., Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest., Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma., Methods and Materials: Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion., Results: From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation., Conclusions: A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Stereotactic body radiation therapy (SBRT) achieves excellent local control for locally advanced pancreatic cancer (LAPC), but may increase late duodenal toxicity. Volumetric-modulated arc therapy (VMAT) delivers intensity-modulated radiation therapy (IMRT) with a rotating gantry rather than multiple fixed beams. This study dosimetrically evaluates the feasibility of implementing duodenal constraints for SBRT using VMAT vs IMRT. Non-duodenal sparing (NS) and duodenal-sparing (DS) VMAT and IMRT plans delivering 25Gy in 1 fraction were generated for 15 patients with LAPC. DS plans were constrained to duodenal Dmax of<30Gy at any point. VMAT used 1 360° coplanar arc with 4° spacing between control points, whereas IMRT used 9 coplanar beams with fixed gantry positions at 40° angles. Dosimetric parameters for target volumes and organs at risk were compared for DS planning vs NS planning and VMAT vs IMRT using paired-sample Wilcoxon signed rank tests. Both DS VMAT and DS IMRT achieved significantly reduced duodenal Dmean, Dmax, D1cc, D4%, and V20Gy compared with NS plans (all p≤0.002). DS constraints compromised target coverage for IMRT as demonstrated by reduced V95% (p = 0.01) and Dmean (p = 0.02), but not for VMAT. DS constraints resulted in increased dose to right kidney, spinal cord, stomach, and liver for VMAT. Direct comparison of DS VMAT and DS IMRT revealed that VMAT was superior in sparing the left kidney (p<0.001) and the spinal cord (p<0.001), whereas IMRT was superior in sparing the stomach (p = 0.05) and the liver (p = 0.003). DS VMAT required 21% fewer monitor units (p<0.001) and delivered treatment 2.4 minutes faster (p<0.001) than DS IMRT. Implementing DS constraints during SBRT planning for LAPC can significantly reduce duodenal point or volumetric dose parameters for both VMAT and IMRT. The primary consequence of implementing DS constraints for VMAT is increased dose to other organs at risk, whereas for IMRT it is compromised target coverage. These findings suggest clinical situations where each technique may be most useful if DS constraints are to be employed., (Copyright © 2013 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this work was to determine predictive factors for gastroduodenal (GD) toxicity in hepatocellular carcinoma (HCC) patients who were treated with radiotherapy (RT)., Patients and Methods: A total of 90 HCC patients who underwent esophagogastroduodenoscopy (EGD) before and after RT were enrolled. RT was delivered as 30-50 Gy (median 37.5 Gy) in 2-5 Gy (median 3.5 Gy) per fraction. All endoscopic findings were reviewed and GD toxicities related to RT were graded by the Common Toxicity Criteria for Adverse Events, version 3.0. The predictive factors for the ≥ grade 2 GD toxicity were investigated., Results: Endoscopic findings showed erosive gastritis in 14 patients (16 %), gastric ulcers in 8 patients (9 %), erosive duodenitis in 15 patients (17 %), and duodenal ulcers in 14 patients (16 %). Grade 2 toxicity developed in 19 patients (21 %) and grade 3 toxicity developed in 8 patients (9 %). V25 for stomach and V35 for duodenum (volume receiving a RT dose of more than x Gy) were the most predictive factors for ≥ grade 2 toxicity. The gastric toxicity rate at 6 months was 2.9 % for V25 ≤ 6.3 % and 57.1 % for V25 > 6.3 %. The duodenal toxicity rate at 6 months was 9.4 % for V35 ≤ 5.4 % and 45.9 % for V35 > 5.4 %. By multivariate analysis including the clinical factors, V25 for stomach and V35 for duodenum were the significant factors., Conclusion: EGD revealed that GD toxicity is common following RT for HCC. V25 for the stomach and V35 for the duodenum were the significant factors to predict ≥ grade 2 GD toxicity.

Objective: This study aimed to investigate Multidetector Computed Tomography (MDCT) manifestations of the normal duodenal papilla, thereby improving the knowledge on the CT manifestations of the normal anatomy of the duodenal papilla., Methods: A retrospective study was conducted by reviewing the CT results of 70 normal duodenal papilla cases examined by 64-MDCT. The analysis particularly focused on the position, size, morphology, and enhancement pattern of the duodenal papilla, as well as the ampulla of Vater., Results: In axial images, the average base diameter of the duodenal papilla was (7.3 ± 1.4)mm, whereas the average height was (6.5 ± 1.8)mm. Majority of the duodenal papilla (52.9%, 37/70) showed a round shape. In most cases (97.1%, 68/70), the duodenal papilla were located at the middle and lower third of the descending duodenum. In 84.3% of the cases (59/70), the arterial phase enhanced CT scan images were optimal for the visualization of the papilla. The "target sign" could be clearly identified from arterial phase images in 71.4% (50/70) of the cases. In 72.9% (51/70) of the cases, the ampulla of Vater had a common channel (Y type)., Conclusion: 64-MDCT can clearly visualize the normal anatomy of the duodenal papilla and surrounding structures, thereby providing valuable information for the diagnosis and treatment of diseases in this region., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To characterize the rates of acute and late duodenal and other gastrointestinal (GI) toxicities among patients treated for cervical and endometrial cancers with extended-field intensity modulated radiation therapy (EF-IMRT) to the paraaortic nodes and to analyze dose-volume relationships of GI toxicities., Methods and Materials: Fifty-three patients with endometrial or cervical cancer underwent EF-IMRT to the paraaortic nodes, of whom 46 met the inclusion criteria for GI toxicity and 45 for duodenal toxicity analysis. The median prescribed dose to the paraaortic nodes was 54 Gy (range, 41.4-65 Gy). The 4 duodenal segments, whole duodenum, small bowel loops, peritoneum, and peritoneum plus retroperitoneal segments of colon were contoured retrospectively, and dosimetric analysis was performed to identify dose-volume relationships to grade ≥3 acute (<90 day) and late (≥90 day) GI toxicity., Results: Only 3/46 patients (6.5%) experienced acute grade ≥3 GI toxicity and 3/46 patients (6.5%) experienced late grade ≥3 GI toxicity. The median dose administered to these 6 patients was 50.4 Gy. One of 12 patients who received 63 to 65 Gy at the level of the renal hilum experienced grade 3 GI toxicity. Dosimetric analysis of patients with and without toxicity revealed no differences between the mean absolute or fractional volumes at any 5-Gy interval between 5 Gy and the maximum dose. None of the patients experienced duodenal toxicity., Conclusions: Treatment of paraaortic nodes with IMRT is associated with low rates of GI toxicities and no duodenal-specific toxicity, including patients treated with concurrent chemotherapy. This technique may allow sufficient dose sparing of the bowel to enable safe dose escalation to at least 65 Gy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To determine how the respiratory phase impacts dose to normal organs during stereotactic body radiation therapy (SBRT) for pancreatic cancer., Methods and Materials: Eighteen consecutive patients with locally advanced, unresectable pancreatic adenocarcinoma treated with SBRT were included in this study. On the treatment planning 4-dimensional computed tomography (CT) scan, the planning target volume (PTV), defined as the gross tumor volume plus 3-mm margin, the duodenum, and the stomach were contoured on the end-expiration (CTexp) and end-inspiration (CTinsp) phases for each patient. A separate treatment plan was constructed for both phases with the dose prescription of 33 Gy in 5 fractions with 95% coverage of the PTV by the 100% isodose line. The dose-volume histogram (DVH) endpoints, volume of duodenum that received 20 Gy (V20), V25, and V30 and maximum dose to 5 cc of contoured organ (D5cc), D1cc, and D0.1cc, were evaluated., Results: Dosimetric parameters for the duodenum, including V25, V30, D1cc, and D0.1cc improved by planning on the CTexp compared to those on the CTinsp. There was a statistically significant overlap of the PTV with the duodenum but not the stomach during the CTinsp compared to the CTexp (0.38 ± 0.17 cc vs 0.01 ± 0.01 cc, P=.048). A larger expansion of the PTV, in accordance with a Danish phase 2 trial, showed even more overlapping volume of duodenum on the CTinsp compared to that on the CTexp (5.5 ± 0.9 cc vs 3.0 ± 0.8 cc, P=.0003) but no statistical difference for any stomach dosimetric DVH parameter., Conclusions: Dose to the duodenum was higher when treating on the inspiratory than on the expiratory phase. These data suggest that expiratory gating may be preferable to inspiratory breath-hold and free breathing strategies for minimizing risk of toxicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Improving local control is critical to improving survival and quality of life for patients with locally advanced unresectable pancreatic cancer (LAPC). However, previous attempts at radiation dose escalation have been limited by duodenal toxicity. In order to guide future studies, we analyzed the clinical and dosimetric factors associated with duodenal toxicity in patients undergoing fractionated chemoradiation for LAPC., Methods and Materials: Medical records and treatment plans of 106 patients with LAPC who were treated with chemoradiation between July 2005 and June 2010 at our institution were reviewed. All patients received neoadjuvant and concurrent chemotherapy. Seventy-eight patients were treated with conventional radiation to 50.4 Gy in 28 fractions; 28 patients received dose-escalated radiation therapy (range, 57.5-75.4 Gy in 28-39 fractions). Treatment-related toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to assess prognostic influence of clinical, pathologic, and treatment-related factors by using Kaplan-Meier and Cox regression methods., Results: Twenty patients had treatment-related duodenal toxicity events, such as duodenal inflammation, ulceration, and bleeding. Four patients had grade 1 events, 8 had grade 2, 6 had grade 3, 1 had grade 4, and 1 had grade 5. On univariate analysis, a toxicity grade ≥2 was associated with tumor location, low platelet count, an absolute volume (cm(3)) receiving a dose of at least 55 Gy (V(55 Gy) > 1 cm(3)), and a maximum point dose >60 Gy. Of these factors, only V(55 Gy) ≥1 cm(3) was associated with duodenal toxicity on multivariate analysis (hazard ratio, 6.7; range, 2.0-18.8; P=.002)., Conclusions: This study demonstrates that a duodenal V(55 Gy) >1 cm(3) is an important dosimetric predictor of grade 2 or greater duodenal toxicity and establishes it as a dosimetric constraint when treating patients with unresectable pancreatic cancer with concurrent chemoradiation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: This study aims to evaluate the interfractional dose variations in the organs-at-risk (OARs) during pancreatic breathhold intensity-modulated radiotherapy (IMRT) and to assess the impacts of "planning organs-at-risk volume" (POV) structures generated by isotropically expanding the dose-limiting OARs, based on the comparison of the interfractional doses to the OARs between IMRT plans and conventional three-dimensional-conformal radiotherapy (3D-CRT) plans., Methods: Thirty repeat CT scans were acquired from ten consecutive patients who were receiving chemoradiotherapy for pancreatic cancer. Six IMRT plans for each patient with two levels of prescription (45 and 51 Gy in 15 fractions) and 3 POV margin sizes (5, 7, and 10 mm) were generated based on the initial CT scan under predetermined constraints. Two 3D-CRT plans (39 and 42 Gy in 15 fractions) were simultaneously generated. The dose distribution of all of the treatment plans was recalculated with the repeat CT scans. The interfractional dose variations in the three OARs (stomach, duodenum, and small intestine) were evaluated, and the absolute volumes ≥39 Gy (V39Gy) of the OARs in the IMRT plans were compared to those in the 3D-CRT plans. Regression analyses were performed to assess the relative impact of the factors of interest on the interfractional dose variations of the OARs., Results: Substantial dose excesses to the three OARs were observed at all of the prescription dose levels and the POV margin sizes on the repeat CT scans. The safety threshold based on the mean stomach V39Gy on the recalculated 39 Gy-3D-CRT plans was 1.9 ml. Statistically significant and marginally insignificant mean V39Gy values above the safety thresholds were observed in the stomach in the 51 Gy-IMRT plans (2.6 and 2.1 ml with the 5- and 7-mm PRV margins, respectively (P = 0.015 and 0.085)). Only in the case of the 10-mm POV margin did the metric fall below the safety threshold to 1.5 ml (P = 0.634). The duodenum and the small intestine did not violate the safety thresholds (1.4 and 3.8 ml, respectively). From the multiple regression analyses, only the margin size (P < 0.001) and the POV V39Gy (P < 0.001) were significantly associated with the distribution of recalculated V39Gy for the stomach. Multiple factors, including the margin size (P = 0.020) and the POV V39Gy (P < 0.001) were associated with the recalculated V39Gy for the duodenum. However, none of the POV parameters for the small intestine were associated with the recalculated V39Gy., Conclusions: Considerable interfractional dose variation was observed in three critical OARs. At the escalated prescription dose of breathhold IMRT, the dose variations could exceed the dose variations using 3D-CRT at the safe prescription dose level, indicating that a dose-escalation strategy based solely on the initial advantageous dose distribution in a breathhold IMRT can be problematic. Given the current limitations for predicting or coping with variation throughout the treatment course, the use of POV should be considered for safely delivering escalated doses to patients with pancreatic cancer.

Purpose: To identify the predictors for the development of severe gastroduodenal toxicity (GDT) in patients treated with stereotactic body radiotherapy (SBRT) using 3 fractionations for abdominopelvic malignancies., Methods and Materials: From 2001 to 2011, 202 patients with abdominopelvic malignancies were treated with curative-intent SBRT. Among these patients, we retrospectively reviewed the clinical records of 40 patients with the eligibility criteria as follows: 3 fractionations, follow-up period≥1 year, absence of previous radiation therapy (RT) history or combination of external-beam RT and the presence of gastroduodenum (GD) that received a dose higher than 20% of prescribed dose. The median SBRT dose was 45 Gy (range, 33-60 Gy) with 3 fractions. We analyzed the clinical and dosimetric parameters, including multiple dose-volume histogram endpoints: V20 (volume of GD that received 20 Gy), V25, V30, V35, and Dmax (the maximum point dose). The grade of GDT was defined by the National Cancer Institute Common Toxicity Criteria version 4.0, and GDT≥grade 3 was defined as severe GDT., Results: The median time to the development of severe GDT was 6 months (range, 3-12 months). Severe GDT was found in 6 patients (15%). Dmax was the best dosimetric predictor for severe GDT. Dmax of 35 Gy and 38 Gy were respectively associated with a 5% and 10% probability of the development of severe GDT. A history of ulcer before SBRT was the best clinical predictor on univariate analysis (P=.0001)., Conclusions: We suggest that Dmax is a valuable predictor of severe GDT after SBRT using 3 fractionations for abdominopelvic malignancies. A history of ulcer before SBRT should be carefully considered as a clinical predictor, especially in patients who receive a high dose to GD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify the dosimetric parameters associated with gastrointestinal (GI) toxicity in patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based chemoradiotherapy., Methods and Materials: The data from 40 patients were analyzed retrospectively. Chemoradiotherapy consisted of conventional fractionated three-dimensional radiotherapy and weekly gemcitabine. Treatment-related acute GI toxicity and upper GI bleeding (UGB) were graded according to the Common Toxicity Criteria Adverse Events, version 4.0. The dosimetric parameters (mean dose, maximal absolute dose which covers 2 cm(3) of the organ, and absolute volume receiving 10-50 Gy [V(10-50)]) of the stomach, duodenum, small intestine, and a composite structure of the stomach and duodenum (StoDuo) were obtained. The planning target volume was also obtained. Univariate analyses were performed to identify the predictive factors for the risk of grade 2 or greater acute GI toxicity and grade 3 or greater UGB, respectively., Results: The median follow-up period was 15.7 months (range, 4-37). The actual incidence of acute GI toxicity was 33%. The estimated incidence of UGB at 1 year was 20%. Regarding acute GI toxicity, a V(50) of ≥ 16 cm(3) of the stomach was the best predictor, and the actual incidence in patients with V(50) <16 cm(3) of the stomach vs. those with V(50) of ≥ 16 cm(3) was 9% vs. 61%, respectively (p = 0.001). Regarding UGB, V(50) of ≥ 33 cm(3) of the StoDuo was the best predictor, and the estimated incidence at 1 year in patients with V(50) <33 cm(3) of the StoDuo vs. those with V(50) ≥ 33 cm(3) was 0% vs. 44%, respectively (p = 0.002). The dosimetric parameters correlated highly with one another., Conclusion: The irradiated absolute volume of the stomach and duodenum are important for the risk of acute GI toxicity and UGB. These results could be helpful in escalating the radiation doses using novel techniques, such as intensity-modulated radiotherapy, for the treatment of pancreatic cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT)., Methods and Materials: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose-volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meier and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity., Results: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V(20Gy) to V(35Gy) of duodenum were significantly associated with GI toxicity (all p ≤ 0.05). On MVA, the V(25Gy) of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V(25Gy) of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V(25Gy) ≤ 45% and V(25Gy) > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V(35Gy) is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V(35Gy) ≤ 20% and V(35Gy) > 20%, respectively (p = 0.04)., Conclusions: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI toxicity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Concurrent chemoradiation therapy (CCRT) is useful in advanced hepatocellular carcinoma (HCC), but little is known about radiation-induced gastroduodenal complications following therapy. To determine risk factors, we investigated the prevalence and patterns of gastroduodenal complications following CCRT using endoscopy., Methods and Materials: Enrolled in the study were 123 patients treated with CCRT for unresectable HCC between January 1998 and December 2005. Radiation-induced gastroduodenal complications were defined as radiation gastritis/duodenitis, radiation gastric/duodenal ulcer, or other gastroduodenal toxicity associated with radiation, based on Common Terminology Criteria for Adverse Events (CTCAE 3.0). Serious gastroduodenal complications were defined as events occurring within 12 months from completion of CCRT, those requiring prompt therapeutic intervention, or symptoms equivalent to Grade 3 or 4 radiation-related gastroduodenal toxicity, including nausea or vomiting, based on CTCAE 3.0., Results: A month after completion of CCRT, 65 (52.8%) patients displayed endoscopic evidence of radiation-induced gastroduodenal complications. Radiation gastric and duodenal ulcers were found in 32 (26.0%) and 20 (16.3%) patients, respectively; radiation gastritis and duodenitis were found in 50 (40.7%) and 42 (34.1%) patients, respectively. Radiation-related bleeding was observed in 13 patients (10.6%). Serious gastroduodenal complications occurred in 18 patients (14.6%) and were significantly more frequent in patients with liver cirrhosis than in those without cirrhosis (p=0.043). There were no radiation-related deaths., Conclusions: Endoscopically detectable radiation-induced gastroduodenal complications were common in HCC following CCRT. Although serious complications were uncommon, the frequency was higher in patients with liver cirrhosis; thus, these patients should be closely monitored when receiving CCRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Purpose: to study the impact of the 4DCT imaging technique on radiotherapy planning for pancreatic carcinoma. To evaluate the possibility of IMRT/IGRT to increase the dose to PTV subvolume., Material and Methods: contrast-enhanced 4DCT scans of 15 patients (PTs) with unresectable pancreatic cancer were acquired. A 4DCT based PTV (4D-PTV) was created by the convolution of contours and then expanded for geometric uncertainties; a standard PTV (STD-PTV) was derived from a single CTV plus conventional margins. Two 3D conformal treatment (3DCRT) plans and one Helical Tomotherapy (HT) plan were generated with a prescription of 60 Gy. Regarding the 3DCRT plans, the 4D-PTV was considered as the target volume for one, and the STD-PTV for the other; the HT plans were performed only for 4D-PTV. Twelve of 15 PTs were admitted to a Phase I hypofractionated study (15 fractions). The prescribed dose was 44.25 Gy to the 4D-PTV and the PTV subvolume around vascular involvement was boosted from 50 to 55 Gy; before treatment, daily patient position was corrected using MVCT., Results: 4D-PTVs were smaller than STD-PTVs with a volume reduction equal to 37%. 3DCRT plans on 4D-PTV showed a significant sparing of most OARs, the use of IMRT allowed a further significant dose reduction. In the Phase I study the PTV subvolume received up to 55 Gy with modest increase in dose to OARs., Conclusions: the 4DCT procedure decreases the overlap between PTV and OARs. HT technique, compared with 3DCRT, allows efficient dose sparing in particular for the duodenum. The IMRT/IGRT approach allows a safe dose escalation to PTV subvolume.

Effect of tripeptide on the process of postradiational restoration of duodenum in rats has been studied in model of accelerated aging. Geroprotective effect of tripeptide was connected with reparation of bloodstream in duodenum and increase proliferative activity of duodenal epiteliocytes.

Introduction: Dose escalation for pancreas cancer is limited by the tolerance of adjacent normal tissues, especially with stereotactic body radiotherapy (SBRT). The duodenum is generally considered to be the organ at greatest risk. This study reports on the dosimetric determinants of duodenal toxicity with single-fraction SBRT., Methods and Materials: Seventy-three patients with locally advanced unresectable pancreatic adenocarcinoma received 25 Gy in a single fraction. Dose-volume histogram (DVH) endpoints evaluated include V(5) (volume of duodenum that received 5 Gy), V(10), V(15), V(20), V(25), and D(max) (maximum dose to 1 cm(3)). Normal tissue complication probability (NTCP) was evaluated with a Lyman model. Univariate and multivariate analyses were conducted with Kaplan-Meier and Cox regression models., Results: The median time to Grade 2-4 duodenal toxicity was 6.3 months (range, 1.6-11.8 months). The 6- and 12-month actuarial rates of toxicity were 11% and 29%, respectively. V(10)-V(25) and D(max) all correlated significantly with duodenal toxicity (p<0.05). In particular, V(15)≥9.1 cm(3) and V(15)<9.1 cm(3) yielded duodenal toxicity rates of 52% and 11%, respectively (p=0.002); V(20)≥3.3 cm(3) and V(20)<3.3 cm(3) gave toxicity rates of 52% and 11%, respectively (p=0.002); and D(max)≥23 Gy and D(max)<23 Gy gave toxicity rates of 49% and 12%, respectively (p=0.004). Lyman NTCP model optimization generated the coefficients m=0.23, n=0.12, and TD(50)=24.6 Gy. Only the Lyman NTCP model remained significant in multivariate analysis (p=0.001)., Conclusions: Multiple DVH endpoints and a Lyman NTCP model are strongly predictive of duodenal toxicity after SBRT for pancreatic cancer. These dose constraints will be valuable in future abdominal SBRT studies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Cancer of unknown primary (CUP) is defined as histologically confirmed metastases in the absence of an identifiable primary tumor. Patients with solely liver metastases from adenocarinomas represent the most frequent subgroup with an unfavourable prognosis. The medium survival averages 6 to 9 months. No chemotherapheutic standard has been established., Case: We present a patient with hepatic CUP. After cycles of chemotherapy and hemihepatectomy the tumor returned and showed hepatic progression. The patient was evaluated for selective internal radiation therapy (SIRT). Three years after diagnosis she is still alive and tumorfree. Despite a good result and disease control our patient suffered radiation-induced ulceration in the oesophagus, stomach, and duodenum. This side effect appears in up to 12 % of patients, often very late after treatment, is refractory to pharmacotherapy and persistent over a long time., Conclusions: SIRT is a new, effective treatment in patients with hepatic CUP. Because of the anticipated increase of this therapy, adverse side effects such as ulcerations in the upper-GI tract secondary to ectopic implantation of microspheres may be seen more commonly. Awareness of this and the recognition of microspheres in biopsies is cardinal for appropriate management and maintenance of the patient's quality of life.

Purpose: A planning study was performed comparing volumetric modulated arcs, RapidArc (RA), fixed beam IMRT (IM), and conformal radiotherapy (CRT) with multiple static fields or short conformal arcs in a series of patients treated with hypofractionated stereotactic body radiation therapy (SBRT) for solitary or oligo-metastases from different tumors to abdominal lymph nodes., Methods and Materials: Fourteen patients were included in the study. Dose prescription was set to 45 Gy (mean dose to clinical target volume [CTV]) in six fractions of 7.5 Gy. Objectives for CTV and planning target volume (PTV) were as follows: Dose(min) >95%, Dose(max) <107%. For organs at risk the following objectives were used: Maximum dose to spine <18 Gy; V(15Gy) <35% for both kidneys, V(36Gy) <1% for duodenum, V(36Gy) <3% for stomach and small bowel, V(15Gy) <(total liver volume--700 cm(3)) for liver. Dose-volume histograms were evaluated to assess plan quality., Results: Planning objectives on CTV and PTV were achieved by all techniques. Use of RA improved PTV coverage (V(95%) = 90.2% +/- 5.2% for RA compared with 82.5% +/- 9.6% and 84.5% +/- 8.2% for CRT and IM, respectively). Most planning objectives for organs at risk were met by all techniques except for the duodenum, small bowel, and stomach, in which the CRT plans exceeded the dose/volume constraints in some patients. The MU/fraction values were as follows: 2186 +/- 211 for RA, 2583 +/- 699 for IM, and 1554 +/- 153 for CRT. Effective treatment time resulted as follows: 3.7 +/- 0.4 min for RA, 10.6 +/- 1.2 min for IM, and 6.3 +/- 0.5 min for CRT., Conclusions: Delivery of SBRT by RA showed improvements in conformal avoidance with respect to standard conformal irradiation. Delivery parameters confirmed logistical advantages of RA, particularly compared with IM.

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.

Objective: To evaluate the dosimetric impact of breath-hold during radiotherapy of hepatocellular carcinoma (HCC) and to determinate the optimal respiratory phase for treatment (exhale or inhale)., Patients and Methods: Two CT scans were performed in inhale and in exhale in 20 patients with HCC. The GTV was delineated slice by slice on the inspiration breath hold acquisition (GTV(insp)) and on the expiration breath hold acquisition (GTV(exp)). The superposition of two GTV allowed to obtain the global GTV (free respiration). PTV was defined by adding a margin of 1cm around each GTV. The liver, the duodenum, the two kidneys, the stomach and the spinal cord were delineated on each acquisition as organs at risk (OAR). Three dosimetric plans were created on inspiration, expiration and on global PTV., Results: The mean reduction in the volume of PTV with conformal radiation therapy (3D-CRT) in the hold-breath group compared to the free respiration group was of 33.5+/-11.9%. The average difference of V50%, V20, V30, V40 and V50 were around 4% in favor of the breath hold. The average value of NTCP was 8.9% in free respiration, 4.5% in expiration and 3.2% in inspiration. Further improvement in the OARs dosimetric parameters for the breath hold was observed., Conclusion: Compared to the conformal radiotherapy with free respiration, the breath-hold allows reducing the volume of the PTV and the doses to the healthy liver and organs at risk. The use of this modality during different radiotherapy techniques (3D-CRT, IMRT and stereotactic) may be recommended. No difference in dosimetric value has been observed between the breath hold in expiratory and inspiratory phases.

In order to reveal the participation of extrapineal melatonin in ageing processes, Wistar rats were (a) exposed to small doses of gamma irradiation and (b) subjected to pinealectomy. It was showed that during a radiation-induced aging simulation occurs a manifest hypoplasia of MT-responder cells in the mucosa of the duodenum, and the number of mast cells is reduced by ten times. During pinealectomy the number of MT-positive enterochromaffin cells increases.