Improving the conformity of the radiation dose to targets in the head and neck promises reduced toxicity and, in some cases, potentially improved local-regional tumor control. Intensity-modulated ...radiotherapy (IMRT) is a method that allows highly conformal delivery of radiotherapy. In recent years, its use has spread rapidly in both academic and community radiation oncology facilities. The use of IMRT has raised multiple issues related to target definition, optimal treatment delivery methods, and the need to account for anatomic changes occurring during therapy. Some of these issues are reviewed in this article.
The Ocean Road Cancer Institute (ORCI) in Tanzania began offering 3D conformal radiation therapy (3DCRT) in 2018. Steep learning curves, high patient volume, and a limited workforce resulted in long ...radiation therapy (RT) planning workflows. We aimed to establish the feasibility of implementing an automation-assisted cervical cancer 3DCRT planning system.
We performed chart abstractions on 30 patients with cervical cancer treated with 3DCRT at ORCI. The Radiation Planning Assistant (RPA) generated a new automated set of contours and plans on the basis of anonymized computed tomography images. Each were assessed for edit time requirements, dose-volume safety metrics, and clinical acceptability by two ORCI physician investigators. Dice similarity coefficient (DSC) agreement analysis was conducted between original and new contour sets.
The average time to manually develop treatment plans was 7 days. Applying RPA, automated same-day contours and plans were developed for 29 of 30 patients (97%). Of the 29 evaluable contours, all were approved with <2 minutes of edit time. Agreement between clinical and RPA contours was highest for the rectum (median DSC, 0.72) and bladder (DSC, 0.90). Agreement was lower with the primary tumor clinical target volume (CTVp; DSC, 0.69) and elective nodal clinical target volume (CTVn; DSC, 0.63). All RPA plans were approved with <4 minutes of edit time. RPA target coverage was excellent, covering the CTVp with median V45 Gy 100% and CTVn with median V45 Gy 99.9%.
Automation-assisted 3DCRT contouring yielded high levels of agreement for normal structures. The RPA met all planning safety metrics and sustained high levels of clinical acceptability with minimal edit times. This tool offers the potential to significantly decrease RT planning timelines while maintaining high-quality RT delivery in resource-constrained settings.
The purpose of this study was to quantify changes in renal length, volume, and function over time after upper abdominal radiation therapy.
Imaging and clinical data were retrospectively reviewed for ...27 adults with abdominal radiation therapy between 2001 and 2012. All had two kidneys, radiation exposure to one kidney, and survival of at least 1 year after therapy. Mean prescribed dose was 52 ± 9 Gy to extrarenal targets. Length and volume of exposed and unexposed kidneys were measured on CT scans before treatment (baseline) and at intervals 0-3, 3-6, 6-12, 12-24, 24-36, and more than 36 months after completion of radiotherapy. Serum creatinine was correlated at each interval. Mixed-models ANOVA was used to test renal length and volume, serum creatinine, and time against multiple models to assess for temporal effects; specific time intervals were compared in pairwise manner.
Mean follow-up duration was 35 months (range, 5-94 months). Exposed kidney length and volume progressively decreased from baseline throughout follow-up, with mean loss of 23% (p < 0.001) and 47% (p < 0.001), respectively. Slight increase in unexposed kidney length was not significant. Mean serum creatinine increased from 0.86 ± 0.18 mg/dL at baseline to 1.12 ± 0.27 mg/dL at 12-24 months (p < 0.001), then stabilized.
Kidneys exposed to radiation during therapy of adjacent malignancies exhibited continuous progressive atrophy for the entire follow-up period, nearly 8 years. Volume changes were twice as great as length changes. Renal function also declined. To accurately interpret follow-up studies in cancer survivors, radiologists should be aware of the potential for progressive renal atrophy, even many years after radiation therapy.
Abstract
Background: Gemcitabine based chemoradiation for locally advanced pancreatic cancer (LAPC) is safe and effective, although most patients remain unresectable and freedom from local ...progression is not ensured. Targeting cell cycle checkpoints may enhance the efficacy of chemoradiation. Tumor cells commonly have an abnormal G1 checkpoint due to mutations in p53 or its pathway making them reliant on the G2 checkpoint to arrest and repair DNA damage after radiation. In our preclinical studies, WEE1 inhibition with AZD1775 abrogates the G2 checkpoint and sensitizes pancreatic cancer cell lines and xenografts to gemcitabine and radiation. Additionally, AZD1775 attenuates homologous recombination and promotes replication stress in cancer cells. Given these preclinical findings, we designed a phase I dose escalation study of the WEE1 inhibitor AZD1775 in combination with gemcitabine and radiation in patients with LAPC (NCT02037230).
Methods: The primary objective of this phase I study is to determine the maximum tolerated dose (MTD) of AZD1775 combined with gemcitabine and radiation in patients with LAPC. Secondary objectives include estimation of the efficacy of this regimen at the target dose and to determine if WEE1 is inhibited by AZD1775 at or below its target dose in surrogate tissues. Protocol therapy consists of the administration of AZD1775 and gemcitabine at an assigned dose level in accordance with a Time-to-Event Continual Reassessment Method (TITE-CRM). Study treatment consists of four 21 day cycles. Gemcitabine is given on day 1 and day 8, and AZD1775 on days 1, 2 and 8, 9 of each cycle. Cycles 2 and 3 are administered with concurrent radiation, 52.5 Gy in 25 daily fractions to gross disease using volumetric modulated arc therapy to spare normal tissues. Following cycle 3, subjects have a 3 week break prior to cycle 4. The MTD will be determined by the development of dose limiting toxicities within the first 105 days of therapy with a target dose limiting toxicity rate of 25%. Tumor assessment using CT or MRI is performed at baseline, 1 month after radiation, and approximately every 3 months afterwards, with response characterized per RECIST. Blood samples obtained at baseline and after cycles 1, 2, and 4 will be used for correlative studies on circulating tumor cells and tumor derived exosomes. Target accrual is 36 patients; to date, 16 patients have been enrolled. Dose Escalation SchemaRadiation (Gy)Gemcitabine(mg/m⁁2)AZD1775 (mg)Level -252.5800100Level -152.51000100Level 052.51000125Level 152.51000150Level 252.51000175
Citation Format: Kyle C. Cuneo, Meredith Morgan, Matthew J. Schipper, Jonathan Maybaum, Mary U. Feng, Mahmoud Al-Hawary, Diane M. Simeone, Leah D. Olson, Vaibhav Sahai, Mark Zalupski, Theodore S. Lawrence. A dose escalation trial of the WEE1 inhibitor AZD1775, gemcitabine, and concurrent radiation in locally advanced pancreatic cancer. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT035.
To assess whether an increase in a subvolume of intrahepatic tumor with elevated arterial perfusion during radiation therapy (RT) predicts tumor progression after RT.
Twenty patients with ...unresectable intrahepatic cancers undergoing RT were enrolled in a prospective, institutional review board-approved study. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before RT (pre-RT), after delivering ∼60% of the planned dose (mid-RT) and 1 month after completion of RT to quantify hepatic arterial perfusion. The arterial perfusions of the tumors at pre-RT were clustered into low-normal and elevated perfusion by a fuzzy clustering-based method, and the tumor subvolumes with elevated arterial perfusion were extracted from the hepatic arterial perfusion images. The percentage changes in the tumor subvolumes and means of arterial perfusion over the tumors from pre-RT to mid-RT were evaluated for predicting tumor progression post-RT.
Of the 24 tumors, 6 tumors in 5 patients progressed 5 to 21 months after RT completion. Neither tumor volumes nor means of tumor arterial perfusion at pre-RT were predictive of treatment outcome. The mean arterial perfusion over the tumors increased significantly at mid-RT in progressive tumors compared with the responsive tumors (P=.006). From pre-RT to mid-RT, the responsive tumors had a decrease in the tumor subvolumes with elevated arterial perfusion (median, -14%; range, -75% to 65%), whereas the progressive tumors had an increase of the subvolumes (median, 57%; range, -7% to 165%) (P=.003). Receiver operating characteristic analysis of the percentage change in the subvolume for predicting tumor progression post-RT had an area under the curve of 0.90.
The increase in the subvolume of the intrahepatic tumor with elevated arterial perfusion during RT has the potential to be a predictor for tumor progression post-RT. The tumor subvolume could be a radiation boost candidate for response-driven adaptive RT.
Abstract
Purpose: Benzalkonium chloride (BAK) is the most commonly found preservative in eye drops, and has been shown to cause ocular surface inflammation and toxicity. Lacritin is a human tear ...glycoprotein secreted from the lacrimal glands that has been found to be cytoprotective. This study was designed to determine if the presence of lacritin confers protection to a cultured human corneal epithelial (HCE) cell line, CRL-11515, and primary HCE cells after exposure to the ocular preservative agent BAK.
Materials and methods: Recombinant human lacritin was cloned into intein fusion vectors, expressed in E. coli, and purified on chitin beads and DEAE Sepharose. Metabolic curves were established using the MTT assay after exposure of sub-confluent CRL-11515 cells to BAK or lacritin. Western blot analysis of lipidated LC3 (LC3-II) provided a measure of autophagy in CRL-11515 cells exposed to lacritin and/or BAK.
Results: BAK reduced CRL-11515 cellular metabolic activity in a time- and dose-dependent manner. BAK-induced cellular stress was evident by elevated autophagy that increased with rising concentrations of BAK compared to control (p < 0.05). Lacritin increased HCE cell proliferation at an optimal dose of 1 nM. Preconditioning HCE cells with 1 nM lacritin for 24 h prior to BAK exposure significantly dampened levels of LC3-II (p < 0.05) and promoted a significant increase in cellular metabolic activity (p < 0.01) compared to BAK alone.
Conclusions: These results suggest lacritin protects cultured HCE cells stressed with BAK. Lacritin may have the potential to be used as a topical adjunctive therapy in eyes chronically exposed to BAK.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We investigated the clinical and dosimetric predictors for radiation-associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS).
We examined 131 patients with ...proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (≥30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated.
Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 ± 8.9 Gy, V30 of 14.5 ± 2.3 cc, V45 of 11.8 ± 1.1 cc, and V60 of 7.2 ± 2.2 cc at the femoral neck compared with 22.9 ± 20.8 Gy, 4.8 ± 5.6 cc, 2.5 ± 3.9 cc, and 0.8 ± 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients.
These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients.
To determine the rate and magnitude of late genitourinary (GU) and gastrointestinal (GI) toxicities after salvage or adjuvant radiotherapy (RT) for prostate cancer, and to determine predictive ...factors for these toxicities.
A large multi-institutional database that included 959 men who received postoperative RT after radical prostatectomy (RP) was analyzed: 19% received adjuvant RT, 81% received salvage RT, 78% were treated to the prostate bed only, and 22% received radiation to the pelvis.
The median follow-up time was 55 months. At 5 years, 10% of patients had Grade 2 late GU toxicity and 1% had Grade 3 late GU toxicity, while 4% of patients had Grade 2 late GI toxicity and 0.4% had Grade 3 late GI toxicity. Multivariate analysis demonstrated that adjuvant RT (p = 0.03), androgen deprivation (p < 0.0001), and prostate bed-only RT (p = 0.007) predicted for Grade 2 or higher late GU toxicity. For GI toxicity, although adjuvant RT was significant in the univariate analysis, no significant factors were found in the multivariate analysis.
Overall, the number of high-grade toxicities for postoperative RT was low. Therefore, adjuvant and salvage RT can safely be used in the appropriate settings.
Abstract OBJECTIVES: The full potential of stereotactic body radiation therapy (SBRT), in the treatment of unresectable intrahepatic malignancies, has yet to be realized as our experience is still ...limited. Thus, we evaluated SBRT outcomes for primary and metastatic liver tumors, with the goal of identifying factors that may aid in optimization of therapy. METHODS: From2005 to 2010, 62 patients with 106 primary and metastatic liver tumors were treated with SBRT to a median biologic effective dose (BED) of 100 Gy (42.6-180). The majority of patients received either three (47%) or five fractions (48%). Median gross tumor volume (GTV) was 8.8 cm3 (0.2-222.4). RESULTS: With a median followup of 18 months (0.46-46.8), freedom from local progression (FFLP) was observed in 97 of 106 treated tumors, with 1- and 2-year FFLP rates of 93% and 82%. Median overall survival (OS) for all patients was 25.2 months, with 1- and 2-year OS of 81%and 52%. Neither BED nor GTV significantly predicted for FFLP. Local failure was associated with a higher risk of death hazard ratio (HR) = 5.1, P = .0007. One Child-Pugh Class B patient developed radiationinduced liver disease. There were no other significant toxicities. CONCLUSIONS: SBRT provides excellent local control for both primary and metastatic liver lesions with minimal toxicity. Future studies should focus on appropriate selection of patients and on careful assessment of liver function to maximize both the safety and efficacy of treatment.
Background
Connexins (Cx) are the basic units of gap junctions and contribute to cellular integrity by promoting intercellular communication. Disruption of the retinal pigment epithelial monolayer ...may be an early event in the pathogenesis of age-related macular degeneration, a condition in which vascular endothelial growth factor (VEGF) is known to be of importance. This study was designed to assess the effect of connexin43 (Cx43) expression and gap junctional intercellular communication (GJIC) on the expression and secretion of VEGF from the retinal pigment epithelium under normal cell culture and oxidative stress conditions.
Methods
Stable cell lines of ARPE-19 were produced in which wild-type Cx43 was either over-expressed, down-regulated by targeted shRNA, or functionally inhibited by co-expression of a disease-linked dominant-negative mutant (G21R). Pharmacologic blockade of GJIC was accomplished with flufenamic acid. Oxidant challenge was performed with tert-butyl hydroperoxide (tBH). VEGF gene expression and secretion were assessed by real-time PCR and ELISA respectively.
Results
Over-expression of Cx43 in ARPE-19 cells reduced both gene expression and secretion of VEGF. Down-regulation of Cx43 increased gene expression and secretion of VEGF. Increased secretion of VEGF was also observed in ARPE-19 cells expressing a dominant-negative mutant of Cx43, and when GJIC was blocked. Over-expression of Cx43 reduced tBH-induced secretion of VEGF from ARPE-19 cells.
Conclusions
These studies show that Cx43 protects against oxidative stress-induced VEGF secretion in ARPE-19 cells, and thus has important implications in understanding the pathogenesis of age-related macular degeneration.
PDF
