Local and Global Function Model of the Liver Wang, Hesheng; Feng, Mary; Jackson, Andrew ...
International journal of radiation oncology, biology, physics,
01/2016, Letnik:
94, Številka:
1
Journal Article
Recenzirano
Odprti dostop
To develop a local and global function model in the liver based on regional and organ function measurements to support individualized adaptive radiation therapy (RT).
A local and global model for ...liver function was developed to include both functional volume and the effect of functional variation of subunits. Adopting the assumption of parallel architecture in the liver, the global function was composed of a sum of local function probabilities of subunits, varying between 0 and 1. The model was fit to 59 datasets of liver regional and organ function measures from 23 patients obtained before, during, and 1 month after RT. The local function probabilities of subunits were modeled by a sigmoid function in relating to MRI-derived portal venous perfusion values. The global function was fitted to a logarithm of an indocyanine green retention rate at 15 minutes (an overall liver function measure). Cross-validation was performed by leave-m-out tests. The model was further evaluated by fitting to the data divided according to whether the patients had hepatocellular carcinoma (HCC) or not.
The liver function model showed that (1) a perfusion value of 68.6 mL/(100 g · min) yielded a local function probability of 0.5; (2) the probability reached 0.9 at a perfusion value of 98 mL/(100 g · min); and (3) at a probability of 0.03 corresponding perfusion of 38 mL/(100 g · min) or lower, the contribution to global function was lost. Cross-validations showed that the model parameters were stable. The model fitted to the data from the patients with HCC indicated that the same amount of portal venous perfusion was translated into less local function probability than in the patients with non-HCC tumors.
The developed liver function model could provide a means to better assess individual and regional dose-responses of hepatic functions, and provide guidance for individualized treatment planning of RT.
Background Aspirin-exacerbated respiratory disease (AERD) differs from aspirin-tolerant disease in part because of eosinophilic tissue infiltration and overexpression of arachidonic acid metabolic ...pathway components that lead to enhanced secretion of cysteinyl leukotrienes and prostaglandin (PG) D2 observed constitutively and paradoxically in response to aspirin and other COX inhibitors. We have previously demonstrated the capacity of IFN-γ to drive cysteinyl leukotriene expression and response. Objective We investigated eosinophils as a source of PGD2 production in patients with AERD. Methods Eosinophils were enriched from tissue and peripheral blood obtained from control subjects, patients with aspirin-tolerant disease, and patients with AERD. mRNA was extracted and evaluated for expression of hematopoietic prostaglandin D synthase (hPGDS). Expression of hPGDS protein was confirmed with Western hybridization and immunofluorescence staining. Cells were stimulated with aspirin, and secretion of PGD2 was quantified. CD34+ progenitor cells were isolated and matured into eosinophils in the presence or absence of IFN-γ and hPGDS mRNA, and PGD2 release was measured. Results Gene expression analysis revealed that eosinophils from tissue and blood of patients with AERD display increased levels of hPGDS compared with asthmatic and control samples. Western hybridization confirmed the increase in hPGDS mRNA translated to increased protein expression. Immunofluorescence confirmed mast cells and eosinophils from tissue of patients with AERD and asthma demonstrated hPGDS expression, with higher levels in eosinophils from patients with AERD. Incubation of eosinophils from blood and tissue with aspirin stimulated PGD2 release. IFN-γ–matured eosinophil progenitors showed enhanced hPGDS expression and increased levels of PGD2 release at baseline and after aspirin stimulation. Conclusions In addition to mast cells, eosinophils represent an important source of PGD2 in patients with AERD and identify a new target for therapeutic intervention.
High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course ...of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT.
Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT.
The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=-0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001).
99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage.
Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in ...contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning.
Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch's interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case.
Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58-40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52-34.27 cc).
In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended.
Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy.
The records of 139 ...sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of ≥grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models.
Sixteen of 116 evaluable patients (14%) developed gastric bleeds at a median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD₅₀ (normal) = 56 Gy and TD₅₀ (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD₅₀ value for the cirrhosis patients points out their greater sensitivity.
This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.
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 The study purpose was to evaluate the ability of 6 biomarkers to improve the prediction of cardiovascular events among persons with established coronary artery disease. Background ...Cardiovascular risk algorithms are designed to predict the initial onset of coronary artery disease but are less effective in persons with preexisting coronary artery disease. Methods We examined the association of N-terminal prohormone brain natriuretic peptide (Nt-proBNP), cystatin C, albuminuria, C-reactive protein (CRP), interleukin-6, and fibrinogen with cardiovascular events in 979 Heart and Soul Study participants with coronary artery disease after adjusting for demographic, lifestyle, and behavior variables; cardiovascular risk factors; cardiovascular disease severity; medication use; and left ventricular ejection fraction. The outcome was a composite of stroke, myocardial infarction, and coronary heart disease death during an average of 3.5 years of follow-up. Results During follow-up, 142 participants (15%) developed cardiovascular events. The highest quartiles (vs lower 3 quartiles) of 5 biomarkers were individually associated with cardiovascular risk after multivariate analysis: Nt-proBNP hazard ratio (HR) = 2.13 (95% confidence interval CI, 1.43-3.18); cystatin C HR = 1.72 (95% CI, 1.10-2.70); albuminuria HR = 1.71 (95% CI, 1.15-2.54); CRP HR = 2.00 (95% CI, 1.40-2.85); and interleukin-6 HR = 1.76 (95% CI, 1.22-2.53). When all biomarkers were included in the multivariable analysis, only Nt-proBNP, albuminuria, and CRP remained significant predictors of events: HR = 1.88 (95% CI, 1.23-2.85), HR = 1.63 (95% CI, 1.09-2.43), and HR = 1.82 (95% CI, 1.24-2.67), respectively. The area under the receiver operator curve for clinical predictors alone was 0.73 (95% CI, 0.68-0.78); adding Nt-proBNP, albuminuria, and CRP significantly increased the area under the receiver operator curve to 0.77 (95% CI, 0.73-0.82, P <.005). Conclusion Among persons with prevalent coronary artery disease, biomarkers reflecting hemodynamic stress, kidney damage, and inflammation added significant risk discrimination for cardiovascular events.
Background Pachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from ...case series and case reports. Most patients in these reports were not genetically tested for PC. Objective We sought to clarify the prevalence of clinical features associated with PC. Methods We surveyed 254 individuals with confirmed keratin mutations regarding their experience with clinical findings associated with PC. Statistical comparison of the groups by keratin mutation was performed using logistic regression analysis. Results Although the onset of clinical symptoms varied considerably among our patients, a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years. Plantar pain had the most profound impact on quality of life. Other clinical findings reported by our patients included fingernail dystrophy, oral leukokeratosis, palmar keratoderma, follicular hyperkeratosis, hyperhidrosis, cysts, hoarseness, and natal teeth. We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation. Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2. Limitations Data were obtained through questionnaires, not by direct examination. Patients were self- or physician-referred. Conclusions We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development.
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