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author:("Li, jiaojiang")
1.  Dosimetric benefits of robust treatment planning for intensity modulated proton therapy for base-of-skull cancers 
Practical radiation oncology  2014;4(6):384-391.
The clinical advantage of intensity modulated proton therapy (IMPT) may be diminished by range and patient setup uncertainties. We evaluated the effectiveness of robust optimization that incorporates uncertainties into the treatment planning optimization algorithm for treatment of base of skull cancers.
Methods and materials
We compared 2 IMPT planning methods for 10 patients with base of skull chordomas and chondrosarcomas: (1) conventional optimization, in which uncertainties are dealt with by creating a planning target volume (PTV); and (2) robust optimization, in which uncertainties are dealt with by optimizing individual spot weights without a PTV. We calculated root-mean-square deviation doses (RMSDs) for every voxel to generate RMSD volume histograms (RVHs). The area under the RVH curve was used for relative comparison of the 2 methods’ plan robustness. Potential benefits of robust planning, in terms of target dose coverage and homogeneity and sparing of organs at risk (OARs) were evaluated using established clinical metrics. Then the plan evaluation metrics were averaged and compared with 2-sided paired t tests. The impact of tumor volume on the effectiveness of robust optimization was also analyzed.
Relative to conventionally optimized plans, robustly optimized plans were less sensitive for both targets and OARs. In the nominal scenario, robust and conventional optimization resulted in similar D95% doses (D95% clinical target volume [CTV]: 63.3 and 64.8 Gy relative biologic effectiveness [RBE]), P <.01]) and D5%-D95% (D5%-D95% CTV: 8.0 and 7.1 Gy[RBE], [P < .01); irradiation of OARs was less with robust optimization (brainstem V60: 0.076 vs 0.26 cm3 [P <.01], left temporal lobe V70: 0.22 vs 0.41 cm3, [P = .068], right temporal lobe V70: 0.016 vs 0.11 cm3, [P = .096], left cochlea Dmean: 28.1 vs 30.1 Gy[RBE], [P = .023], right cochlea Dmean: 23.7 vs 25.2 Gy [RBE], [P = .059]). Results in the worst-case scenario were analogous.
Robust optimization is effective for creating clinically feasible IMPT plans for tumors of the base of skull.
PMCID: PMC4238033  PMID: 25407859
2.  A single-field integrated boost treatment planning technique for spot scanning proton therapy 
Intensity modulated proton therapy (IMPT) plans are normally generated utilizing multiple field optimization (MFO) techniques. Similar to photon based IMRT, MFO allows for the utilization of a simultaneous integrated boost in which multiple target volumes are treated to discrete doses simultaneously, potentially improving plan quality and streamlining quality assurance and treatment delivery. However, MFO may render plans more sensitive to the physical uncertainties inherent to particle therapy. Here we present clinical examples of a single-field integrated boost (SFIB) technique for spot scanning proton therapy based on single field optimization (SFO) treatment-planning techniques.
Methods and materials
We designed plans of each type for illustrative patients with central nervous system (brain and spine), prostate and head and neck malignancies. SFIB and IMPT plans were constructed to deliver multiple prescription dose levels to multiple targets using SFO or MFO, respectively. Dose and fractionation schemes were based on the current clinical practice using X-ray IMRT in our clinic. For inverse planning, dose constraints were employed to achieve the desired target coverage and normal tissue sparing. Conformality and inhomogeneity indices were calculated to quantify plan quality. We also compared the worst-case robustness of the SFIB, sequential boost SFUD, and IMPT plans.
The SFIB technique produced more conformal dose distributions than plans generated by sequential boost using a SFUD technique (conformality index for prescription isodose levels; 0.585 ± 0.30 vs. 0.435 ± 0.24, SFIB vs. SFUD respectively, Wilcoxon matched-pair signed rank test, p < 0.01). There was no difference in the conformality index between SFIB and IMPT plans (0.638 ± 0.27 vs. 0.633 ± 0.26, SFIB vs. IMPT, respectively). Heterogeneity between techniques was not significantly different. With respect to clinical metrics, SFIB plans proved more robust than the corresponding IMPT plans.
SFIB technique for scanning beam proton therapy (SSPT) is now routinely employed in our clinic. The SFIB technique is a natural application of SFO and offers several advantages over SFUD, including more conformal plans, seamless treatment delivery and more efficient planning and QA. SFIB may be more robust than IMPT and has been the treatment planning technique of choice for some patients.
PMCID: PMC4262206  PMID: 25212571
Proton therapy; Spot scanning; Single-field optimization; Single field integrated boost; SFIB
3.  Role for Heat Shock Protein 90α in the Proliferation and Migration of HaCaT Cells and in the Deep Second-Degree Burn Wound Healing in Mice 
PLoS ONE  2014;9(8):e103723.
Inflammation, proliferation, and tissue remodeling are essential steps for wound healing. The hypoxic wound microenvironment promotes cell migration through a hypoxia—heat shock protein 90 alpha (Hsp90α)—low density lipoprotein receptor-related protein-1 (LRP-1) autocrine loop. To elucidate the role of this autocrine loop on burn wound healing, we investigated the expression profile of Hsp90α at the edge of burn wounds and found a transient increase in both mRNA and protein levels. Experiments performed with a human keratinocyte cell line—HaCaT also confirmed above results. 17-dimethylaminoethylamino-17demethoxygeldanamycin hydrochloride (17-DMAG), an Hsp90α inhibitor, was used to further evaluate the function of Hsp90α in wound healing. Consistently, topical application of Hsp90α in the early stage of deep second-degree burn wounds led to reduced inflammation and increased tissue granulation, with a concomitant reduction in the size of the wound at each time point tested (p<0.05). Consequently, epidermal cells at the wound margin progressed more rapidly causing an expedited healing process. In conclusion, these results provided a rationale for the therapeutic effect of Hsp90α on the burn wound management.
PMCID: PMC4128658  PMID: 25111496
4.  Incorporating deliverable monitor unit constraints into spot intensity optimization in intensity modulated proton therapy treatment planning 
Physics in medicine and biology  2013;58(15):5113-5125.
The purpose of this study is to investigate the feasibility and impact of incorporating deliverable monitor unit (MU) constraints into spot intensity optimization in intensity modulated proton therapy (IMPT) treatment planning. The current treatment planning system (TPS) for IMPT disregards deliverable MU constraints in the spot intensity optimization (SIO) routine. It performs a post-processing procedure on an optimized plan to enforce deliverable MU values that are required by the spot scanning proton delivery system. This procedure can create a significant dose distribution deviation between the optimized and post-processed deliverable plans, especially when small spot spacings are used. In this study, we introduce a two-stage linear programming (LP) approach to optimize spot intensities and constrain deliverable MU values simultaneously, i.e., a deliverable spot intensity optimization (DSIO) model. Thus, the post-processing procedure is eliminated and the associated optimized plan deterioration can be avoided. Four prostate cancer cases at our institution were selected for study and two parallel opposed beam angles were planned for all cases. A quadratic programming (QP) based model without MU constraints, i.e., a conventional spot intensity optimization (CSIO) model, was also implemented to emulate the commercial TPS. Plans optimized by both the DSIO and CSIO models were evaluated for five different settings of spot spacing from 3 mm to 7 mm. For all spot spacings, the DSIO-optimized plans yielded better uniformity for the target dose coverage and critical structure sparing than did the CSIO-optimized plans. With reduced spot spacings, more significant improvements in target dose uniformity and critical structure sparing were observed in the DSIO- than in the CSIO-optimized plans. Additionally, better sparing of the rectum and bladder was achieved when reduced spacings were used for the DSIO-optimized plans. The proposed DSIO approach ensures the deliverability of optimized IMPT plans that take into account MU constraints. This eliminates the post-processing procedure required by the TPS as well as the resultant deteriorating effect on ultimate dose distributions. This approach therefore allows IMPT plans to adopt all possible spot spacings optimally. Moreover, dosimetric benefits can be achieved using smaller spot spacings.
PMCID: PMC3947922  PMID: 23835656
5.  Adverse Events Associated with Hospitalization or Detected through the RAI-HC Assessment among Canadian Home Care Clients 
Healthcare Policy  2013;9(1):76-88.
The occurrence of adverse events (AEs) in care settings is a patient safety concern that has significant consequences across healthcare systems. Patient safety problems have been well documented in acute care settings; however, similar data for clients in home care (HC) settings in Canada are limited. The purpose of this Canadian study was to investigate AEs in HC, specifically those associated with hospitalization or detected through the Resident Assessment Instrument for Home Care (RAI-HC).
A retrospective cohort design was used. The cohort consisted of HC clients from the provinces of Nova Scotia, Ontario, British Columbia and the Winnipeg Regional Health Authority.
The overall incidence rate of AEs associated with hospitalization ranged from 6% to 9%. The incidence rate of AEs determined from the RAI-HC was 4%. Injurious falls, injuries from other than fall and medication-related events were the most frequent AEs associated with hospitalization, whereas new caregiver distress was the most frequent AE identified through the RAI-HC.
The incidence of AEs from all sources of data ranged from 4% to 9%. More resources are needed to target strategies for addressing safety risks in HC in a broader context. Tools such as the RAI-HC and its Clinical Assessment Protocols, already available in Canada, could be very useful in the assessment and management of HC clients who are at safety risk.
PMCID: PMC3999553  PMID: 23968676
6.  Identifying Network Public Opinion Leaders Based on Markov Logic Networks 
The Scientific World Journal  2014;2014:268592.
Public opinion emergencies have important effect on social activities. Recognition of special communities like opinion leaders can contribute to a comprehensive understanding of the development trend of public opinion. In this paper, a network opinion leader recognition method based on relational data was put forward, and an opinion leader recognition system integrating public opinion data acquisition module, data characteristic selection, and fusion module as well as opinion leader discovery module based on Markov Logic Networks was designed. The designed opinion leader recognition system not only can overcome the incomplete data acquisition and isolated task of traditional methods, but also can recognize opinion leaders comprehensively with considerations to multiple problems by using the relational model. Experimental results demonstrated that, compared with the traditional methods, the proposed method can provide a more accurate opinion leader recognition and has good noise immunity.
PMCID: PMC3995098  PMID: 24977188
7.  A comprehensive comparison of IMRT and VMAT plan quality for prostate cancer treatment 
We performed a comprehensive comparative study of the plan quality between volumetric modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) for the treatment of prostate cancer.
Methods and Materials
Eleven patients with prostate cancer treated at our institution were randomly selected for this study. For each patient, a VMAT plan and a series of IMRT plans using an increasing number of beams (8, 12, 16, 20, and 24 beams) were examined. All plans were generated using our in-house-developed automatic inverse planning (AIP) algorithm. An existing 8-beam clinical IMRT plan, which was used to treat the patient, was used as the reference plan. For each patient, all AIP-generated plans were optimized to achieve the same level of planning target volume (PTV) coverage as the reference plan. Plan quality was evaluated by measuring mean dose to and dose-volume statistics of the organs-at-risk, especially the rectum, from each type of plan.
For the same PTV coverage, the AIP-generated VMAT plans had significantly better plan quality in terms of rectum sparing than the 8-beam clinical and AIP-generated IMRT plans (p < 0.0001). However, the differences between the IMRT and VMAT plans in all the dosimetric indices decreased as the number of beams used in IMRT increased. IMRT plan quality was similar or superior to that of VMAT when the number of beams in IMRT was increased to a certain number, which ranged from 12 to 24 for the set of patients studied. The superior VMAT plan quality resulted in approximately 30% more monitor units than the 8-beam IMRT plans, but the delivery time was still less than 3 minutes.
Considering the superior plan quality as well as the delivery efficiency of VMAT compared with that of IMRT, VMAT may be the preferred modality for treating prostate cancer.
PMCID: PMC3805837  PMID: 22704703
Volumetric modulated arc therapy; Intensity-modulated radiation therapy; Treatment planning; Prostate cancer; OAR sparing
8.  Automated VMAT treatment planning for stage III lung cancer: how does it compare with IMRT? 
To compare the quality of volumetric modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) plans generated by an automated inverse planning system with that of dosimetrist-generated IMRT treatment plans for patients with stage III lung cancer.
Methods and Materials
Two groups of eight patients with stage III lung cancer were randomly selected. For group I, the dosimetrists spent their best effort in designing IMRT plans to compete with the automated inverse planning system (mdaccAutoPlan); for group II, the dosimetrists were not in competition and spent their regular effort. Five experienced radiation oncologists independently blind-reviewed and ranked the three plans for each patient, a rank of “1” being the best and “3” the worst. Dosimetric measures were also performed to quantitatively evaluate the three types of plans.
Blind rankings from different oncologists were generally consistent. For group I, the auto-VMAT, auto-IMRT, and manual-IMRT plans received average ranks of 1.6, 2.13, and 2.18, respectively. The auto-VMAT plans in group I had 10% higher PTV conformality and 24% lower esophagus V70 than the manual-IMRT plans; they also resulted in over 20% higher complication-free tumor control probability (p+) than either type of IMRT plans. The auto- and manual-IMRT plans in this group yielded generally comparable dosimetric measures. For group II, the auto-VMAT, auto-IMRT, and manual-IMRT plans received average ranks of 1.55, 1.75, and 2.75, respectively. Compared to the manual-IMRT plans in this group, the auto-VMAT plans and the auto-IMRT plans showed, respectively, 17% and 14% higher PTV dose conformality, 8% and 17% lower mean lung dose, 17% and 26% lower mean heart dose, and 36% and 23% higher p+.
mdaccAutoPlan is capable of generating high-quality VMAT and IMRT treatment plans for stage III lung cancer. Manual-IMRT plans could achieve quality similar to auto-IMRT plans if best effort were spent.
PMCID: PMC3428745  PMID: 22901421
VMAT; IMRT; Stage III lung cancer; Automated inverse planning
9.  Adverse events among Ontario home care clients associated with emergency room visit or hospitalization: a retrospective cohort study 
Home care (HC) is a critical component of the ongoing restructuring of healthcare in Canada. It impacts three dimensions of healthcare delivery: primary healthcare, chronic disease management, and aging at home strategies. The purpose of our study is to investigate a significant safety dimension of HC, the occurrence of adverse events and their related outcomes. The study reports on the incidence of HC adverse events, the magnitude of the events, the types of events that occur, and the consequences experienced by HC clients in the province of Ontario.
A retrospective cohort design was used, utilizing comprehensive secondary databases available for Ontario HC clients from the years 2008 and 2009. The data were derived from the Canadian Home Care Reporting System, the Hospital Discharge Abstract Database, the National Ambulatory Care Reporting System, the Ontario Mental Health Reporting System, and the Continuing Care Reporting System. Descriptive analysis was used to identify the type and frequency of the adverse events recorded and the consequences of the events. Logistic regression analysis was used to examine the association between the events and their consequences.
The study found that the incident rate for adverse events for the HC clients included in the cohort was 13%. The most frequent adverse events identified in the databases were injurious falls, injuries from other than a fall, and medication-related incidents. With respect to outcomes, we determined that an injurious fall was associated with a significant increase in the odds of a client requiring long-term-care facility admission and of client death. We further determined that three types of events, delirium, sepsis, and medication-related incidents were associated directly with an increase in the odds of client death.
Our study concludes that 13% of clients in homecare experience an adverse event annually. We also determined that an injurious fall was the most frequent of the adverse events and was associated with increased admission to long-term care or death. We recommend the use of tools that are presently available in Canada, such as the Resident Assessment Instrument and its Clinical Assessment Protocols, for assessing and mitigating the risk of an adverse event occurring.
PMCID: PMC3751652  PMID: 23800280
10.  Interplay between the Westerlies and Asian monsoon recorded in Lake Qinghai sediments since 32 ka 
Scientific Reports  2012;2:619.
Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.
PMCID: PMC3431539  PMID: 22943005
11.  A 4D IMRT planning method using deformable image registration to improve normal tissue sparing with contemporary delivery techniques 
We propose a planning method to design true 4-dimensional (4D) intensity-modulated radiotherapy (IMRT) plans, called the t4Dplan method, in which the planning target volume (PTV) of the individual phases of the 4D computed tomography (CT) and the conventional PTV receive non-uniform doses but the cumulative dose to the PTV of each phase, computed using deformable image registration (DIR), are uniform. The non-uniform dose prescription for the conventional PTV was obtained by solving linear equations that required motion-convolved 4D dose to be uniform to the PTV for the end-exhalation phase (PTV50) and by constraining maximum inhomogeneity to 20%. A plug-in code to the treatment planning system was developed to perform the IMRT optimization based on this non-uniform PTV dose prescription. The 4D dose was obtained by summing the mapped doses from individual phases of the 4D CT using DIR. This 4D dose distribution was compared with that of the internal target volume (ITV) method. The robustness of the 4D plans over the course of radiotherapy was evaluated by computing the 4D dose distributions on repeat 4D CT datasets. Three patients with lung tumors were selected to demonstrate the advantages of the t4Dplan method compared with the commonly used ITV method. The 4D dose distribution using the t4Dplan method resulted in greater normal tissue sparing (such as lung, stomach, liver and heart) than did plans designed using the ITV method. The dose volume histograms of cumulative 4D doses to the PTV50, clinical target volume, lung, spinal cord, liver, and heart on the 4D repeat CTs for the two patients were similar to those for the 4D dose at the time of original planning.
PMCID: PMC3162508  PMID: 21771333
4D CT; IMRT; treatment planning; respiratory motion; deform
12.  Intensity-Modulated Proton Therapy Reduces Normal Tissue Doses Compared with Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small Cell Lung Cancer: A Virtual Clinical Study 
To compare dose-volume histograms (DVHs) for intensity-modulated proton therapy (IMPT) with intensity-modulated radiation therapy (IMRT) and passive scattering proton therapy (PSPT) for stage IIIB non-small cell lung cancer (NSCLC) and explore the possibility of individualized radical radiotherapy.
Methods and Materials
DVHs for IMPT, PSPT, and IMRT designed to deliver IMRT at 60 to 63 Gy, PSPT at 74 Gy, and IMPT at the same doses and individualized radical radiotherapy in patients with extensive stage IIIB NSCLC (N = 10 for each approach) were compared. These patients were selected based on their extensive disease and considered to have no or borderline tolerance of IMRT at 60 to 63 Gy based on normal tissue dose-volume constraints (lung V20<35%, total mean lung dose <20 Gy; spinal cord dose, <45 Gy). The possibility of increasing the total tumor dose with IMPT for each patient without exceeding the dose-volume constraints (maximum tolerant dose, MTD) was also investigated.
Compared with IMRT, IMPT spared more lung, heart, spinal cord, and esophagus even with dose escalation from 63 Gy to 83.5 Gy, with a mean MTD of 74 Gy. Compared with PSPT, IMPT allowed further dose escalation from 74 Gy to mean MTD of 84.4 Gy (range 79.4-88.4 Gy) while keeping all parameters of normal tissue sparing lower or similar. In addition, IMPT prevented lower target coverage in patients with complicated tumor anatomies. Conclusions: IMPT reduces the normal tissue dose and allows individualized radical radiotherapy for extensive stage IIIB NSCLC.
PMCID: PMC2868090  PMID: 19660879
Lung cancer; Proton therapy; Intensity-modulated radiation therapy; Passive scattering proton therapy; Intensity-modulated proton therapy

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