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Biomedical subjects

Ping Xia

Publications and source records attributed to Ping Xia.

At least 19 recordsLinked to original sources
PubMed2007

Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses.

PURPOSE: To report the clinical outcome of patients treated with intensity-modulated radiation therapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses. METHODS AND MATERIALS: Between 1998 and 2004, 36 patients with malignancies of the sinonasal region were treated with IMRT. Thirty-two patients (89%) were treated in the postoperative setting after gross total resection. Treatment plans were designed to provide a dose of 70 Gy to 95% or more of the gross tumor volume (GTV) and 60 Gy to 95% or more of the clinical tumor volume (CTV) while sparing neighboring critical structures including the optic chiasm, optic nerves, eyes, and brainstem. The primary sites were: 13 ethmoid sinus, 10 maxillary sinus, 7 nasal cavity, and 6 other. Histology was: 12 squamous cell, 7 esthesioneuroblastoma, 5 adenoid cystic, 5 undifferentiated, 5 adenocarcinoma, and 2 other. Median follow-up was 51 months among surviving patients (range, 9-82 months). RESULTS: The 2-year and 5-year estimates of local control were 62% and 58%, respectively. One patient developed isolated distant metastasis, and none developed isolated regional failure. The 5-year rates of disease-free and overall survival were 55% and 45%, respectively. The incidence of ocular toxicity was minimal with no patients reporting decreased vision. Late complications included xerophthalmia (1 patient), lacrimal stenosis (1 patient), and cataract (1 patient). CONCLUSION: Although IMRT for malignancies of the sinonasal region does not appear to lead to significant improvements in disease control, the low incidence of complications is encouraging.

Adenocarcinoma↗
PubMed2006

Intensity-modulated radiotherapy improves lymph node coverage and dose to critical structures compared with three-dimensional conformal radiation therapy in clinically localized prostate cancer.

PURPOSE: The aim of this study was to quantify gains in lymph node coverage and critical structure dose reduction for whole-pelvis (WP) and extended-field (EF) radiotherapy in prostate cancer using intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3DCRT) for the first treatment phase of 45 Gy in the concurrent treatment of lymph nodes and prostate. METHODS AND MATERIALS: From January to August 2005, 35 patients with localized prostate cancer were treated with pelvic IMRT; 7 had nodes defined up to L5-S1 (Group 1), and 28 had nodes defined above L5-S1 (Group 2). Each patient had 2 plans retrospectively generated: 1 WP 3DCRT plan using bony landmarks, and 1 EF 3DCRT plan to cover the vascular defined volumes. Dose-volume histograms for the lymph nodes, rectum, bladder, small bowel, and penile bulb were compared by group. RESULTS: For Group 1, WP 3DCRT missed 25% of pelvic nodes with the prescribed dose 45 Gy and missed 18% with the 95% prescribed dose 42.75 Gy, whereas WP IMRT achieved V(45 Gy) = 98% and V(42.75 Gy) = 100%. Compared with WP 3DCRT, IMRT reduced bladder V(45 Gy) by 78%, rectum V(45 Gy) by 48%, and small bowel V(45 Gy) by 232 cm3. EF 3DCRT achieved 95% coverage of nodes for all patients at high cost to critical structures. For Group 2, IMRT decreased bladder V(45 Gy) by 90%, rectum V(45 Gy) by 54% and small bowel V(45 Gy) by 455 cm3 compared with EF 3DCRT. CONCLUSION: In this study WP 3DCRT missed a significant percentage of pelvic nodes. Although EF 3DCRT achieved 95% pelvic nodal coverage, it increased critical structure doses. IMRT improved pelvic nodal coverage while decreasing dose to bladder, rectum, small bowel, and penile bulb. For patients with extended node involvement, IMRT especially decreases small bowel dose.

Aged↗
PubMed2006

Image-guided radiotherapy using megavoltage cone-beam computed tomography for treatment of paraspinous tumors in the presence of orthopedic hardware.

PURPOSE: This report describes a new image-guided radiotherapy (IGRT) technique using megavoltage cone-beam computed tomography (MV-CBCT) to treat paraspinous tumors in the presence of orthopedic hardware. METHODS AND MATERIALS: A patient with a resected paraspinous high-grade sarcoma was treated to 59.4 Gy with an IMRT plan. Daily MV-CBCT imaging was used to ensure accurate positioning. The displacement between MV-CBCT and planning CT images were determined daily and applied remotely to the treatment couch. The dose-volume histograms of the original and a hypothetical IMRT plan (shifted by the average daily setup errors) were compared to estimate the impact on dosimetry. RESULTS: The mean setup corrections in the lateral, longitudinal, and vertical directions were 3.6 mm (95% CI, 2.6-4.6 mm), 4.1 mm (95% CI, 3.2-5.0 mm), and 1.0 mm (95% CI, 0.6-1.3 mm), respectively. Without corrected positioning, the dose to 0.1 cc of the spinal cord increased by 9.4 Gy, and the doses to 95% of clinical target volumes 1 and 2 were reduced by 4 Gy and 4.8 Gy, respectively. CONCLUSIONS: Megavoltage-CBCT provides a new alternative image-guided radiotherapy approach for treatment of paraspinous tumors in the presence of orthopedic hardware by providing 3D anatomic information in the treatment position, with clear imaging of metallic objects and without compromising soft-tissue information.

Female↗
PubMed2006

Germinal vesicle chromatin configurations of bovine oocytes.

A common feature in the configuration of germinal vesicle (GV) chromatin in most species is that diffuse chromatin condenses into a perinucleolar ring during follicular growth; however, no such ring was observed in goat oocytes. Reports on whether bovine GV chromatin condenses into a perinucleolar ring are controversial. Besides, it is not known whether the perinucleolar ring in an oocyte represents a step toward final maturation or atresia. Changes in GV chromatin configurations during growth and maturation of bovine oocytes were studied using a new method that allows a clearer visualization of both the nucleolus and the chromatin after Hoechst and chromomycin A(3) staining. On the basis of the degree of condensation and distribution, the GV chromatin of bovine oocytes were classified into five configurations: NSN with diffuse chromatin in the whole nuclear area, N with condensed netlike chromatin, C with clumped chromatin, SN with clumped chromatin surrounding the nucleoli, and F with floccular chromatin near the nucleoli and near the nuclear envelope. Most of the oocytes were at the NSN stage in the <1.4-mm follicles, but the NSN pattern disappeared completely in follicles larger than 1.5mm. The SN pattern began to emerge in 1.5-mm follicles, and the number of SN oocytes increased while the number of oocytes with N and C configurations decreased with follicular growth. During maturation in vivo, while the number of N, C, and SN oocytes decreased, that of the F oocytes increased and reached maximum at 51h post prostaglandin injection. After that, the number of F oocytes decreased significantly because of germinal vesicle breakdown (GVBD). During maturation in vitro, GV chromatin configurations changed in a similar manner as during maturation in vivo. Fewer oocytes were at N, C, and SN stages, but more were at F and GVBD stages in the atretic than in the healthy follicles. Serum starvation slowed the F-GVBD transition of the in vitro maturing oocytes. More oocytes were of the SN or C configuration when ovaries were transported at 45-40 degrees C than at 35-30 degrees C. Most of the heated oocytes were blocked at the SN stage during in vitro maturation. It is concluded that (i) bovine GV chromatin condenses into a perinucleolar ring during follicular growth; (ii) bovine oocytes were synchronized at the F stage before GVBD; (iii) oocyte GV chromatin configurations were affected by serum starvation, high temperature, and follicular atresia.

Animals↗
PubMed2005

Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer.

PURPOSE: Many patients with head-and-neck (H&N) cancer have tumor shrinkage and/or weight loss during the course of radiotherapy. We conducted this retrospective study to determine the dosimetric effects of repeat computed tomography (CT) imaging and replanning during the course of intensity-modulated radiotherapy (IMRT) on both normal tissues and target volumes. METHODS AND MATERIALS: A retrospective chart review identified 13 patients with H&N cancer treated with IMRT who had repeat CT imaging and replanning during the course of radiotherapy. The first IMRT plan for each patient was generated based on the original planning CT scan acquired before the start of treatment. Because of tumor shrinkage or weight loss during radiotherapy, a second CT scan was acquired, and a new plan was generated and used to complete the course of IMRT. CT-CT fusion was used to correct patient positioning differences between the scans. By using a commercial inverse IMRT planning system, a hybrid IMRT plan was generated for each patient by applying the beam configurations of the first IMRT plan (including the intensity profile of each beam) to the anatomy of the second CT scan. The dose-volume histograms of the actual and hybrid IMRT plans were compared using analysis of variance methods for repeated measures. RESULTS: All patients had locally advanced, nonmetastatic Stage III or IV disease, including 6 nasopharynx, 6 oropharynx, and 1 unknown primary site. All patients were treated with concurrent platinum-based chemotherapy. When replanning vs. not replanning was compared, the hybrid IMRT plans (without replanning) demonstrated reduced doses to target volumes and increased doses to critical structures. The doses to 95% (D95) of the planning target volumes of the gross tumor volume (PTVGTV) and the clinical target volume (PTVCTV) were reduced in 92% of patients, by 0.8-6.3 Gy (p=0.02) and 0.2-7.4 Gy (p=0.003), respectively. The maximum dose (Dmax) to the spinal cord increased in all patients (range, 0.2-15.4 Gy; p=0.003) and the brainstem Dmax increased in 85% of patients without replanning (range, 0.6-8.1 Gy; p=0.007). CONCLUSIONS: Repeat CT imaging and replanning during the course of IMRT for selected patients with H&N cancer is essential to identify dosimetric changes and to ensure adequate doses to target volumes and safe doses to normal tissues. Future prospective studies with larger sample sizes will help to determine criteria for repeat CT imaging and IMRT replanning for H&N cancer patients undergoing radiotherapy.

Adult↗
PubMed2005

Synthesis and biological evaluation of 3-ethylidene-1,3-dihydro-indol-2-ones as novel checkpoint 1 inhibitors.

Chk1 inhibitors have emerged as a novel class of neoplastic agents for abrogating the G2 DNA damage checkpoint arrest. Analogs of the Chk1 inhibitor, 3-ethylidene-1,3-dihydro-indol-2-one, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analog 28, which possesses potent enzymatic and cellular activities.

Cell Proliferation↗
PubMed2005

Method to account for dose fractionation in analysis of IMRT plans: modified equivalent uniform dose.

PURPOSE: To propose a modified equivalent uniform dose (mEUD) to account for dose fractionation using the biologically effective dose without losing the advantages of the generalized equivalent uniform dose (gEUD) and to report the calculated mEUD and gEUD in clinically used intensity-modulated radiotherapy (IMRT) plans. METHODS AND MATERIALS: The proposed mEUD replaces the dose to each voxel in the gEUD formulation by a biologically effective dose with a normalization factor. We propose to use the term mEUD(D(o))(/n(o)) that includes the total dose (D(o)) and number of fractions (n(o)) and to use the term mEUD(o) that includes the same total dose but a standard fraction size of 2 Gy. A total of 41 IMRT plans for patients with nasopharyngeal cancer treated at our institution between October 1997 and March 2002 were selected for the study. The gEUD and mEUD were calculated for the planning gross tumor volume (pGTV), planning clinical tumor volume (pCTV), parotid glands, and spinal cord. The prescription dose for these patients was 70 Gy to >95% of the pGTV and 59.4 Gy to >95% of the pCTV in 33 fractions. RESULTS: The calculated average gEUD was 72.2 +/- 2.4 Gy for the pGTV, 54.2 +/- 7.1 Gy for the pCTV, 26.7 +/- 4.2 Gy for the parotid glands, and 34.1 +/- 6.8 Gy for the spinal cord. The calculated average mEUD(D(o))(/n(o)) using 33 fractions was 71.7 +/- 3.5 Gy for mEUD(70/33) of the pGTV, 49.9 +/- 7.9 Gy for mEUD(59.5/33) of the pCTV, 27.6 +/- 4.8 Gy for mEUD(26/33) of the parotid glands, and 32.7 +/- 7.8 Gy for mEUD(45/33) of the spinal cord. CONCLUSION: The proposed mEUD, combining the gEUD with the biologically effective dose, preserves all advantages of the gEUD while reflecting the fractionation effects and linear and quadratic survival characteristics.

Algorithms↗
PubMed2005

Low-dose megavoltage cone-beam CT for radiation therapy.

PURPOSE: The objective of this work was to demonstrate the feasibility of acquiring low-exposure megavoltage cone-beam CT (MV CBCT) three-dimensional (3D) image data of sufficient quality to register the CBCT images to kilovoltage planning CT images for patient alignment and dose verification purposes. METHODS AND MATERIALS: A standard clinical 6-MV Primus linear accelerator, operating in arc therapy mode, and an amorphous-silicon (a-Si) flat-panel electronic portal-imaging device (EPID) were employed. The dose-pulse rate of 6-MV Primus accelerator beam was windowed to expose an a-Si flat panel by using only 0.02 to 0.08 monitor unit (MUs) per image. A triggered image-acquisition mode was designed to produce a high signal-to-noise ratio without pulsing artifacts. Several data sets were acquired for an anthropomorphic head phantom and frozen sheep and pig cadaver head, as well as for a head-and-neck cancer patient on intensity-modulated radiotherapy (IMRT). For each CBCT image, a set of 90 to 180 projection images incremented by 1 degree to 2 degrees was acquired. The two-dimensional (2D) projection images were then synthesized into a 3D image by use of cone-beam CT reconstruction. The resulting MV CBCT image set was used to visualize the 3D bony anatomy and some soft-tissue details. The 3D image registration with the kV planning CT was performed either automatically by application of a maximization of mutual information (MMI) algorithm or manually by aligning multiple 1D slices. RESULTS: Low-noise 3D MV CBCT images without pulsing artifacts were acquired with a total delivered dose that ranged from 5 to 15 cGy. Acquisition times, including image readout, were on the order of 90 seconds for 180 projection images taken through a continuous gantry rotation of 180 degrees. The processing time of the data required an additional 90 seconds for the reconstruction of a 256(3) cube with 1.0-mm voxel size. Implanted gold markers (1 mm x 3 mm) were easily visible or all exposure levels without artifacts. In general, the presence of high Z materials such as tooth fillings or implanted markers did not result in visible streak artifacts. The registration of structures such as the spinal canal and the nasopharynx in the MV CBCT and kV CT data sets was possible with millimeter and degree accuracy as assessed by displacement simulations and subsequent visual evaluation. CONCLUSIONS: We believe that the quality of these images, along with the rapid acquisition and reconstruction times, demonstrates that MV CBCT performed by use of a standard linear accelerator equipped with a flat-panel imager can be applied clinically for patient alignment.

Animals↗
PubMed2005

Investigation of using a power function as a cost function in inverse planning optimization.

The purpose of this paper is to investigate the use of a power function as a cost function in inverse planning optimization. The cost function for each structure is implemented as an exponential power function of the deviation between the resultant dose and prescribed or constrained dose. The total cost function for all structures is a summation of the cost function of every structure. When the exponents of all terms in the cost function are set to 2, the cost function becomes a classical quadratic cost function. An independent optimization module was developed and interfaced with a research treatment planning system from the University of North Carolina for dose calculation and display of results. Three clinical cases were tested for this study with various exponents set for tumor targets and sensitive structures. Treatment plans with these exponent settings were compared, using dose volume histograms. The results of our study demonstrated that using an exponent higher than 2 in the cost function for the target achieved better dose homogeneity than using an exponent of 2. An exponent higher than 2 for serial sensitive structures can effectively reduce the maximum dose. Varying the exponent from 2 to 4 resulted in the most effective changes in dose volume histograms while the change from 4 to 8 is less drastic, indicating a situation of saturation. In conclusion, using a power function with exponent greater than 2 as a cost function can effectively achieve homogeneous dose inside the target and/or minimize maximum dose to the critical structures.

Algorithms↗
PubMed2004

Successful correction of the human beta-thalassemia major phenotype using a lentiviral vector.

beta-thalassemias are the most common single gene disorders and are potentially amenable to gene therapy. However, retroviral vectors carrying the human beta-globin cassette have been notoriously unstable. Recently, considerable progress has been made using lentiviral vectors, which stably transmit the beta-globin expression cassette. Thus far, mouse studies have shown correction of the beta-thalassemia intermedia phenotype and a partial, variable correction of beta-thalassemia major phenotype. We tested a lentiviral vector carrying the human beta-globin expression cassette flanked by a chromatin insulator in transfusion-dependent human thalassemia major, where it would be ultimately relevant. We demonstrated that the vector expressed normal amounts of human beta-globin in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes beta-thalassemia. The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3 to 4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal controls. Our results show genetic modification of primitive progenitor cells with correction of the human thalassemia major phenotype.

Animals↗
PubMed2004

A population-based atlas and clinical target volume for the head-and-neck lymph nodes.

PURPOSE: To develop a population-based three-dimensional lymph node target volume of the head and neck. METHODS AND MATERIALS: The T2 weighted axial magnetic resonance imaging (MRI) images of 35 patients with known head and neck cancer were reviewed. An experienced head and neck radiologist marked each lymph node (LN) electronically. The images were distributed to one of 12 axial levels of the head and neck with each level representing a distinct portion of the neck based on external contours and the presence of anatomic structures. The LNs were marked with five different symbols to distinguish the superior/inferior extent of each LN within each level. With the categorization of each image into a different superior/inferior level of the neck, the registration of the images was limited to two dimensions. Nonlinear transformation accounted for inter-patient differences although no local warping was used. The co-registration used recognizable anatomic landmarks (vertebral body, mandible, maxilla, clivus as well as the sternocleidomastoid muscle, external skin contour, spinal cord) to match the patient anatomy. RESULTS: In total, 503 images were co-registered with the baseline images. The majority of the co-registrations were of good quality; 361, 122, and 20 image co-registrations scored as global, limited, and poor co-registrations respectively. One thousand and fifty seven LNs were marked, with 122 LNs marked as submandibular and submental LN. Among the levels A, B, C, D, E, F, G, H, 22, 44, 206, 199, 196, 175, 63, 35 LN were marked respectively. Noteworthy anatomic variation was observed among the different nodal groups that are summarized in the representative baseline images. CONCLUSIONS: Image registration of a series of head and neck images generates a valuable population-based lymph node map that can be used to guide the three-dimensional delineation of the elective lymph node target volume. Significant variation in the lymph node location was seen in all LN groups. The medial border of the internal jugular vein can be used as an important landmark structure in delineating the jugular LN clinical target volume and, for that reason, intravenous contrast is recommended to improve visualization. The location of the submandibular LN appear to be limited to the space anterior and lateral to the submandibular gland and are found mostly along the inferior edge of the mandible. The location of the retropharyngeal LN does vary but their location does not appear to vary with any other recognizable axial structure. The lymph node map provides another collaborating piece of evidence in defining the head and neck LN clinical target volume.

Adolescent↗
PubMed2004

A study of planning dose constraints for treatment of nasopharyngeal carcinoma using a commercial inverse treatment planning system.

PURPOSE: The purpose of this study was to develop and test planning dose constraint templates for tumor and normal structures in the treatment of nasopharyngeal carcinoma (NPC) using a specific commercial inverse treatment planning system. METHODS AND MATERIALS: Planning dose constraint templates were developed based on the analyses of dose-volume histograms (DVHs) of tumor targets and adjacent sensitive structures by clinically approved treatment plans of 9 T1-2 and 16 T3-4 NPC patients treated with inverse planned intensity-modulated radiation therapy (IP-IMRT). DVHs of sensitive structures were analyzed by examining multiple defined endpoints, based on the characteristics of each sensitive structure. For each subgroup of patients with T1-2 and T3-4 NPC, the resulting mean values of these defined endpoint doses were considered as templates for planning dose constraints and subsequently applied to a second group of patients, 5 with T1-2 NPC and 5 with T3-4 NPC. The 10 regenerated plans (called new plans) were compared to the original clinical plans that were used to treat the second group of patients, based on plan conformity index and DVHs. RESULTS: The conformity indices of the new plans were comparable to the original plans with no statistical difference (p = 0.85). Among the serial sensitive structures evaluated, there was a significant decrease with the new plans in the dose to the spinal cord when analyzed by the maximum dose (p = 0.001), doses encompassing 1 cc of the spinal cord volume (p = 0.001) and 3 cc of the spinal cord volume (p = 0.001). There was no significant difference in the mean maximum dose to the brainstem between the new plans and the original plans (p = 0.36). However, a significant difference in the mean maximum dose to the brainstem was seen among the different T-stages (p = 0.04). A decrease with the new plan to the brainstem in the doses encompassing 5% and 10% of the volume was of borderline statistical significance (p = 0.08 and p = 0.06, respectively). There were no statistical differences between the new plans and the original plans in the mean doses to the chiasm, optic nerve, or eye for each of the endpoints considered. For parallel sensitive structures in the new plans, there was a significant increase in the average mean dose to the parotid glands (p = 0.01), a decrease that was of borderline significance in the average mean dose to the temporomandibular joint (p = 0.07), but no difference in the average mean dose to the ear. CONCLUSIONS: The statistical analysis showed that new plans are comparable to the original plans for most of the sensitive structures except for a trade-off between a dose reduction to the spinal cord in the new plans and an increase in the mean dose to the parotid glands. These tested planning dose constraint templates can serve as good "starting points" for an inverse plan of NPC using a specific commercial inverse treatment planning system.

Brain Stem↗
PubMed2004

A forward-planned treatment technique using multisegments in the treatment of head-and-neck cancer.

PURPOSE: To describe in detail a forward-planned multisegment technique (FPMS) as an alternative treatment method for patients who are not suitable for inverse-planned intensity-modulated radiation therapy (IP-IMRT), or for situations where IP-IMRT is not available in a medical clinic. METHODS AND MATERIALS: Between April 1995 and February 2002, 38 primary head-and-neck patients were treated using the FPMS technique, which has evolved over the past 7 years at our medical center. In the most recent version of the FPMS technique, which includes 5 patients examined in this analysis, the primary tumor and the upper neck nodes were treated with 7 gantry angles, including an anterior, 2 lateral, 2 anterior oblique, and 2 posterior oblique beams with a total of 13 beam shapes formed by multileaf collimators (MLC), called MLC segments. The shape of each MLC segment was carefully designed, and the associated weights were optimized through manual iterations. The lower neck nodes and the supraclavicular nodes were treated with a split-beam anterior field, matched to the inferior border of the FPMS plan at the isocenter. With an autosequencing delivery system, all fields, including dynamic wedges, can be automatically treated. The dosimetric accuracy of this technique was verified with a phantom plan and measured with an ionization chamber, as well as film dosimetry. A sample FPMS plan is described in detail, and the average results for the 5 patients treated with FPMS are retrospectively compared to results for similar patients treated with IP-IMRT. RESULTS: The gross tumor volume was prescribed to 70 Gy (2.12 Gy/fraction) at the 88% isodose line, whereas the clinical target volume received a dose of 59.4 Gy (1.8 Gy/fraction) at the 75% isodose line. The maximum dose to the brainstem and spinal cord was below 54 and 45 Gy, respectively, comparable to IP-IMRT. The mean dose to the parotid glands was 32 Gy with FPMS vs. 26 Gy with IP-IMRT. Average delivery time was shorter for FPMS (15 min) than IP-IMRT (30 min), whereas the planning time depended on the expertise of the planner. Dosimetric accuracy for FPMS and IP-IMRT plans using phantom measurements was similar, within 1% of the phantom plan. With a median follow-up of 31 months, there was no local-regional recurrence, and the incidence of xerostomia is reduced compared to conventional techniques. CONCLUSION: FPMS achieved plans comparable to those for IP-IMRT and is an ideal alternative treatment technique for a center without the capabilities of IP-IMRT or for a patient who is not a suitable candidate, because of prolonged treatment time. The treatment outcomes from our clinical experience indicate that FPMS can achieve excellent local freedom from progression rates without causing excessive toxicity. Lastly, IP-IMRT plans should be comparable to, if not better than, FPMS plans in the treatment of head-and-neck cancer.

Brain Stem↗
PubMed2004

Self-inactivating lentiviral vectors resist proviral methylation but do not confer position-independent expression in hematopoietic stem cells.

Oncoretroviral expression is transcriptionally silenced in embryonic and hematopoietic stem cells (HSCs). This is associated with methylation of viral and internal promoters. We determined whether self-inactivating (SIN) lentiviral vectors (LV) would circumvent proviral silencing in HSCs. We studied long-term expression, methylation, and position effects (PE) from two GFP-encoding SIN-LV containing erythroid enhancers and the human ankyrin-1 promoter (h-Ank-P) using the murine secondary bone marrow (BM) transplant assay. Proviral expression was detected in RBC 6-11 months following transplant only in 28 of 49 secondary mice, with 0.9 +/- 0.2 copy/cell and oligoclonally integrated provirus in BM, spleen, and thymus. Twenty-one of 49 secondary mice lacked integrated provirus. Secondary mice containing provirus also had GFP-expressing RBCs, although proviral copy number did not always correlate with expression, suggesting either proviral methylation or chromatin PE. The endogenous h-Ank-P was partially methylated in nonerythroid cell lines and unmethylated in erythroid cell lines. However, h-Ank-P in the provirus was unmethylated in erythroid and nonerythroid cells within secondary murine BM. Despite lack of methylation, GFP expression was variable in secondary BFU-e and in single-copy mouse erythroleukemia cell clones. Taken together, these data show that erythroid-specific SIN-LV express long term and resist methylation-associated proviral silencing, but may require additional elements to confer position-independent expression.

Animals↗
PubMed2004

A new smoothing procedure to reduce delivery segments for static MLC-based IMRT planning.

In the application of pixel-based intensity-modulated radiation therapy (IMRT) using the step-and-shoot delivery method, one major difficulty is the prolonged delivery time. In this study, we present an integrated IMRT planning system that involves a simple smoothing method to reduce the complexity of the beam profiles. The system consists of three main steps: (a) an inverse planning process based on a least-square dose-based cost function; (b) smoothing of the intensity maps; (c) reoptimization of the segment weights. Step (a) obtains the best plan with the lowest cost value using a simulated annealing optimization algorithm with discrete intensity levels. Step (b) takes the intensity maps obtained from (a) and reduces the complexity of the maps by smoothing the adjacent beamlet intensities. During this process each beamlet is assigned a structure index based on anatomical information. A smoothing update is applied to average adjacent beamlets with the same index. To control the quality of the plan, a predefined clinical protocol is used as an acceptance criterion. The smoothing updates that violate the criterion are rejected. After the smoothing process, the segment weights are reoptimized in step (c) to further improve the plan quality. Three clinical cases were studied using this system: a medulloblastoma, a prostate cancer, and an oropharyngeal carcinoma. While the final plans demonstrate a degradation of the original plan quality, they still meet the plan acceptance criterion. On the other hand, the segment numbers or delivery times are reduced by 40%, 20%, and 20% for the three cases, respectively.

Algorithms↗
PubMed2004

Effects of the intensity levels and beam map resolutions on static IMRT plans.

In this study we focus on how the intensity level and multileaf collimator (MLC) resolution affect the quality of IMRT plans using the static MLC delivery technique. The planning process is based on a least-square dose-based quadratic function and uses a simulated annealing algorithm to sample the discrete variables. Three clinical cases are studied empirically: a medulloblastoma, a prostate, and an oropharyngeal carcinoma. The intensity levels used are 3, 5, 10, 20, and continuous; the map resolution varies from 0.15-1.5 cm, with the leaf width equal to the step size. The influence of these two parameters are studied by comparing the cost value and the cost of delivery time from a trade-off point of view. An "efficient frontier" is drawn by connecting the plans with the lowest cost value at any given resolutions. For each case, a practical delivery region is defined by doubling the delivery time needed at a normal setting (five levels, 1.0 cm). Within this region, the "efficient frontier" demonstrates that the plans with five intensity levels are the most efficient comparing with plans with higher levels. This is a confirmation of the conclusion from Keller-Reichenbecher et al. [Int. J. Radiat. Oncol., Biol., Phys. 45, 1315-1324 (1999)]. It indicates that to further improve the plan quality with the minimal cost of extra delivery time, the most economical way is to improve the resolution rather than using higher intensity levels.

Algorithms↗
PubMed2003

Intensity-modulated radiation therapy for head-and-neck cancer: the UCSF experience focusing on target volume delineation.

PURPOSE: To review the University of California-San Francisco (UCSF) experience of using intensity-modulated radiation therapy (IMRT) to treat head-and-neck cancer focusing on the importance of target volume delineation and adequate target volume coverage. METHODS AND MATERIALS: Between April 1995 and January 2002, 150 histologically confirmed patients underwent IMRT for their head-and-neck cancer at our institution. Sites included were nasopharynx 86, oropharynx 22, paranasal sinus 22, thyroid 6, oral tongue 3, nasal cavity 2, salivary 2, larynx 2, hypopharynx 1, lacrimal gland 1, skin 1, temporal bone 1, and trachea 1. One hundred seven patients were treated definitively with IMRT +/- concurrent platinum chemotherapy (92/107), whereas 43 patients underwent gross surgical resection followed by postoperative IMRT +/- concurrent platinum chemotherapy (15/43). IMRT was delivered using three different techniques: 1) manually cut partial transmission blocks, 2) computer-controlled auto-sequencing segmental multileaf collimator, and 3) sequential tomotherapy using dynamic multivane intensity-modulating collimator. Forty-two patients were treated with a forward plan, 102 patients with an inverse plan, and 6 patients with both forward and inverse plans. The gross target volume (GTV) was defined as tumor detected on physical examination or imaging studies. In postoperative cases, the GTV was defined as the preoperative gross tumor volume. The clinical target volume (CTV) included all potential areas at risk for microscopic tumor involvement by either direct extension or nodal spread including a margin for patient motion and setup errors. The average prescription doses to the GTV were 70 Gy and 66 Gy for the primary and the postoperative cases, respectively. The site of recurrence was determined by the diagnostic neuroradiologist to be either within the GTV or the CTV volume by comparison of the treatment planning computed tomography with posttreatment imaging studies. RESULTS: For the primary definitive cases with a median follow-up of 25 months (range 6 to 78 months), 4 patients failed in the GTV. The 2- and 3-year local freedom from progression (LFFP) rates were 97% and 95%. With a median follow-up of 17 months (range 8 to 56 months), 7 patients failed in the postoperative setting. The 2-year LFFP rate was 83%. For the primary group, the average maximum, mean, and minimum doses delivered were 80 Gy, 74 Gy, 56 Gy to the GTV, and 80 Gy, 69 Gy, 33 Gy to the CTV. An average of only 3% of the GTV and 3% of the CTV received less than 95% of the prescribed dose. For the postoperative group, the average maximum, mean, and minimum doses delivered were 79 Gy, 71 Gy, 37 Gy to the GTV and 79 Gy, 66 Gy, 21 Gy to the CTV. An average of only 6% of the GTV and 6% of the CTV received less than 95% of the prescribed dose. CONCLUSION: Accurate target volume delineation in IMRT treatment for head-and-neck cancer is essential. Our multidisciplinary approach in target volume definition resulted in few recurrences with excellent LFFP rates and no marginal failures. Higher treatment failure rates were noted in the postoperative setting in which lower doses were prescribed. Potential dose escalation studies may further improve the local control rates in the postoperative setting.

Academic Medical Centers↗