Biomedical subjects

Jeffrey Y C Wong

Publications and source records attributed to Jeffrey Y C Wong.

17 recordsLinked to original sources

PubMed2006

Multimodal management, including precisely targeted irradiation, in a severe refractory case of Evans syndrome.

A challenging case of acute autoimmune thrombocytopenia (ITP) which evolved into a chronic refractory case of Evans syndrome over a period of more than 23 years is presented and may illustrate current therapeutic dilemmas now perplexing patients and clinicians. Newer modalities are being developed and their eventual role in the scheme of clinical management remains to be established. While this development unfolds, highly targeted radiotherapy was applied in this case to reduce platelet uptake by a refractory recurrent splenule with the goal of stabilizing the platelet count until promising investigational thrombopoietic agents or other newer, less toxic therapies might become available for wider application.

Adult↗

PubMed2006

Dosimetric comparison of helical tomotherapy treatment and step-and-shoot intensity-modulated radiotherapy of retroperitoneal sarcoma.

PURPOSE: To compare step-and-shoot intensity-modulated radiation therapy (SAS-IMRT) and helical tomotherapy (Tomo) dosimetry plans for patients who have received adjuvant radiation therapy for retroperitoneal sarcomas (RSTS). METHODS AND MATERIALS: A retrospective review was performed for seven patients who received either SAS-IMRT or Tomo as adjuvant radiation therapy for RSTS. In each case, a treatment plan of the other modality was generated so that SAS-IMRT and Tomo could be compared. RESULTS: The average percentage of clinical target volume (CTV) that received less than the prescription dose was 1.4% for Tomo compared to 3.8% for SAS-IMRT. Both SAS-IMRT and Tomo plans provided comparable and significant reductions in volume of small bowel receiving greater than 45 Gy compared to simple opposing standard radiation fields. For the ipsilateral kidney, Tomo significantly reduced the volume of kidney that received at least 15 Gy (average 22% for Tomo vs. 56% for SAS-IMRT). CONCLUSION: Both SAS-IMRT and Tomo can encompass the large CTV often required for patients with RSTS, although Tomo provides superior dose uniformity. Both SAS-IMRT and Tomo can minimize the volume of small bowel receiving greater than 45 Gy. Tomo was superior to SAS-IMRT in minimizing the volume of ipsilateral kidney irradiated to greater than 15 Gy when the CTV is adjacent to a kidney. Dose escalation and target margin expansion may thus become realistic possibilities.

Adult↗

PubMed2006

Pitch, roll, and yaw variations in patient positioning.

PURPOSE: To use pretreatment megavoltage-computed tomography (MVCT) scans to evaluate positioning variations in pitch, roll, and yaw for patients treated with helical tomotherapy. METHODS AND MATERIALS: Twenty prostate and 15 head-and-neck cancer patients were selected. Pretreatment MVCT scans were performed before every treatment fraction and automatically registered to planning kilovoltage CT (KVCT) scans by bony landmarks. Image registration data were used to adjust patient setups before treatment. Corrections for pitch, roll, and yaw were recorded after bone registration, and data from fractions 1-5 and 16-20 were used to analyze mean rotational corrections. RESULTS: For prostate patients, the means and standard deviations (in degrees) for pitch, roll, and yaw corrections were -0.60 +/- 1.42, 0.66 +/- 1.22, and -0.33 +/- 0.83. In head-and-neck patients, the means and standard deviations (in degrees) were -0.24 +/- 1.19, -0.12 +/- 1.53, and 0.25 +/- 1.42 for pitch, roll, and yaw, respectively. No significant difference in rotational variations was observed between Weeks 1 and 4 of treatment. Head-and-neck patients had significantly smaller pitch variation, but significantly larger yaw variation, than prostate patients. No difference was found in roll corrections between the two groups. Overall, 96.6% of the rotational corrections were less than 4 degrees. CONCLUSIONS: The initial rotational setup errors for prostate and head-and-neck patients were all small in magnitude, statistically significant, but did not vary considerably during the course of radiotherapy. The data are relevant to couch hardware design for correcting rotational setup variations. There should be no theoretical difference between these data and data collected using cone beam KVCT on conventional linacs.

Head and Neck Neoplasms↗

PubMed2006

Dosimetric comparisons of helical tomotherapy treatment plans and step-and-shoot intensity-modulated radiosurgery treatment plans in intracranial stereotactic radiosurgery.

PURPOSE: To evaluate dose conformity, dose homogeneity, and dose gradient in helical tomotherapy treatment plans for stereotactic radiosurgery, and compare results with step-and-shoot intensity-modulated radiosurgery (IMRS) treatment plans. METHODS AND MATERIALS: Sixteen patients were selected with a mean tumor size of 14.65 +/- 11.2 cm3. Original step-and-shoot IMRS treatment plans used coplanar fields because of the constraint of the beam stopper. Retrospective step-and-shoot IMRS plans were generated using noncoplanar fields. Helical tomotherapy treatment plans were generated using the tomotherapy planning station. Dose conformity index, dose gradient score index, and homogeneity index were used in plan intercomparisons. RESULTS: Noncoplanar IMRS plans increased dose conformity and dose gradient, but not dose homogeneity, compared with coplanar IMRS plans. Tomotherapy plans increased dose conformity and dose gradient, yet increased dose heterogeneity compared with noncoplanar IMRS plans. The average dose conformity index values were 1.53 +/- 0.38, 1.35 +/- 0.15, and 1.26 +/- 0.10 in coplanar IMRS, noncoplanar IMRS, and tomotherapy plans, respectively. The average dose homogeneity index values were 1.15 +/- 0.05, 1.13 +/- 0.04, and 1.18 +/- 0.09 in coplanar IMRS, noncoplanar IMRS, and tomotherapy plans, respectively. The mean dose gradient score index values were 1.37 +/- 19.08, 22.32 +/- 19.20, and 43.28 +/- 13.78 in coplanar IMRS, noncoplanar IMRS, and tomotherapy plans, respectively. The mean treatment time in tomotherapy was 42 +/- 16 min. CONCLUSIONS: We were able to achieve better dose conformity and dose gradient in tomotherapy plans compared with step-and-shoot IMRS plans for intracranial stereotactic radiosurgery. However, tomotherapy treatment time was significantly larger than that in step-and-shoot IMRS.

Algorithms↗

PubMed2006

Targeted total marrow irradiation using three-dimensional image-guided tomographic intensity-modulated radiation therapy: an alternative to standard total body irradiation.

Total body irradiation (TBI) is an important part of bone marrow transplantation conditioning regimens. In TBI, dose escalation is difficult, because of associated normal organ toxicities. A method to deliver a more targeted dose of TBI preferentially to sites of greatest tumor burden is needed to reduce the dose to normal organs, reduce toxicities, and permit dose escalation. The purpose of this study was to evaluate, through a dosimetric analysis, the potential advantages and feasibility of selectively delivering targeted myeloablative doses of radiation to bone and marrow using a recently developed image-guided tomographic intensity-modulated radiation therapy delivery system (helical tomotherapy). Whole-body computed tomography datasets from 3 patients, age 5, 20, and 53 years, were used for treatment planning studies to evaluate 2 targeted TBI strategies: total marrow irradiation (TMI), in which the target region was defined as the skeletal bone, and total marrow and lymphoid irradiation (TMLI), in which the target regions were defined as bone, major lymph node chains, liver, spleen, and sanctuary sites, such as brain. Organ doses and dose distributions were compared with those in conventional TBI. A 1.7- to 7.5-fold reduction in median organ doses was observed with TMI and TMLI compared with conventional TBI. With this more targeted approach, a dose-volume histogram analysis predicted the potential to escalate the dose to bone (and containing marrow) up to 20 Gy, while maintaining doses to normal organs at lower levels than in conventional TBI to 12 Gy. Results were similar for the adult and pediatric patients, indicating that this form of targeted TBI will be applicable to most patients regardless of frame size. TMI to 10 Gy was delivered as part of a tandem transplant regimen to the 53-year-old patient with multiple myeloma. Clinical results confirmed the treatment planning predictions. After TMI, the patient experienced the expected blood count nadir, followed by successful engraftment. Grade 2 nausea and grade 1 emesis occurred only briefly on day 2 of TMI. Skin erythema, oral mucositis, esophagitis, and enteritis were not observed. This report demonstrates the feasibility and potential dosimetric advantages of selectively delivering myeloablative doses of radiation to bone and marrow using an image-guided tomographic intensity-modulated radiation therapy delivery system. Organ doses are substantially lower than those associated with standard TBI and predict the potential to significantly reduce associated toxicities and allow for dose escalation. The results also suggest that this form of targeted TBI may have potential advantages over other forms of targeted TBI, such as radioimmunotherapy or bone-seeking radionuclide therapy. Ongoing clinical trials will define the maximum TMI and TMLI doses achievable and define the potential advantages and limitations of this new approach for patients undergoing hematopoietic stem cell transplantation.

Adult↗

PubMed2006

Systemic targeted radionuclide therapy: potential new areas.

Radiation oncology is entering an exciting new era with therapies being delivered in a targeted fashion through an increasing number of novel approaches. External beam radiotherapy now integrates functional and anatomic tumor imaging to guide delivery of conformal radiation to the tumor target. Systemic targeted radionuclide therapy (STaRT) adds an important new dimension by making available to the radiation oncologist biologically targeted radiation therapy. Impressive clinical results with antibody-targeted radiotherapy, leading to the Food and Drug Administration's approval of two anti-CD20 radiolabeled antibodies, highlight the potential of STaRT. Optimization strategies will further improve the efficacy of STaRT by improving delivery systems, modifying the tumor microenvironment to increase targeted dose, and maximizing dose effect. Ultimately, the greatest potential for STaRT will not be as monotherapy, but as therapy integrated into established multimodality regimens and used as adjuvant or consolidative therapy in patients with minimal or micrometastatic disease.

Antibodies, Bispecific↗

PubMed2006

Basic immunology of antibody targeted radiotherapy.

Antibody targeted radiotherapy brings an important new treatment modality to the radiation oncology clinic. Radiation dose to tumor and normal tissues are determined by a complex interplay of antibody, antigen, tumor, radionuclide, and host-related factors. A basic understanding of these immunologic and physiologic factors is important to optimally utilize this therapy in the clinic. Preclinical and clinical studies need to be continued to broaden our understanding and to develop new strategies to further improve the efficacy of this promising form of targeted therapy.

Animals↗

PubMed2006

A phase I trial of (90)Y-DOTA-anti-CEA chimeric T84.66 (cT84.66) radioimmunotherapy in patients with metastatic CEA-producing malignancies.

PURPOSE/OBJECTIVE: Previous radioimmunotherapy (RIT) clinical trials at this institution with (90)Y-labeled cT84.66 anti-CEA (carcinoembryonic antigen) evaluated the antibody conjugated to diethylenetriaminepentaacetic acid (DTPA). The aim of this phase I therapy trial was to evaluate cT84.66 conjugated to the macrocyclic chelate (90)Y-DOTA and labeled with (90)Y in a comparable patient population. EXPERIMENTAL DESIGN: Patients with metastatic CEA-producing cancers were entered in this trial. If antibody targeting to tumor was observed after the administration of (111)In-DTPA cT84.66, the patient then received the therapy infusion of (90)Y-DOTA-cT84.66 1 week later. Serial nuclear scans, blood and urine collections, and computed tomography (CT) scans were performed to assess antibody biodistribution, pharmacokinetics, toxicities, and antitumor effects. RESULTS: Thirteen (13) patients were treated in this study. Dose-limiting hematologic toxicity was experienced at initial starting activity levels of 12 and 8 mCi/m(2). Subsequent patients received systemic Ca-DTPA at 125 mg/m(2) every 12 hours for 3 days post-therapy to allow for a dose escalation to 16 mCi/m(2), where hematologic toxicity was observed with an associated maximum tolerated dose (MTD) of 13.4 mCi/m(2). Tumor doses ranged from 4.4 to 569 cGy/mCi, which translated to 97-12,500 cGy after a single infusion of (90)Y-DOTA-cT84.66. Human anti-chimeric antibody (HACA) response developed in 8 of 13 patients and prevented additional therapy in 4 patients. CONCLUSIONS: This study demonstrates the feasibility of using (90)Y-DOTA-cT84.66 for antibody-guided radiation therapy. Immunogenicity of the DOTA-conjugated cT84.66 antibody was not appreciably greater than that observed with (90)Y-DTPA-cT84.66 in previous trials. Dose-limiting hematopoietic toxicity with (90)Y-DOTA-cT84.66 decreased with Ca-DTPA infusions post-therapy and appears to be comparable to previously published results for (90)Y-DTPA-cT84.66. The highest antibody uptake and tumor doses were to small nodal lesions, which supports the predictions from preclinical and clinical data that RIT may be best applied in the minimal tumor burden setting.

Adult↗

PubMed2005

Organ sparing by conformal avoidance intensity-modulated radiation therapy for anal cancer: dosimetric evaluation of coverage of pelvis and inguinal/femoral nodes.

PURPOSE: To describe a novel and straightforward conformal avoidance intensity-modulated radiation therapy (IMRT) technique for coverage of pelvis and inguinal/femoral nodes and to compare the dosimetry of the new method with that of other traditional methods of radiation treatment. METHODS AND MATERIALS: Data of 2 patients with anal cancer were used as example cases to illustrate details and advantages of conformal avoidance IMRT technique. Conventional photons with enface electrons design was created first, thereby providing "outermost boundaries" defined as planning target volume (PTV) for subsequent conformal avoidance IMRT design. Organs at risk (OARs), including femoral head and neck and external genitalia, were contoured as conformal avoidance structures. A step-and-shoot inverse IMRT planning was subsequently generated. For dosimetric comparison, a recently published technique by modified segmental boost was also generated. These treatment techniques were evaluated by dose-volume histogram (DVH) of PTV and OARs. Dose profiles at four different depths from each treatment planning were generated for comparison. RESULTS: The DVH of PTV showed that coverage of the PTV was comparable among three treatment techniques. Percent volume of PTV receiving more than 90% prescription dose was in the range 94-98% for the three treatment techniques, and all had only 0-2% of PTV receiving more than 110% of prescription dose. The DVH of OARs confirmed that both femoral head and neck and external genitalia could be spared well by conformal avoidance IMRT as compared with the other two techniques. Although greater inhomogeneity of dose distribution within the PTV was noted by conformal avoidance IMRT technique, as shown by dose profiles at four different depths, the maximum doses at different depths were less than 115%, which was comparable to those planned by modified segmental boost technique. Planning by photons and enface electrons technique, however, showed a greater dose variation up to 134% of the prescription dose at 1.5 cm depth along photon-electron match-line. CONCLUSIONS: To cover pelvis and inguinal/femoral nodes, conformal avoidance IMRT is technically simple to simulate, plan, and execute. Dosimetric study has demonstrated that it achieves comparable PTV coverage compared with other approaches while at the same time significantly sparing the surrounding OARs.

Aged↗

PubMed2005

Optimizing radiolabeled engineered anti-p185HER2 antibody fragments for in vivo imaging.

We have recently described the in vivo properties of an iodinated anti-p185HER2 engineered antibody fragment [minibody (scFv-C(H)3)2; 80 kDa], made from the internalizing 10H8 monoclonal antibody. Although the 10H8 minibody showed excellent binding to the target in vitro, only modest tumor uptake [5.6 +/- 1.7% injected dose per gram (ID/g) of tissue] was achieved in nude mice bearing MCF7/HER2 breast cancer tumors. Here, in an attempt to improve targeting, the 10H8 minibody was conjugated to 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA), radiometal labeled, and evaluated in vivo. The tumor uptake of 111In-DOTA 10H8 minibody was 5.7 +/- 0.1% ID/g, similar to the radioiodinated 10H8 minibody. However, in addition to the expected liver clearance, the kidneys had unexpectedly high activity (34.0 +/- 4.0% ID/g). A minibody derived from a second anti-p185(HER2) antibody (trastuzumab; hu4D5v8) was also made. Tumor uptakes, evaluated by quantitative microPET using 64Cu-DOTA hu4D5v8 minibody, were 4.2 +/- 0.5% ID/g. Furthermore, in non-tumor-bearing mice, 111In-DOTA hu4D5v8 minibody exhibited similar elevated uptake in the kidneys (28.4 +/- 6.5% ID/g). Immunohistochemical staining of kidneys from non-tumor-bearing mice showed strong specific staining of the proximal tubules, and Western blot analysis of kidney lysate confirmed the presence of cross-reactive antigen. To further improve tumor uptake and normal tissue distribution, a larger hu4D5v8 fragment [(scFv-C(H)2-C(H)3)2; 105 kDa] was made, engineered to exhibit rapid clearance kinetics. This fragment, when evaluated by microPET, exhibited improved tumor targeting (12.2 +/- 2.4% ID/g) and reduced kidney uptake (13.1 +/- 1.5% ID/g). Thus, by manipulating the size and format of anti-p185(HER2) antibody fragments, the kidney activity was reduced and high or low expression of p185HER2 in xenografts could be distinguished by microPET imaging.

Animals↗

PubMed2004

Humanization of the anti-CEA T84.66 antibody based on crystal structure data.

Chimeric T84.66 (cT84.66) is a monoclonal antibody (mAb) of high specificity and affinity for the tumor-associated carcinoembryonic antigen (CEA). Radiolabeled cT84.66 has demonstrated utility in the clinic as a reagent for the radioimmunoscintigraphy and radioimmunotherapy of CEA-positive colorectal and breast malignancies. To extend the therapeutic efficacy of T84.66, humanization by complementary determining region (CDR) grafting was employed. CDR grafting is a well-established technique, though often a series of framework back-mutations is required to restore high affinity. Recently, the crystal structure of the T84.66 diabody (scFv dimer) derived from the murine T84.66 mAb was determined, facilitating the humanization process by the availability of crystal structure data for both the graft donor and graft acceptor. A search of the Protein Data Bank revealed close structural similarity (r.m.s.d. of 1.07 A) between the Fv of T84.66 and the Fv of 4D5v8, a humanized anti-p185HER2 antibody marketed as Herceptin (Trastuzumab). This resulted in two humanized versions of the T84.66 M5A and M5B mAbs that differed only in the number of murine residues present in the C-terminal half of CDR-H2. Biochemical analysis and animal biodistribution studies were conducted to evaluate the humanized mAbs. The M5A, M5B and cT84.66 mAbs showed sub-nanomolar affinity for CEA and as radiolabeled mAbs exhibited specific tumor localization in tumor bearing mice. The T84.66 M5A mAb was selected for clinical development due to a slightly higher tumor uptake and a larger content of human residues, and was renamed hT84.66. A limited-scale production and animal imaging study have demonstrated hT84.66's ability to support clinical trials. Planned clinical trials will determine the effective utilization of this structure-based approach in the development of a promising new therapeutic.

Amino Acid Sequence↗

PubMed2004

Pilot trial evaluating an 123I-labeled 80-kilodalton engineered anticarcinoembryonic antigen antibody fragment (cT84.66 minibody) in patients with colorectal cancer.

PURPOSE: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (V(L)-linker-V(H)-C(H)3; 80 kDa) that demonstrates bivalent and high affinity (4 x 10(10) m(-1)) binding to carcinoembryonic antigen (CEA). The variable regions (V(L) and V(H)) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the C(H)3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab')(2) fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether (123)I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer. EXPERIMENTAL DESIGN: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5-10 mCi (1 mg) of (123)I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48-72 h. Surgery was performed immediately after the last nuclear scan. RESULTS: Tumor imaging was observed with (123)I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. (123)I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9-65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed. CONCLUSION: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as (111)In.

Adult↗

PubMed2003

A Phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer.

PURPOSE: Targeted systemic radiation therapy using radiolabeled antibodies results in tumor doses sufficient to produce significant objective responses in the radiosensitive hematological malignancies. Although comparable doses to tumor are achieved with radioimmunotherapy (RIT) in solid tumors, results have been modest primarily because of their relative lack of radiosensitivity. For solid tumors, as with external beam radiotherapy, RIT should have a more important clinical role if combined with other systemic, potentially radiation-enhancing chemotherapy agents and if used as consolidative therapy in the minimal tumor burden setting. The primary objective of this trial was to evaluate the feasibility and toxicities of systemic 90Y-chimeric T84.66 (cT84.66) anti-carcinoembryonic antigen RIT in combination with continuous infusion 5-fluorouracil (5-FU). EXPERIMENTAL DESIGN: Patients with chemotherapy-refractory metastatic colorectal cancer were entered. The study was designed for each patient to receive 90Y-cT84.66 anti-carcinoembryonic antigen at 16.6 mCi/m2 as an i.v. bolus infusion combined with 5-FU delivered as a 5-day continuous infusion initiated 4 h before antibody infusion. Cohorts of patients were entered at 5-FU dose levels of 700, 800, 900, and 1000 mg/m2/day. Upon reaching the highest planned dose level of 5-FU, a final cohort received 90Y-cT84.66 at 20.6 mCi/m2 and 5-FU at 1000 mg/m2/day. For all patients, Ca-diethylenetriaminepentaacetic acid at 125 mg/m2 every 12 h was administered for the first 72 h after 90Y-cT84.66. Patients were eligible to receive up to three cycles of 90Y-cT84.66/5-FU every 6 weeks. RESULTS: Twenty-one patients were treated on this study. All had been heavily pretreated with 19 having previously received 5-FU and 16 having failed two to four chemotherapy regimens. A maximum-tolerated dose of 16.6 mCi/m2 90Y-cT84.66 combined with 1000 mg/m2/day 5-FU was reached. These dose levels are comparable with maximum-tolerated dose levels of each agent alone. Thirteen patients received one cycle and 8 patients two cycles of therapy. Hematopoietic toxicity was dose-limiting and reversible. RIT did not appear to increase nonhematopoietic toxicities associated with 5-FU. Two of 19 patients assayed developed a human anti-chimeric antibody immune response after the first cycle of therapy, which is significantly less than that observed in a previous trial evaluating 90Y-cT84.66 alone. No objective responses were observed. However, 11 patients with progressive disease entering the study demonstrated radiological stable disease of 3-8 months duration and 1 patient demonstrated a mixed response. CONCLUSIONS: Results from this trial are encouraging and demonstrate the feasibility and possible advantages of combining continuous infusion 5-FU with 90Y-cT84.66 RIT. The addition of 5-FU does not appear to significantly enhance hematological toxicities of the radiolabeled antibody. In addition, 5-FU reduces the development of human anti-chimeric antibody response, permitting multicycle therapy in a larger number of patients. Future efforts should continue to focus on integrating radiation therapy delivered by radiolabeled antibodies into established 5-FU regimens.

Antibodies, Monoclonal↗

PubMed2002

The two types of correction of absorbed dose estimates for internal emitters.

BACKGROUND: Two types of correction for absorbed dose (D) estimates are described for clinical applications of internal emitters. The first is appropriate for legal and scientific reasons involving phantom-based estimates; the second is patient-specific and primarily intended for radioimmunotherapy (RIT). METHODS: The Medical Internal Radiation Dose (MIRD) relationship (D) = S A is used, where S is a geometric matrix factor and A is the integral of source organ activities. Internal consistency of the data and the size of organ systems in the humanoid phantom must be assured in both types of estimation. RESULTS: The first dose estimate correction (I) is one whereby computations refer to one or another standard (e.g., MIRD-type) phantom. In this case the S value remains as given, but the measured patient A data must be standardized. The correction factor is the phantom's ratio of organ mass to whole-body mass divided by the same ratio for the volunteer or patient. The second dose estimate correction (II) is patient-specific. While the A value is unchanged for this application, a correction term is provided for the phantom-derived S matrix. The dominant (nonpenetrating radiation) component of this correction factor can be obtained via the ratio of the patient to phantom organ masses. In both corrections, we recommend that true organ sizes, necessary in each method of estimation, be determined in a separate sequence of anatomic images. CONCLUSIONS: In both dose estimation corrections, true sizes of the patient's or volunteer's internal organs must be obtained. Correction due to organ mass size can be severalfold and is probably the dominant uncertainty in the internal emitter absorbed dose calculation process.

Absorption↗

PubMed2002

Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes.

Many tumors show a mutant or inactive tumor suppressor p53 (TP53) status, and TP53 in the tumor-carrying human papillomavirus (HPV) may be dysfunctional because of inhibition by the viral protein HPV E6. Molecular mechanisms underlying radiation responses and the radiation-induced resistant phenotype in the TP53-inactive tumor have not been well investigated. In the present study, using a human keratinocyte line (HK18) with TP53 inhibited by HPV18 infection, we demonstrated that nuclear factor (NF)-kappaB is responsible for a major portion of the radioresistance observed in a cell population (HK18-IR) derived from HK18 cells by fractionated ionizing radiation (FIR; 2 Gy/fraction; total dose, 60 Gy). HK18-IR cells showed increased clonogenic radioresistance [dose-modifying factor (DMF), 1.47], reduced apoptotic response, and a shortened radiation-induced growth delay. Both DNA-binding and reporter transcriptional activity of NF-kappaB, but not of TP53, were activated in HK18-IR cells compared with the parental HK18 cells; this activation was observed both before and after a single dose of 5 Gy. To determine target genes responsive to NF-kappaB activation, DNA microarray profiles for 588 genes were matched in HK18-IR cells compared with those in HK18 cells; the paired comparisons were made for basal levels before irradiation or for levels 24 h after 5 Gy. For 25 genes, a 2- to 5-fold up-regulation in HK18-IR cells relative to HK18 cells was similar when comparisons were made for basal levels or for levels after irradiation. Included in the approximately 4% of genes activated in HK18-IR cells, were six genes (Cyclin B1, Cyclin D1, HIAP, BAG-1, TTF, and fibronectin) putatively linked to NF-kappaB regulation. We then measured the expression of this group of FIR-regulated genes in HK18-IR cells expressing a dominant-negative mutant IkappaB (mIkappaB) that inhibited NF-kappaB activation. Clonogenic radioresistance was reduced greatly in the mIkappaB transfectants (DMF, 1.18 and 1.10, respectively, at 10% and 1% of isosurvival for mIkappaB transfectants compared with 1.47 and 1.45, respectively, for vector control transfectants). Expressions of Cyclin B1, Cyclin D1, and HIAP were down-regulated by the inhibition of NF-kappaB. These results suggest that transcription of NF-kappaB and a group of NF-kappaB target genes are involved in radioresistance in FIR-treated tumor cells with inactive TP53.

Apoptosis↗

PubMedDate not supplied

Combined radioimmunotherapy and chemotherapy of breast tumors with Y-90-labeled anti-Her2 and anti-CEA antibodies with taxol.

Because breast cancer cells often express either Her2/neu or carcinoembryonic antigen (CEA) or both, these tumor markers are good targets for radioimmunotherapy using Y-90-labeled antibodies. We performed studies on nude mice bearing xenografts from MCF7, a cell line that has low Her2 and CEA expression, to more accurately reflect the more usual situation in breast cancer. Although uptake of In-111 anti-CEA into tumors was lower than that for In-111-labeled anti-Her2, radioimmunotherapy (RIT) with Y-90 anti-CEA was equivalent to that of Y-90 anti-Her2. When either Y-90 antibody was combined with a split-dose treatment with Taxol, the antitumor effect was greater than with either agent alone. When Y-90 anti-CEA was combined with a single dose of Taxol, the results were equivalent to the split-dose regimen. RIT plus cold Herceptin had no additional effects on tumor size reduction over RIT alone. When animals were first treated with Y-90 anti-Her2 and imaged 1-2 weeks later with In-111 anti-CEA or anti-Her2, tumor uptake was higher for anti-CEA and improved over tumor uptake with no prior RIT. These results suggest that a split dose of RIT with anti-Her2 antibody followed by anti-CEA antibody would be more effective than a single dose of either. This prediction was partially confirmed in a controlled study comparing single- vs split-dose anti-Her2 RIT followed by either anti-Her2 or anti-CEA RIT. These studies suggest that combined RIT and Taxol therapy are suitable in breast cancers expressing either low amounts of Her2 or CEA, thus expanding the number of eligible patients for combined therapies. They further suggest that split-dose RIT using different combinations of Y-90-labeled antibodies is effective in antitumor therapy.

Animals↗

PubMedDate not supplied

Improved biodistribution and radioimmunoimaging with poly(ethylene glycol)-DOTA-conjugated anti-CEA diabody.

Diabodies are single chain antibody fragments (scFvs) that spontaneously form bivalent dimers of molecular size 50-55000. Radiolabeled diabodies are almost ideal tumor targeting agents due to their high avidity (bivalent) binding to tumor antigens and small size (50-55000) that leads to improved tumor-to-blood ratio compared to intact antibodies (150000). However, due to their high retention and metabolism in the kidney, radioiodine is the current radiolabel of choice for diabodies since radioiodine is rapidly excreted from the kidney once metabolized. We have previously shown that 111In-DOTA-diabody gives higher tumor uptake in nude mouse xenografts than 125I-diabody, but has extremely high kidney retention since its 111In-labeled metabolites are retained by and only slowly excreted from the kidney. When a diabody is conjugated to a bifunctional PEG-3400 derivative followed by reaction with cysteinyl-DOTA, the resulting product has an apparent molecular size of 75000 and a Stokes radius of 35 angstroms on size exclusion chromatography, compared to a Stokes radius of 25 angstroms for intact diabody. When radiolabeled, the conjugate gives high yields of 111In-labeled product, retains high immunoreactivity, and gives improved biodistributions (30-40%ID/g, 12-48 h) compared to 111In-DOTA-diabody (12-13%ID/g, 6-12 h). We show that the improved biodistribution is due to an increase in Stokes radius caused by the linear PEG-3400 since conjugation of diabody with multiple (PEG)12 linkers followed by reaction with cysteinyl-DOTA does not reduce kidney accumulation. We also show that 111In-cysteinyl-DOTA-PEG3400-diabody gives excellent tumor images in the nude mouse xenograft model and that 125I-PEG3400-diabody gives equivalent images to 125I-minibody (molecular size, 80000), but improved tumor-to-liver ratios, suggesting that this imaging agent can be used to image liver metastases.

Animals↗