Prediction of Therapy Tumor-Absorbed Dose Estimates in I-131 Radioimmunotherapy Using Tracer Data Via a Mixed-Model Fit to Time Activity

Abstract Background: For individualized treatment planning in radioimmunotherapy (RIT), correlations must be established between tracer-predicted and therapy-delivered absorbed doses. The focus of this work was to investigate this correlation for tumors. Methods: The study analyzed 57 tumors in 19 follicular lymphoma patients treated with I-131 tositumomab and imaged with SPECT/CT multiple times after tracer and therapy administrations. Instead of the typical least-squares fit to a single tumor's measured time-activity data, estimation was accomplished via a biexponential mixed model in which the curves from multiple subjects were jointly estimated. The tumor-absorbed dose estimates were determined by patient-specific Monte Carlo calculation. Results: The mixed model gave realistic tumor time-activity fits that showed the expected uptake and clearance phases even with noisy data or missing time points. Correlation between tracer and therapy tumor-residence times (r=0.98; p<0.0001) and correlation between tracer-predicted and therapy-delivered mean tumor-absorbed doses (r=0.86; p<0.0001) were very high. The predicted and delivered absorbed doses were within±25% (or within±75 cGy) for 80% of tumors. Conclusions: The mixed-model approach is feasible for fitting tumor time-activity data in RIT treatment planning when individual least-squares fitting is not possible due to inadequate sampling points. The good correlation between predicted and delivered tumor doses demonstrates the potential of using a pretherapy tracer study for tumor dosimetry-based treatment planning in RIT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98438/1/cbr%2E2011%2E1053.pd

Observations consistent with autocrine stimulation of hybridoma cell growth and implications for large-scale antibody production

Existence of autocrine growth factors (aGFs) may influence the serum requirement for growth of hybridoma cells and thus significantly influence process economics. For the murine hybridoma cell line S3H5/γ2bA2, critical inoculum density (cID) and serum requirement for growth were inversely related for cultivation in both T flasks and spinner flasks. In spinner flasks, an inoculum density of 10 6 cells/ml was necessary for the cells to grow in RPMI 1640 medium without serum supplement, and an inoculum density of 10 3 cell/ml was necessary in RPMI 1640 medium with 10% serum. In T flasks, where the local cell density is higher than in spinner flasks, an inoculum density of 10 6 cells/ml was necessary for the cells to grow in RPMI 1640 medium without serum supplement, and an inoculum density of 1 cell/ml was also necessary in RPMI 1640 medium with 10% serum. Further, immobilized cells at high local cell density could grow under conditions where cells in T flasks at corresponding overall cell density could not grow. The cells at high inoculum density were less sensitive to shear induced by mechanical agitation than the cells at low inoculum density. Taken together these observations support the existence of secreted aGF(s) by the hybridoma cell line used. Since the specific MAb production rate was independent of cultivation method and inoculum density, the existence of autocrine growth factors would suggest that the use of immobilized cells should improve the economics of MAb production.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42316/1/10529_2005_Article_BF01022320.pd

Biological-Effect Modeling of Radioimmunotherapy for Non-Hodgkins Lymphoma: Determination of Model Parameters

Treatment with Tositumomab and 131I tositumomab anti-CD20 radioimmunotherapy (Bexxar) yields a nonradioactive antibody antitumor response (the so-called cold effect) and a radiation response. Numerical parameter determination by least-squares (LS) fitting was implemented for more accurate parameter estimates in equivalent biological-effect calculations. Methods: One hundred thirty-two tumors in 37 patients were followed using five or six SPECT/CT studies per patient, three each (typical) post-tracer (0.2 GBq) and post-therapy (?3 GBq) injections. The SPECT/CT data were used to calculate position- and time-dependent dose rates and antibody concentrations for each tumor. CT-defined tumor volumes were used to track tumor volume changes. Combined biological-effect and cell-clearance models were fit to tumor volume changes. Optimized parameter values determined using LS fitting were compared to previous fitted values that were determined by matching calculated to measured tumor volume changes using visual assessment. Absorbed dose sensitivity (α) and cold-effect sensitivity (?p) parameters were the primary fitted parameters, yielding equivalent biological-effect (E) values. Results: Individual parameter uncertainties were approximately 10% and 30% for α and ?p, respectively. LS versus previously fit parameter values were highly correlated, although the averaged α value decreased and the averaged ?p value increased for the LS fits compared to the previous fits. Correlation of E with 2-month tumor shrinkage data was similar for the two fitting techniques. The LS fitting yielded improved fit quality and likely improved parameter estimation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140326/1/cbr.2012.1467.pd

A retrospective comparative outcome analysis following systemic therapy in Mycosis fungoides and Sezary syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134845/1/ajh24564_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134845/2/ajh24564.pd

A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T‐cell lymphomas

The transcription factor GATA‐3, highly expressed in many cutaneous T‐cell lymphoma (CTCL) and peripheral T‐cell lymphomas (PTCL), confers resistance to chemotherapy in a cell‐autonomous manner. As GATA‐3 is transcriptionally regulated by NF‐κB, we sought to determine the extent to which proteasomal inhibition impairs NF‐κB activation and GATA‐3 expression and cell viability in malignant T cells. Proteasome inhibition, NF‐κB activity, GATA‐3 expression, and cell viability were examined in patient‐derived cell lines and primary T‐cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF‐κB activation, and GATA‐3 expression were observed preclinically in ixazomib‐treated cells. Therefore, an investigator‐initiated, single‐center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF‐κB activation and GATA‐3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF‐κB/GATA‐3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139920/1/ajh24895.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139920/2/ajh24895_am.pd

Effect of mechanical agitation on hybridoma cell growth

Hybridoma cells (S3H5/γ2bA2) were grown in spinner flasks at different agitation speeds. It was found that cells in stationary and decline phases of growth were sensitive to shear force caused by agitation but cells in growth phase seemed less sensitive to the shear forces introduced. The death rate was found to be. 0.007 hr −1 in T flasks but 0.018 hr −1 and 0.028 hr −1 at 100 and 200 rpm, respectively, while the growth rate was about 0.05 hr −1 for all cases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42280/1/10529_2005_Article_BF01024713.pd

Volume reduction versus radiation dose for tumors in previously untreated lymphoma patients who received iodine-131 tositumomab therapy

BACKGROUND A Phase II study of previously untreated patients with malignant low grade follicular lymphoma given a combination of unlabeled tositumomab and tositumomab labeled with iodine-131 has recently been completed. The responses of these patients have been characterized, and for some of them tumor dosimetry during therapy has been estimated not only by pretherapy tracer conjugate views but also by a hybrid method. METHODS Available patients were studied if they had had a pelvic or abdominal tumor evaluation by single photon emission computed tomography (SPECT) and achieved a partial response. A tumor outlined on the iodine-131 conjugate-view images was called a composite tumor. Its volume estimate came from multiple, not necessarily contiguous, regions of interest (ROI) on the pretherapy computed tomography (CT) scan. Its radiation dose was estimated from the weeklong series of pretherapy images and standard Medical Internal Radiation Dose methods. Computed tomography ROI were also grouped into smaller, contiguous volumes that defined individual tumors. Their radiation doses were estimated by the hybrid method. This method employed the activity measured for each individual tumor by a single intratherapy SPECT scan, as well as the tumor's volume, to individually normalize the composite time-activity curve as appropriate. The individual normalization factors then converted the composite radiation dose to radiation doses for individual tumors. Reduction in tumor volume was calculated for both composite and individual tumors at 12 weeks posttherapy. RESULTS For 14 composite tumors in 10 patients, the median pretherapy volume was 170 cm 3 . Application of a sigmoidal curve function to the plot of volume reduction versus radiation absorbed dose resulted in degeneration of the curve into a straight line with a negative slope. There was no statistical significance in the relationship ( P = 0.73). For 43 individual tumors, the median pretherapy tumor volume was 26 cm 3 . The plot of volume reduction versus dose was fairly well fit by a sigmoidal curve, and the relationship approached statistical significance ( P = 0.06). The representation assigned 56% of the shrinkage to the effects of unlabeled tositumomab. For the subset of individual tumors with a pretherapy volume less than 10 cm 3 from 6 patients (n = 15), the relationship was significant ( P = 0.03). The sigmoidal representation assigned only 12% of the shrinkage to unlabeled tositumomab, as contrasted with 72% for tumors with pretherapy volume greater than 10 cm 3 . CONCLUSIONS For patients who attained a partial response, analysis of individual tumors by a hybrid dosimetric method led to a dependence between volume reduction at 12 weeks and radiation dose that tended to be significant. The same was not true with dosimetry of composite tumors based on pretherapy conjugate views alone. It appeared that volume reductions from both unlabeled antibody and radiation dose were important in tositumomab therapy of lymphoma patients, with unlabeled antibody relatively more important for larger tumors. Cancer 2002;94:1258–63. © 2002 American Cancer Society. DOI 10.1002/cncr.10294Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34359/1/10294_ftp.pd

Transformed non‐Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100290/1/bjh12570.pd

Use of Integrated SPECT/CT Imaging for Tumor Dosimetry in I-131 Radioimmunotherapy: A Pilot Patient Study

Abstract Integrated systems combining functional (single-photon emission computed tomography; SPECT) imaging with anatomic (computed tomography; CT) imaging have the potential to greatly improve the accuracy of dose estimation in radionuclide therapy. In this article, we present the methodology for highly patient-specific tumor dosimetry by utilizing such a system and apply it to a pilot study of 4 follicular lymphoma patients treated with I-131 tositumomab. SPECT quantification included three-dimensional ordered-subset expectation-maximization reconstruction and CT-defined tumor outlines at each time point. SPECT/CT images from multiple time points were coupled to a Monte Carlo algorithm to calculate a mean tumor dose that incorporated measured changes in tumor volume. The tumor shrinkage, defined as the difference between volumes drawn on the first and last CT scan (a typical time period of 15 days) was in the range 5%-49%. The therapy-delivered mean tumor-absorbed dose was in the range 146-334cGy. For comparison, the therapy dose was also calculated by assuming a static volume from the initial CT and was found to underestimate this dose by up to 47%. The agreement between tracer-predicted and therapy-delivered tumor-absorbed dose was in the range 7%-21%. In summary, malignant lymphomas can have dramatic tumor regression within days of treatment, and advanced imaging methods allow for a highly patient-specific tumor-dosimetry calculation that accounts for this regression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78152/1/cbr.2008.0568.pd