A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^

Bayesian Adaptive Designs for Early Phase Clinical Trials

My dissertation focuses mainly on Bayesian adaptive designs for phase I and phase II clinical trials. It includes three specific topics: (1) proposing a novel two-dimensional dose-finding algorithm for biological agents, (2) developing Bayesian adaptive screening designs to provide more efficient and ethical clinical trials, and (3) incorporating missing late-onset responses to make an early stopping decision. Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which toxicity and efficacy monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a phase I/II trial design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Simulation studies show that the proposed design substantially outperforms the conventional multi-arm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while at the same time allocating substantially more patients to efficacious treatments. The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while at the same time providing higher power to identify the best treatment at the end of the trial. Phase II trial studies usually are single-arm trials which are conducted to test the efficacy of experimental agents and decide whether agents are promising to be sent to phase III trials. Interim monitoring is employed to stop the trial early for futility to avoid assigning unacceptable number of patients to inferior treatments. We propose a Bayesian single-arm phase II design with continuous monitoring for estimating the response rate of the experimental drug. To address the issue of late-onset responses, we use a piece-wise exponential model to estimate the hazard function of time to response data and handle the missing responses using the multiple imputation approach. We evaluate the operating characteristics of the proposed method through extensive simulation studies. We show that the proposed method reduces the total length of the trial duration and yields desirable operating characteristics for different physician-specified lower bounds of response rate with different true response rates.

Bayesian estimation of multilevel item response model with missing data

This study proposed a novel statistical method that modeled the multiple outcomes and missing data process jointly using item response theory. This method follows the "intent-to-treat" principle in clinical trials and accounts for the correlation between outcomes and missing data process. This method may provide a good solution to chronic mental disorder study. ^ The simulation study demonstrated that if the true model is the proposed model with moderate or strong correlation, ignoring the within correlation may lead to overestimate of the treatment effect and result in more type I error than specified level. Even if the within correlation is small, the performance of proposed model is as good as naïve response model. Thus, the proposed model is robust for different correlation settings if the data is generated by the proposed model.^

Application of the general linear model to assess the effect of missing data on bone marrow mononuclear cell therapy with infusion timing and follow-up MRI

With most clinical trials, missing data presents a statistical problem in evaluating a treatment's efficacy. There are many methods commonly used to assess missing data; however, these methods leave room for bias to enter the study. This thesis was a secondary analysis on data taken from TIME, a phase 2 randomized clinical trial conducted to evaluate the safety and effect of the administration timing of bone marrow mononuclear cells (BMMNC) for subjects with acute myocardial infarction (AMI).^ We evaluated the effect of missing data by comparing the variance inflation factor (VIF) of the effect of therapy between all subjects and only subjects with complete data. Through the general linear model, an unbiased solution was made for the VIF of the treatment's efficacy using the weighted least squares method to incorporate missing data. Two groups were identified from the TIME data: 1) all subjects and 2) subjects with complete data (baseline and follow-up measurements). After the general solution was found for the VIF, it was migrated Excel 2010 to evaluate data from TIME. The resulting numerical value from the two groups was compared to assess the effect of missing data.^ The VIF values from the TIME study were considerably less in the group with missing data. By design, we varied the correlation factor in order to evaluate the VIFs of both groups. As the correlation factor increased, the VIF values increased at a faster rate in the group with only complete data. Furthermore, while varying the correlation factor, the number of subjects with missing data was also varied to see how missing data affects the VIF. When subjects with only baseline data was increased, we saw a significant rate increase in VIF values in the group with only complete data while the group with missing data saw a steady and consistent increase in the VIF. The same was seen when we varied the group with follow-up only data. This essentially showed that the VIFs steadily increased when missing data is not ignored. When missing data is ignored as with our comparison group, the VIF values sharply increase as correlation increases.^

(Table 2) Geochemical composition of suspended matter samples from the northern Dvina River

The results of the analysis of samples of the Northern Dvina River's suspended particulate matter obtained by the sedimentation method from large water volumes in the periods of the spring high water and summer low water are presented. By the method of sequential leaching using different reagents, four fractions have been separated: the F1 is the sorbed complex and carbonates, the F2 is the amorphous hydroxides of Fe and Mn, the F3 is the form connected with the organic matter, and the F4 is the residual or silicate-detrital (inert) form. The data have shown that all ten elements determined were grouped with respect to the ratio of the distinguished forms: F4 is the predominant form for Al and Fe (73-88% of all the forms; however, the summer sample contains only 38% of this form of iron, and F2 is the predominant form for this period with 46.6%). As to Mn, the F1, F2, and F4 are nearly equally distributed in the spring high water samples, and only the F3 form is less important (5.4%). In the summer sample, the manganese sorbed complex is predominant (53.5%); for Cu, Ni, Cr, and Co, the inert F4 form is predominant (60-70%) in the sample of the spring suspended matter. The summer low water suspended matter has a lower F4 contribution (25-45%); for Zn, Pb, and Cd, the equal distribution of the forms in the spring samples is typical, while the summer suspended matter differs by the F2 form's predominance (53-61% for Zn and Pb). The main conclusion from the acquired data is that the geochemical mobility of all the studied elements, except for cadmium, in the summer low water suspended matter is higher than in the spring suspended matter. The more intensive biogeochemical processes in August, the high level of organic matter, and the higher contribution of phytoplankton lead to the intensification of the metals' geochemical activity in the Northern Dvina suspended matter in the end of the summer compared to the spring high water period when the physical processes are predominant over the biogeochemical ones due to the high speeds of the freshened waters flow.

Tab. 1: Trace-element concentrations in ore samples collected from mercury mines and deposits in southwestern Alaska

A belt of small but numerous mercury deposits extends for about 500 km in the Kuskokwim River region of southwestern Alaska. The southwestern Alaska mercury belt is part of widespread mercury deposits of the circum Pacific region that are similar to other mercury deposits throughout the world because they are epithermal with formation temperatures of about 200 °C, the ore is dominantly cinnabar with Hg-Sb-As±Au geochemistry, and mineralized forms include vein, vein breccias, stockworks, replacements, and disseminations. The southwestern Alaska mercury belt has produced about 1400 t of mercury, which is small on an international scale. However, additional mercury deposits are likely to be discovered because the terrain is topographically low with significant vegetation cover. Anomalous concentrations of gold in cinnabar ore suggest that gold deposits are possible in higher temperature environments below some of the Alaska mercury deposits. We correlate mineralization of the southwestern Alaska mercury deposits with Late Cretaceous and early Tertiary igneous activity. Our 40Ar/39Ar ages of 70 ±3 Ma from hydrothermal sericites in the mercury deposits indicate a temporal association of igneous activity and mineralization. Furthermore, we suggest that our geological ancl geochemical data from the mercury deposits indicate that ore fluids were generated primarily in surrounding sedimentary wall rocks when they were cut by Late Cretaceous and early Tertiary intrusions. In our ore genesis model, igneous activity provided the heat to initiate dehydration reactions and expel fluids from hydrous minerals and formational waters in the surrounding sedimentary wall rocks, causing thermal convection and hydrothermal fluid flow through permeable rocks and along fractures and faults. Our isotopic data from sulfide and alteration minerals of the mercury deposits indicate that ore fluids were derived from multiple sources, with most ore fluids originating from the sedimentary wall rocks.