Minimizing Metastatic Risk in Radiotherapy Fractionation Schedules

Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor $\alpha/\beta$ values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger $\alpha/\beta$ values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the $\alpha/\beta$ values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor $\alpha$/$\beta$ values. Numerical results indicate potential for significant reduction in metastatic risk.Comment: 12 pages, 3 figures, 2 table

Investigations on microbiome of the used clinical device revealed many uncultivable newer bacterial species associated with persistent chronic infections

Introduction. Chronic persistent device-related infections (DRIs) often give culture-negative results in a microbiological investigation. In such cases, investigations on the device metagenome might have a diagnostic value. Materials and Methods. The 16SrRNA gene sequence analysis and next-generation sequencing (NGS) of clinical metagenome were performed to detect bacterial diversity on invasive medical devices possibly involved in culture-negative DRIs. Device samples were first subjected to microbiological investigation followed by metagenome analysis. Environmental DNA (e-DNA) isolated from device samples was subjected to 16SrRNA gene amplification followed by Sanger sequencing (n=14). In addition, NGS of the device metagenome was also performed (n=12). Five samples were only common in both methods. Results. Microbial growth was observed in only nine cases; among these, five cases were considered significant growth, and in the remaining four cases, growth was considered either insignificant or contaminated. Culture and sequencing analysis yielded identical results only in six cases. In culture-negative cases, Sanger sequencing of 16SrRNA gene and NGS of 16SrDNA microbiome was able to identify the presence of rarely described human pathogens, namely Streptococcus infantis, Gemella haemolysans, Meiothermus silvanus, Schlegelella aquatica, Rothia mucilaginosa, Serratia nematodiphila, and Enterobacter asburiae, along with some known common nosocomial pathogens. Bacterial species such as M. silvanus and S. nematodiphila that are never reported in human infection were also identified. Conclusions. Results of a small number of diverse samples of this pilot study might lead to a path to study a large number of device samples that may validate the diversity witnessed. The study shows that a culture free, a holistic metagenomic approach using NGS could help identify the pathogens in culture-negative chronic DRIs

A Dynamic Programming Approach to Adaptive Fractionation

We conduct a theoretical study of various solution methods for the adaptive fractionation problem. The two messages of this paper are: (i) dynamic programming (DP) is a useful framework for adaptive radiation therapy, particularly adaptive fractionation, because it allows us to assess how close to optimal different methods are, and (ii) heuristic methods proposed in this paper are near-optimal, and therefore, can be used to evaluate the best possible benefit of using an adaptive fraction size. The essence of adaptive fractionation is to increase the fraction size when the tumor and organ-at-risk (OAR) are far apart (a "favorable" anatomy) and to decrease the fraction size when they are close together. Given that a fixed prescribed dose must be delivered to the tumor over the course of the treatment, such an approach results in a lower cumulative dose to the OAR when compared to that resulting from standard fractionation. We first establish a benchmark by using the DP algorithm to solve the problem exactly. In this case, we characterize the structure of an optimal policy, which provides guidance for our choice of heuristics. We develop two intuitive, numerically near-optimal heuristic policies, which could be used for more complex, high-dimensional problems. Furthermore, one of the heuristics requires only a statistic of the motion probability distribution, making it a reasonable method for use in a realistic setting. Numerically, we find that the amount of decrease in dose to the OAR can vary significantly (5 - 85%) depending on the amount of motion in the anatomy, the number of fractions, and the range of fraction sizes allowed. In general, the decrease in dose to the OAR is more pronounced when: (i) we have a high probability of large tumor-OAR distances, (ii) we use many fractions (as in a hyper-fractionated setting), and (iii) we allow large daily fraction size deviations.Comment: 17 pages, 4 figures, 1 tabl

Global, regional, and national sex differences in the global burden of tuberculosis by HIV status, 1990–2019: results from the Global Burden of Disease Study 2019

Background Tuberculosis is a major contributor to the global burden of disease, causing more than a million deaths annually. Given an emphasis on equity in access to diagnosis and treatment of tuberculosis in global health targets, evaluations of differences in tuberculosis burden by sex are crucial. We aimed to assess the levels and trends of the global burden of tuberculosis, with an emphasis on investigating differences in sex by HIV status for 204 countries and territories from 1990 to 2019. Methods We used a Bayesian hierarchical Cause of Death Ensemble model (CODEm) platform to analyse 21 505 site-years of vital registration data, 705 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, and 680 site-years of mortality surveillance data to estimate mortality due to tuberculosis among HIV-negative individuals. We used a population attributable fraction approach to estimate mortality related to HIV and tuberculosis coinfection. A compartmental meta-regression tool (DisMod-MR 2.1) was then used to synthesise all available data sources, including prevalence surveys, annual case notifications, population-based tuberculin surveys, and tuberculosis cause-specific mortality, to produce estimates of incidence, prevalence, and mortality that were internally consistent. We further estimated the fraction of tuberculosis mortality that is attributable to independent effects of risk factors, including smoking, alcohol use, and diabetes, for HIV-negative individuals. For individuals with HIV and tuberculosis coinfection, we assessed mortality attributable to HIV risk factors including unsafe sex, intimate partner violence (only estimated among females), and injection drug use. We present 95% uncertainty intervals for all estimates. Findings Globally, in 2019, among HIV-negative individuals, there were 1.18 million (95% uncertainty interval 1.08-1.29) deaths due to tuberculosis and 8.50 million (7.45-9.73) incident cases of tuberculosis. Among HIV-positive individuals, there were 217 000 (153 000-279 000) deaths due to tuberculosis and 1.15 million (1.01-1.32) incident cases in 2019. More deaths and incident cases occurred in males than in females among HIV-negative individuals globally in 2019, with 342 000 (234 000-425 000) more deaths and 1.01 million (0.82-1.23) more incident cases in males than in females. Among HIV-positive individuals, 6250 (1820-11 400) more deaths and 81 100 (63 300-100 000) more incident cases occurred among females than among males in 2019. Age-standardised mortality rates among HIV-negative males were more than two times greater in 105 countries and age-standardised incidence rates were more than 1.5 times greater in 74 countries than among HIV-negative females in 2019. The fraction of global tuberculosis deaths among HIV-negative individuals attributable to alcohol use, smoking, and diabetes was 4.27 (3.69-5.02), 6.17 (5.48-7.02), and 1.17 (1.07-1.28) times higher, respectively, among males than among females in 2019. Among individuals with HIV and tuberculosis coinfection, the fraction of mortality attributable to injection drug use was 2.23 (2.03-2.44) times greater among males than females, whereas the fraction due to unsafe sex was 1.06 (1.05-1.08) times greater among females than males. Interpretation As countries refine national tuberculosis programmes and strategies to end the tuberculosis epidemic, the excess burden experienced by males is important. Interventions are needed to actively communicate, especially to men, the importance of early diagnosis and treatment. These interventions should occur in parallel with efforts to minimise excess HIV burden among women in the highest HIV burden countries that are contributing to excess HIV and tuberculosis coinfection burden for females. Placing a focus on tuberculosis burden among HIV-negative males and HIV and tuberculosis coinfection among females might help to diminish the overall burden of tuberculosis. This strategy will be crucial in reaching both equity and burden targets outlined by global health milestone

Dynamic optimization of fractionation schedules in radiation therapy

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (p. 145-156).In this thesis, we investigate the improvement in treatment effectiveness when dynamically optimizing the fractionation scheme in radiation therapy. In the first part of the thesis, we consider delivering a different dose each day depending on the observed patient anatomy. Given that a fixed prescribed dose must be delivered to the tumor over the course of the treatment, such an approach results in a lower cumulative dose to a radio-sensitive organ-at-risk when compared to that resulting from standard fractionation. We use the dynamic programming algorithm to solve the problem exactly. Next, we suggest an approach which optimizes the fraction size and selects a treatment plan from a plan library. Computational results from patient datasets indicate this approach is beneficial. In the second part of the thesis, we analyze the effect of repopulation on the optimal fractionation scheme. A dynamic programming framework is developed to determine an optimal fractionation scheme based on a model of cell kill due to radiation and tumor growth in between treatment days. We prove that the optimal dose fractions are increasing over time. We find that the presence of accelerated tumor repopulation suggests larger dose fractions later in the treatment to compensate for the increased tumor proliferation.by Jagdish Ramakrishnan.Ph.D

Optimization of Radiation Therapy Fractionation Schedules in the Presence of Tumor Repopulation

We analyze the effect of tumor repopulation on optimal dose delivery in radiation therapy. We are primarily motivated by accelerated tumor repopulation toward the end of radiation treatment, which is believed to play a role in treatment failure for some tumor sites. A dynamic programming framework is developed to determine an optimal fractionation scheme based on a model of cell kill from radiation and tumor growth in between treatment days. We find that faster tumor growth suggests shorter overall treatment duration. In addition, the presence of accelerated repopulation suggests larger dose fractions later in the treatment to compensate for the increased tumor proliferation. We prove that the optimal dose fractions are increasing over time. Numerical simulations indicate a potential for improvement in treatment effectiveness

Virtual screening of anti-HIV1 compounds against SARS-CoV-2: machine learning modeling, chemoinformatics and molecular dynamics simulation based analysis

COVID-19 caused by the SARS-CoV-2 is a current global challenge and urgent discovery of potential drugs to combat this pandemic is a need of the hour. 3-chymotrypsin-like cysteine protease (3CLpro) enzyme is the vital molecular target against the SARS-CoV-2. Therefore, in the present study, 1528 anti-HIV1compounds were screened by sequence alignment between 3CLpro of SARS-CoV-2 and avian infectious bronchitis virus (avian coronavirus) followed by machine learning predictive model, drug-likeness screening and molecular docking, which resulted in 41 screened compounds. These 41 compounds were re-screened by deep learning model constructed considering the IC50 values of known inhibitors which resulted in 22 hit compounds. Further, screening was done by structural activity relationship mapping which resulted in two structural clefts. Thereafter, functional group analysis was also done, where cluster 2 showed the presence of several essential functional groups having pharmacological importance. In the final stage, Cluster 2 compounds were re-docked with four different PDB structures of 3CLpro, and their depth interaction profile was analyzed followed by molecular dynamics simulation at 100 ns. Conclusively, 2 out of 1528 compounds were screened as potential hits against 3CLpro which could be further treated as an excellent drug against SARS-CoV-2