Repopulation Time Research Articles

Spatiotemporal Optimization of Pelvic Radiation Therapy

Conformal and adaptive Radiation Therapy (RT) remains critical in the treatment of locally advanced pelvic cancers despite acute and late bowel complications. This work introduces spatiotemporal optimization of pelvic RT including mathematical modelling of intestinal radiobiology to evaluate a novel treatment planning approach for fractionated pelvic RT. A single-plan fractionated RT delivery has n-fractions at dose/fraction = d and has biologically effective dose BED = nd ( 1 + d / [α/β] ) - ln(2) ([T - Tk] / [αTp]), where Tk and Tp are the kickoff time and doubling time of repopulation, and T is the time to deliver all fractions (including off-days). We present a parameterization of the repopulation BED-term to estimate a range of daily recovered BED including uncertainties in α and Tp. Recovery of BED as currently formulated is independent of the delivered dose; however, the assumption of spatiotemporal optimization is that a regional reduction of dose during RT by mixing treatment plans is critical to allow for normal tissue healing. We evaluate an achievable spatiotemporal optimization treatment planning strategy for an advanced stage prostate and a cervical cancer patient using 25-fraction delivery over 5-weeks and 4-weekends (T = 33 days) and propose 3 treatment plans: (1) a conformal "clinical standard" plan, (2) a right-bowel sparing plan, and (3) a left-bowel sparing plan. The plans are optimized to ensure no increased dose in opposing bowel or normal organs at risk (OARs). For radiobiological parameters ranging from α = 0.2-0.35/Gy, α/β = 2-3 Gy, Tk = 5-10 days, and Tp = 3-7 days, parameterization shows daily BED recovery of 0.44±0.08 Gy (range = 0.28-0.69 Gy), or an average of 4Gy BED recovery for 5-days treatment surrounded by 2 weekends. Conservatively evaluating the 3.6Gy BED distribution in treatment planning may identify regions for complete recovery (after Tk days). In a prostate 3-plan set, the right- and left- bowel sparing plans deliver equivalent mean dose to targets and OARs to within 5cGy/fx. The clinical plan includes 298cc of bowel under 14Gy, but this same bowel will be spared throughout treatment. Delivery of the clinical plan in week 1 to achieve Tk days, followed by alternating the left and right plan each week has the potential to reduce BED to zero for an additional 116cc of bowel using the left-sparing plan in weeks 2 and 4, and 91cc using the right-bowel sparing plan in weeks 3 and 5. The cervical cancer plan-set was more challenging due to right-sided nodal volumes and higher clinical bowel dose; OAR mean dose variations were >8cGy/fx in a few organs, but the left- and right- sided sparing plans results in 394 cc and 139cc, respectively of unique spared bowel at the 3.6Gy/week threshold to potentially reach zero BED during treatment. A novel spatiotemporal optimization of pelvic RT has the potential to preserve bowel, allow for increased intra-treatment intestinal tissue regeneration, and reduce radiation-induced complications.

Heterotopic Implantation of Decellularized Pulmonary Artery Homografts In A Rodent Model: Technique Description and Preliminary Report

ABSTRACTPurpose: Despite a substantial amount of literature on tissue-guided regeneration, decellularization process, repopulation time points and stem cell turnover, more in-depth study on the argument is required. Currently, there are plenty of reports involving large animals, as well as clinical studies facing cardiac repair with decellularized homografts, but no exhaustive rodent models are described. The purpose of this study was to develop such a model in rats; preliminary results are also herein reported. Material and Methods: Fresh or decellularized pulmonary homografts from wild type rats were implanted in the abdominal aorta of green fluorescent protein positive rats. Three experimental groups were build up: sham, fresh homograft recipients and decellularized homograft recipients. The homograft decellularization process was performed with three cycles of detergent-enzymatic treatment protocol. Surgical technique of pulmonary homograft implantation and postoperative ultrasonographic evaluation were also reported; gross, histology and immunohistochemistry analysis on unimplanted and postoperative homografts were also carried out. Results: The median total recipient operating time was 148 minutes, with a surgical success rate of 82%. The decellularization protocol resulted effective and showed a complete decellularization with intact extracellular matrix. At 15 days from surgery, the implanted decellularized pulmonary homografts exhibited cell repopulation in the outer media wall and partial endothelial lining in absence of rejection. Conclusions: Our technique is a feasible and reproducible model that can be fundamental for building a valid study for further exploitation on the field. Even in a short-term follow up, the decellularized pulmonary homografts showed autologous repopulation in absence of rejection.

Correlation between cellular expression of complement regulatory proteins with depletion and repopulation of B-lymphocytes in peripheral blood of patients with rheumatoid arthritis treated with rituximab

ObjectivesTo correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B-lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. MethodsTen patients with RA received two infusions of 1g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B-lymphocytes was carried out immediately before the first infusion. The population of B-lymphocytes was analyzed by means of basal CD19 expression and after 1, 2, and 6 months after the infusion of RTX, and then quarterly until clinical relapse. Depletion of B-lymphocytes in peripheral blood was defined as a CD19 expression <0.005×109/L. ResultsTen women with a median of 49 years and a baseline DAS28=5.6 were evaluated; 9 were seropositive for rheumatoid factor. Five patients showed a repopulation of B-lymphocytes after 2 months, and the other five after 6 months. There was a correlation between the basal expression of CD46 and the time of repopulation (correlation coefficient=−0.733, p=0.0016). A similar trend was observed with CD35, but without statistical significance (correction coefficient=−0.522, p=0.12). ConclusionThe increased CD46 expression was predictive of a faster repopulation of B-lymphocytes in patients treated with RTX. Studies involving a larger number of patients will be needed to confirm the utility of basal expression of CRPs as a predictor of clinical response.

Correlação entre expressão celular de proteínas reguladoras do complemento com a depleção e repopulação de linfócitos B no sangue periférico de pacientes com artrite reumatoide tratada com rituximabe

ObjectivesTo correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B‐lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. MethodsTen patients with RA received two infusions of 1g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B‐lymphocytes was carried out immediately before the first infusion. The population of B‐lymphocytes was analyzed by means of basal CD19 expression and after 1, 2, and 6 months after the infusion of RTX, and then quarterly until clinical relapse. Depletion of B‐lymphocytes in peripheral blood was defined as a CD19 expression <0,005×109/L. ResultsTen women with a median of 49 years and a baseline DAS28=5.6 were evaluated; 9 were seropositive for rheumatoid factor. Five patients showed a repopulation of B‐lymphocytes after 2 months, and the other five after 6 months. There was a correlation between the basal expression of CD46 and the time of repopulation (correlation coefficient=‐0.733, p=0.0016). A similar trend was observed with CD35, but without statistical significance (correction coefficient=‐0.522, p=0.12). ConclusionThe increased CD46 expression was predictive of a faster repopulation of B‐lymphocytes in patients treated with RTX. Studies involving a larger number of patients will be needed to confirm the utility of basal expression of CRPs as a predictor of clinical response.

Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer's disease.

Immune cells of myeloid lineage are encountered in the Alzheimer's disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.

FRI0499 Retrospective CASE Series of Refractory Antisynthetase Syndrome Successfully Treated with Rituximab (3 CASES)

BackgroundAntisynthetase syndrome (ASS) is an idiopathic inflammatory myopathy characterised by the presence of anti-Jo-1 antibodies. Patients usually present with myositis, interstitial lung diseases, and arthritis. Corticosteroid therapy is the first...

SU-E-T-114: Dose Modification for Cs-131 Permanent Implants Using Resensitization-Corrected Normal Tissue BED

Purpose: To apply resensitization (redistribution and reoxygenation) correction to normal tissue BED calculation and have it verified with clinical outcomes. Method and Materials: The BED formalism without resensensitization for permanent implants was BED = D*RE - BF, where D is the prescribed dose, RE = 1 + (β/α)R0/(μr+λ), BF = K*Teff, K = ln(2)/(αTp), and Teff = Taveln(αDTp/T1/2). α and β are LQ parameters, R0 the initial dose rate, μr the repair constant, λ the source decay constant, and Tp the repopulation time. Resensitization can be included in the extended LQ equation (LQR) S = exp[-αD − βG(Tr)D2 + 1/2σ2 G(Ts)D2 + Teff/Tp], where G(Tr) and G(Ts) describe repair and resensitization, and 1/2σ2 represents cell-to-cell diversity. Combining Dale's formalism with LQR led to RE = 1+(β/α)R0/(μr+λ)−(1/2σ2/α)R0/(μs+λ), where μs is the resensitization constant. We used this formula to calculate the BED for normal tissue based on the prescribed dose for Au-198 GYN permanent implants from which we have gained extensive clinical experience. Then, we calculated the dose with Cs-131 which has the equal BED as Au-198. Results: The prescribed doses for Au-198 ranged from 10 to 120 Gy. The converted doses for Cs-131 implants ranged from 9 to 161 Gy (without resensitization correction) and 8.9 to 156 Gy (with resensitization correction), which resulted in the average value of dose conversion factor, Fn (no resensitization correction) = 1.14, and 1.10 for Fr (with resensitization correction) which agreed with the results from the calculation for tumor. The doses derived with 1.10 reduced the complications such as brisk moist desquamation in actual clinical cases. Conclusion: Resensitization correction in BED for normal tissues led to significant reduction in prescription dose and thus in toxicity. The results further show that resensitization correction is needed for permanent implant dose calculation.

Femtosecond Laser Spectroscopy and DFT Studies of Photochromic Dithizonatomercury Complexes

The ultrafast dynamics of the photochromic reaction of dithizonatophenylmercury(II) was recently reported. For purpose of investigating the effect of electronically different substituents (X = o-F, m-F, p-F, p-Cl, o-CH3, m-CH3, p-CH3, m,p-diCH3, p-OCH3, o-SCH3, and p-SCH3) on this reaction, a series of phenyl-substituted dithizones were synthesized and complexed with phenylmercury(II). A variation of more than 3 ps in ground state repopulation times was observed, with the o-methyl derivative absorbing both at shortest wavelength and having the fastest repopulation time, while the p-S-methyl derivative lies at the opposite extremity. An increase in both decay times and λmax values is generally reflected by an increase in electron density in the chromophore. Ultrafast rates also proved to be dependent on solvent polarity, while a profound solvatochromic effect was observed in the transition state absorbance. Density functional theory realistically simulated isomer stabilities, electronic spectra and molecular orbitals. Increased electron density enhances stability in the photoexcited blue isomer relative to the orange resting state, as seen from a comparison between orange and blue isomer total bonding energies. A linear trend between computed HOMO energies and experimental λmax of related aliphatic substituted derivatives was found.

Comparison of Traditional and Simultaneous IMRT Boost Technique Basing on Therapeutic Gain Calculation

Two different radiotherapy techniques, a traditional one (CRT) - based on consecutive decreasing of irradiation fields during treatment, and intensity modulated radiation therapy technique (IMRT) with concomitant boost, deliver different doses to treated volumes, increasing the dose in regions of interest. The fractionation schedule differs depending on the applied technique of irradiation. The aim of this study was to compare different fractionation schedules considering tumor control and normal tissue complications. The analysis of tumor control probability (TCP) and normal tissue complication probability (NTCP) were based on the linear quadratic (LQ) model of biologically equivalent dose. A therapeutic gain (TG) formula that combines NTCP and TCP for selected irradiated volumes was introduced to compare CRT and simultaneous boost (SIB) methods. TG refers to the different doses per fraction, overall treatment time (OTT), and selected biological factors such as tumor cell and repopulation time. Therapeutic gain increases with the dose per fraction and reaches the maximum for the doses at about 3 Gy. Further increase in dose per fraction results in decrease of TG, mainly because of the escalation of NTCP. The presented TG formula allows the optimization of radiotherapy planning by comparing different treatment plans for individual patients and by selecting optimal fraction dose.

Cytokine treatment or accessory cells are required to initiate engraftment of purified primitive human hematopoietic cells transplanted at limiting doses into NOD/SCID mice.

Little is known about the cell types or mechanisms that underlie the engraftment process. Here, we have examined parameters affecting the engraftment of purified human Lin-CD34+CD38- normal and AML cells transplanted at limiting doses into NOD/SCID recipients. Mice transplanted with 500 to 1000 Lin-CD34+CD38- cord blood (CB) or AML cells required the co-transplantation of accessory cells (ACs) or short-term in vivo cytokine treatment for engraftment, whereas transplantation of higher doses (>5000 Lin-CD34+CD38- cells) did not show these requirements suggesting that ACs are effective for both normal and leukemic stem cell engraftment in this model. Mature Lin+CD34- and primitive Lin-CD34+CD38+ cells were capable of acting as ACs even though no repopulating cells are present. Cytokine treatment of NOD/SCID mice could partially replace the requirement for co-transplantation of AC. Furthermore, no difference was seen between the percentage of engrafted mice treated with cytokines for only the first 10 days after transplant compared to those receiving cytokines for the entire time of repopulation. Surprisingly, no engraftment was detected in mice when cytokine treatment was delayed until 10 days posttransplant. Together, these studies suggest that the engraftment process requires pluripotent stem cells plus accessory cells or cytokine treatment which act early after transplantation. The NOD/SCID xenotransplant system provides the means to further clarify the processes underlying human stem cell engraftment.

Is early repopulation of macrophage-depleted lymph node independent of blood monocyte immigration?

Popliteal lymph nodes (LN) of mice were depleted of their macrophage (M phi) populations in the subcapsular sinus and medulla by subcutaneous injection of dichloromethylene diphosphonate (Cl2MDP)-containing liposomes into the footpads. Complete restoration of both M phi populations could be observed as late as 5 months after liposome administration. This relatively long repopulation time could be due to a depot of liposomes, directly killing all M phi precursors after extravasation into the interstitial tissue of the footpad. On the other hand, local interstitial precursors with very low turnover rates may have been depleted in the interstitial tissue of the hind leg. Therefore, two different types of experiments were performed; one in which M phi-depleted LN were replaced by control LN at various time points after liposome treatment, and another whereby M phi-depleted LN were transplanted into control animals. When liposome-treated, M phi-depleted LN were transplanted into control animals, a complete restoration of both populations in the subcapsular sinus and medulla could be observed within 5 weeks. Control LN transplanted into a Cl2MDP-liposome-treated leg showed a rapid disappearance of M phi from the subcapsular sinus and medulla and these cell populations remained absent for at least 7-8 weeks after liposome treatment, when the first cells started to reappear. Complete repopulation of these areas by M phi took as long as 15 weeks. Using labeled liposomes the presence of a continuous liposome depot was found to be very unlikely. These results suggest that the population of precursor cells that will give rise to M phi in the subcapsular sinus and medulla of a LN is probably contained within the interstitial tissue and is almost independent of precursor supply from the blood compartment.

Repopulation of Macrophages in Popliteal Lymph Nodes of Mice After Liposome-Mediated Depletion

Macrophages lining the subcapsular sinus (SCS) and those located in the medulla of popliteal lymph nodes (PLN) of mice were eliminated after subcutaneous (s.c.) injection of dichloromethylene diphosphonate (Cl2MDP)-containing liposomes. No effect of liposome-entrapped Cl2MDP could be seen on nonphagocytic cells, e.g., interdigitating cells (IDC) and B- and T-lymphocytes. One month after injection the eliminated subsets of macrophages were still absent. After 2 mo a small number of macrophages had reappeared along the SCS and in the medulla of the PLN of a few animals. Complete repopulation of the PLN with macrophages was observed only after 5 mo. This extremely long repopulation time could be shortened drastically by local administration of Freund's complete adjuvant (FCA). A small number of macrophages reappeared along the SCS and in the medulla 1 wk after FCA and after 3 wk the repopulation of the PLN with macrophages was complete. Such rapid repopulation of macrophages was not achieved after s.c. injection of paraffin oil or paratyphoid vaccine. These results indicate that the normal rate of influx of mononuclear phagocytes into the PLN is low, but that it can be sped up after administration of FCA.

Ground-state repopulation time of BDN I and BDN II in a variety of solvent and plastic hosts

Abstract Ground-state recovery (GSR) times for BDN I and BDN II (bis(4-dimethylaminodithiobenzil) nickel and bis(4-diethylaminodithiobenzil) nickel) have been measured in a variety of solvent and plastic hosts. These and previous measurements are collated and methods of analysing data discussed with a view to explaining some inconsistencies in the published data. Analysis of transmission recovery, which is non-exponential, leads to ambiguous results which can differ drastically from the GSR times - the time constant of the exponential recovery of optical density. The strong solvent dependence of BDN II GSR times, which range from 175 ps in dimethyl sulphoxide to 6.5 ns in benzene is discussed. For electronically active solvents correlations are found between GSR times, dipole moments and coordinating abilities as indicated by solvent structure and basicity.

Ground state repopulation time and saturation behaviour of BDN II in tetrahydrothiophene-1, 1-dioxide

The dyes BDN I and BDN II are nickel complexes used in the Q-switching of neodymium and iodine lasers. The ground state repopulation time of BDN II in tetrahydrothiophene-1, 1-dioxide has been measured by the pump and probe technique to be 1.2 ns, a factor 40 greater than published indirect measurements. We have also measured the saturation behaviour of the dye, which exhibits strong residual absorption even at large incident energy fluence, the cross section for which is deduced to be 2.5 x 10 -17 cm 2 at 1.06 μm. Possible assignments of the states involved are discussed.

Electron drift velocity in silicon

Experimental results for electrons obtained with the time-of-flight technique are presented for temperatures between 8 and 300\ifmmode^\circ\else\textdegree\fi{}K and fields ranging between 1.5 and 5 \ifmmode\times\else\texttimes\fi{} ${10}^{4}$ V ${\mathrm{cm}}^{\ensuremath{-}1}$ oriented along $〈111〉$, $〈110〉$, and $〈100〉$ crystallographic directions. At 8\ifmmode^\circ\else\textdegree\fi{}K the dependence of the transit time upon sample thickness has allowed a measurement of the valley repopulation time when the electric field is $〈100〉$ oriented. These experimental results have been interpreted with Monte Carlo calculations in the same ranges of temperature and field. The theoretical model includes the many-valley structure of the Si conduction band, acoustic intravalley scattering with correct momentum and energy relaxation and correct equilibrium phonon population, several intervalley scatterings, and ionized impurity scattering.

The effect of age on the long-term response of bone marrow to local fractionated irradiation.

The in-field long-term progressive response of bone marrow to localized fractionatedradiation to the thoracic spine was observed in weanling and adult rats. Total dose levels were 1800,3600 and 5400 rads given in daily fractions of 180 rads for 900 rads perweek, to simulate the clinical setting. Animals were sacrificed at 4 1/2, 6, 8, and 10months after irradiation, and bone marrow from within the treated area was ezamined. The juvenile marrow repopulated to higher levels of cellularity and after higher doses of radiation than the adult. The degree of marrow depletion, time of repopulation, and ultimate level of repopulation after cessation of irradiation were all dependent on the total dose. Some of the suggested clinical implications include re-evaluation of the lower doses given to children.

Picosecond internal conversion in crystal violet

Using the second harmonic of a mode-locked Nd 3+ laser, we show that the efficient quenching of the S 1 state in crystal violet (τ R < 10 −8 sec, yet Q < 10 −4 in ethanol), involves very rapid repopulation of the ground state. The repopulation time exhibits a cube root dependence on solvent viscosity. We argue that our data are best explained by direct internal conversion. We suggest that the class of triphenyl and diphenylmethane dyes should prove to be efficient and versatile bleachable shutters and passive mode-locking elements for laser construction.

Cell Population Analysis of Radiation Damage and Recovery of Thymus and Lymph Nodes in Mice

C57BL/6 mice received whole-body x-irradiation, and differential cell counts were made on cellular suspensions of the lymphatic tissues at regular intervals. A two-phase pattern of thymic lymphopoiesis was demonstrated: The first phase of blast cell proliferation lasted for three to four generations and was followed by a period of differentiation to small lymphocytes. The difference in the time of repopulation between the thymus and the lymph nodes was ascribed to the difference in the absolute number and the doubling time of primitive cells. The doubling time of blast cells was 12 hours in thymus and 20 hours in lymph nodes. The relation between dose and the number of surviving cells at 24 hours after irradiation revealed the existence of two classes of lymphocytes with different radiosensitivity. The $D_{37}$ was 145 R and 425 R for small lymphocytes and 57 R and 520 R for medium and large lymphocytes in thymus. The $D_{37}$ values for small and larger lymphocyt...

Electronic States of theFCenter in Alkali Halide Crystals

The possible importance of $F$-center states in alkali halides associated with the energy-band minimum at ${X}_{3}$ in the Brillouin zone is discussed. The coexistence of these states with the "traditional" $F$-center states associated with ${\ensuremath{\Gamma}}_{1}$ may lead to new and interesting phenomena. In particular, it is speculated that the discrepancy between radiative lifetime and ground-state repopulation time observed by Fulton in the CsF $F$ center can be resolved by including ${X}_{3}$ $F$-center states.