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Interbody fusion cages made of poly-ether-ether-ketone (PEEK) have been widely used in clinics for spinal disorders treatment; however, they do not integrate well with surrounding bone tissue. Ti-6Al-4V (Ti) has demonstrated greater osteoconductivity than PEEK, but the traditional Ti cage is

Three-dimensional (3D) tumor models have been established in various microfluidic systems for drug delivery and resistance studies in vitro. However, one of the main drawbacks of these models is non-uniform distribution of cells, leaving regions with very low cell density within the 3D structures. As a result, molecular diffusion in the cell compartments is faster than that observed in solid tumors. To solve this problem, we developed a new technique for preparation of 3D tumor models in vitro. It was based on a microfluidic device containing three parallel channels separated by narrowly spaced posts. Tumor cells were loaded into the central channel at high density. To test the system, B16.F10 melanoma cells were perfusion-cultured overnight and the resulting 3D structure was characterized in terms of viability, density, and morphology of cells as well as transport properties of small fluorescent molecules. Immediately upon loading of tumor cells, the cell density was comparable to those observed in B16.F10 tumor tissues in vivo; and the viability of tumor cells was maintained through the overnight culture. The tumor model displayed low extracellular space and high resistance to diffusion of small molecules. For membrane-permeant molecules (e.g., Hoechst 33342), the rate of interstitial penetration was extremely slow, compared to membrane-impermeant molecules (e.g., sodium fluorescein). This versatile tumor model could be applied to in vitro studies of transport and cellular uptake of drugs and genes.

In addition to its established role in initiating the endocrine arm of the stress response, corticotropin-releasing factor (CRF) can act in the brain to modulate neural pathways that effect coordinated physiological and behavioral adjustments to stress. Although CRF is expressed in a set of interconnected limbic and autonomic cell groups implicated as primary sites of stress-related peptide action, most of these are lacking or impoverished in CRF receptor (CRFR) expression. Understanding the distribution of functional receptor expression has been hindered by the low resolution of ligand binding approaches and the lack of specific antisera, which have supported immunolocalizations at odds with analyses at the mRNA level. We have generated a transgenic mouse that reports expression of the principal, or type 1, CRFR (CRFR1). This mouse expresses GFP in a cellular distribution that largely mimics that of CRFR1 mRNA and is extensively colocalized with it in individual neurons. GFP-labeled cells display indices of activation (Fos induction) in response to central CRF injection. At the cellular level, GFP labeling marks somatic and proximal dendritic morphology with high resolution, and is also localized to axonal projections of at least some labeled cell groups. This includes a presence in synaptic inputs to central autonomic structures such as the central amygdalar nucleus, which is implicated as a stress-related site of CRF action, but lacks cellular CRFR1 expression. These findings validate a new tool for pursuing the role of central CRFR signaling in stress adaptation, and suggest means by which the pervasive ligand-receptor mismatch in this system may be reconciled.

The aims of the present study were to determine if melatonin exerts an effect on prolactin (PRL) secretion via the tuberoinfundibular dopaminergic (TIDA) neurons and if endogenous or exogenous melatonin has an entraining effect on the rhythmic changes of TIDA neuronal activity and PRL secretion. Melatonin given in the morning (10:00 h), dose- (0.01-1 mg/kg, ip) and time- (at 15 and 60 min, but not at 30 min) dependently stimulated TIDA neuronal activity in ovariectomized (OVX), estrogen-treated rats as determined by 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME). Serum PRL was concurrently inhibited by the injection. Melatonin administered in the afternoon (15:00 h) was even more effective in stimulating the lowered TIDA neuronal activity and inhibiting the increased PRL level than that given in the morning (10:00 h). S-20098, a melatonin agonist was also effective in stimulating the TIDA neurons. In contrast, S-20928, a putative melatonin antagonist, while it had no effect by itself, blocked the effect of S-20098. Although S-20928 failed to prevent melatonin's effect on ME DOPAC levels, six interspaced injections of S-20928, from 18:00 to 01:30 h, significantly blocked the increase of ME DOPAC levels at 03:00 h, indicating that the endogenous melatonin may play a role. We further used rats that received daily injection of melatonin (1 mg/kg, ip) at 18:00 h for 10 days and found that the injection augmented basal TIDA neuronal activity at 11:00 h and blunted the afternoon PRL surge. In all, melatonin can have an inhibitory effect on PRL secretion by stimulating the TIDA neurons, and it may help to entrain the circadian rhythms of both TIDA neuronal activity and PRL secretion.

Background and Objectives The median of pO2 values in tumor measured by Eppendorf “Histograph” with a needle-type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO2 value can be used as a universal predictor of local control probability, because the variation in pO2 values, especially in hypoxic tissue, among institutes may not allow comparison of measured “absolute pO2 values.” The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf “Histograph” among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2-nitroimidazole adducts. Methods C3H mice bearing FSaII murine fibrosarcoma subcutaneously were shipped to all laboratories, and the oxygen status in tumors and in normal subcutis was examined using Eppendorf “Histograph” and immunohistochemical hypoxic marker. Results All laboratories showed that the FSaII tumor was hypoxic with at least 77% of measured points under 10 mmHg in pO2 and with a median pO2 value less than that of normal subcutis. These results were further confirmed immunohistochemically. These findings are interpreted as evidence that the pO2 values measured by Eppendorf “Histograph” can be useful. However, the median values 5of tumor pO2 varied from 1.5 mmHg to 5.6 mmHg among the laboratories, and pO2 of normal subcutis also varied from 28 mmHg to 38 mmHg. There were also significant differences in hypoxic fraction, defined as the fraction under a given oxygen partial pressure (i.e., under 2.5, 5, or 10 mmHg), among institutes. Conclusions Caution needs to be exercised in using the absolute, median, or distribution of pO2 values measured by the Eppendorf “Histograph” to compare the data between laboratories or to predict the radiation response in an individual subject. J. Surg. Oncol. 1997;66:30–38. © 1997 Wiley-Liss, Inc.

Purpose: The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor-control-probability(TCP) with an acceptable normal-tissue-complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose-based plans. PET image is incorporated to evaluate gain in TCP for dose escalation. Methods: We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on the targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise-linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET-image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV-dose, and two variations (37Gy-boost to BTV vs 40Gy-boost) to PET-image-pockets. Results: TCP for standard clinical plans range from 59.4% - 63.6%. TCP for dose-based PET-guided escalated-dose-plan ranges from 63.8%–98.6% for all patients; whereas TCP-optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy-boosted vs 40Gy-boosted. There is no increase in rectum and bladder dose among all plans. Conclusion: Optimizing TCP directly results in highly conformed treatment plans. The TCP-optimized plan is individualized based on the biological PET-image of the patients. The TCP-optimization framework is generalizable and has been applied successfully to other external-beam delivery modalities. A clinical trial is on-going to gauge the clinical significance. Partially supported by the National Science Foundation.

Purpose: Tumor control probability(TCP) measures the probability that no malignant cells are left in the affected organ. It is an important clinical metric for measuring treatment success. Zaider and Minerbo provide a complex yet important TCP formalism which links the treatment duration, dose deposit, radiobiology of tumor cells and cell life characteristics. We perform feasibility tests on TCP‐driven biological planning for high‐dose‐rate brachytherapy(HDR) where the objective maximizes TCP of the treatment plans. Plan robustness is tested, and plan quality and potential outcome significance are evaluated. Methods: CT and 18F‐fluorodeoxyglucose based‐PET images are obtained for 15 cervical cancer patients. All received prior external‐beam radiation. The CTV prescribed dose is 5Gy for 4 fractionations, with the PET‐identified pockets prescribed an escalated‐dose ranging from 7.5–9.0Gy per fraction. The treatment model determines the dwell time and seed location that maximizes TCP while constraining PTV coverage, the lower/upper dose, and dose‐volume shape for organs‐at‐risk and PTV. We contrast the standard HDR plan and PET‐pocket escalated plan. Results: TCP ranges from 48–63% for standard plans versus 82–99% for PET‐guided escalated plans. The increase is most significant with the smallest PET‐identified pockets. Uniformly, urethra and rectum receive 5–8% reduced dose. There is marginal difference in PTV dose between standard and escalated plans. All resulting TCP‐driven plans are clinically acceptable. Conclusion: TCP can be a very important objective for treatment plan optimization. With advances in biological/functional imaging, there is an urgent need to incorporate radiobiological parameters and TCP within planning. This study marks the first use of TCP as the driving objective for treatment planning. The optimization problem is very difficult to solve and requires computational breakthroughs. The resulting plans improve significantly the overall local tumor control, and reduce organs‐at‐risk dose. Rush University began clinical studies in 2011. A long term outcome study must be carried out to gauge the overall impact.

Purpose: Tumor metabolic activities obtained from PET studies may facilitate targeted dose delivery to improve local tumor control. We perform feasibility tests on TCP‐driven PET‐image‐guided dose escalation in high‐ dose‐rate‐brachytherapy(HDR). Quality and robustness of plans, TCP, and potential outcome significance are evaluated. Methods: CT and 18F‐ fluorodeoxyglucosebased‐PET images are obtained for cervical cancer patients. Planning‐target‐volumes(PTV) and critical structures are delineated. Enhanced PET signal defines boost‐target‐volume(BTV). HDR plans are optimized to deliver 35Gy Ir‐192 to PTV and 37–40Gy to BTV following 45Gy external‐beam‐radiotherapy. Each dwell location is modeled via two variables: a binary variable to indicate whether a radioactive seed will be deposited and a continuous variable to denote dwell time. The treatment planning model ensures 95% PTV‐coverage. The objective seeks rapid dose fall‐off from the prescribed dose while maximizing TCP. For each patient‐case, we compare 3 plans: 1)standard HDR plan, 2)escalation with same PTV prescription dose, and 3)escalation with reduced PTV prescription dose. Results: Standard plans have TCP values 48% to 73%. In all patients(15), escalated plans of >=37Gy to BTV result in slight reduction in rectum and bladder dose, and 40Gy for over 99% of BTV. TCP values range from 81% to 96%. When BTV is less than 15% of PTV, dose escalation and standard plans have virtually identical PTV dose. When BTV occupies over 20% of PTV, dose escalation to PET intrinsically increases PTV dose(1–5%). When PTV is prescribed 33Gy, independent of BTV, escalation can be achieved while dose to PTV, bladder and rectum are reduced. Conclusions: The presented algorithm allows for PET‐enhanced treatment, which facilitates targeted delivery of escalated dose and potential improvements in clinical outcome. Our study reveals significant improvement in tumor control and organs‐at‐risk dose reduction. Clinical studies for PET hot‐HDR dose re‐steering are in progress to test its feasibility, validate its importance, and measure potential gain in clinical outcome. The work of the first author is partially supported by funds from the National Science Foundation.