Predicting survival in patients with hepatocellular carcinoma: a UK perspective.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a cancer of rising incidence in the UK. The aim of this study was to compare the Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) classifications as predictors of survival in UK patients with HCC. METHODS: Data were analysed from a prospective database maintained in a specialist hepatobiliary unit from 1998 to 2003. Each system was assessed for its discriminatory power, monotonicity of gradient, and independent contribution to prediction of mortality status based on a multivariate model. RESULTS: One hundred and two patients (77 males, 25 females) were identified with a median age of 65 (range, 14-87) years. The overall median survival time was 13 months and the one- and five-year survival rates were 52.9% (95% CI: 43.2%, 62.6%) and 35.3% (95% CI: 26.0%, 44.6%), respectively. All three classification systems had the capacity to differentiate between patient survival times across different stages. The Okuda system was superior in overall discriminatory power and in strength of monotonicity. The BCLC system, however, made the highest independent contribution of all three systems in predicting survival in the Cox regression model. CONCLUSIONS: All three classification systems were effective in predicting survival for patients with HCC in a UK population.     

A monitor unit verification calculation in intensity modulated radiotherapy as a dosimetry quality assurance

In standard teletherapy, a treatment plan is generated with the aid of a treatment planning system, but it is common to perform an independent monitor unit verification calculation (MUVC). In exact analogy, we propose and demonstrate that a simple and accurate MUVC in intensity modulated radiotherapy (IMRT) is possible. We introduce the concept of modified Clarkson integration (MCI). In MCI, we exploit the rotational symmetry of scattering to simplify the dose calculation. For dose calculation along a central axis (CAX), we first replace the incident IMRT fluence by an azimuthally averaged fluence. Second, the Clarkson integration is carried over annular sectors instead of over pie sectors. We wrote a computer code, implementing the MCI technique, in order to perform a MUVC for IMRT purposes. We applied the code to IMRT plans generated by CORVUS. The input to the code consists of CORVUS plan data (e.g., DMLC files, jaw settings, MU for each IMRT field, depth to isocenter for each IMRT field), and the output is dose contribution by individual IMRTs field to the isocenter. The code uses measured beam data for Sc, Sp, TPR, (D/MU)ref and includes effects from multileaf collimator transmission, and radiation field offset. On a 266 MHz desktop computer, the code takes less than 15 to calculate a dose. The doses calculated with the MCI algorithm agreed within +/-3% with the doses calculated by CORVUS, which uses a 1 cm x 1 cm pencil beam in dose calculation. In the present version of MCI, skin contour variations and inhomogeneities were neglected.     

Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3

Tissue inhibitor of metalloproteinases-3(TEMP-3), a novel memberof TEMP family genes, has been recently cloned and shown tobe expressed in preneoplastic but not in neoplastic mouse JB6epidermal cells (Sun et al. 1994 Cancer Res., 54, 11139). Thisdown regulation of the gene appears to be attributable at leastin part to alteration of gene methylation (Sun et al. 1995 J.Biol Chem., 270, 19312). Little is known, however, about therole of TEMP-3 in human cancers. We screened several human tumorcell lines for TEMP-3 expression and found that a colon carcinomaline, DLD-1, did not express TEMP-3. If down regulation of TIMP-3is causally related to carcino-genesis, re-expression by transfectionmay reverse the tumor cell phenotype. We therefore overexpressedhuman TEMP-3 in DLD-1 cells. TEMP-3 transfectants showed a serum-dependentgrowth inhibition in monolayer culture and a decreased growthpotential in nude mice in a manner dependent on the level ofTEMP-3 expression. A transfectant expressing a high level ofactive hTEMP-3 completely lost the ability to form tumors followings.c. injection into nude mice. We also tested TEMP-3 expressingcells and neocontrol TEMP-3 negative cells for their abilityto grow in liquid suspension culture, since both cells grewin semi-solid soft agar. As compared to neocontrol cells, TIMP-3over-expressors formed large aggregates, followed by cell death.This effect was not mimicked by BB94, a broad MMP inhibitor.We conclude from this study that (i) TEMP-3 overexpression inhuman colon carcinoma cells induces growth arrest in low serumconditions and inhibits in vivo tumor growth and (ii) the TEMP-3-inducedlarge aggregate formation and subsequent cell death under suspensiongrowth cannot be explained by its MMP inhibitory activity.     

New PET imaging agent for the serotonin transporter: [(18)F]ACF (2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine)

A new F-18-labeled phenylthiophenyl derivative specific for imaging of serotonin transporters (SERT) in the brain by positron emission tomography (PET) is described. Fluorinated phenylthiophenyl derivative, ACF, 2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine, was prepared by first coupling 2,5-dichloro-4-nitroaniline with 2-mercapto-N,N-dimethylbenzamide. The amino group of the coupled adduct was converted to a fluoro group through a Schiemann reaction. Subsequently, a one pot reduction of both nitro and amide groups by BH(3)-tetrahydrofuran yielded the nonradioactive ACF (yield 25%). In vitro binding assays using cell membrane homogenates of LLC cells expressing SERT, dopamine transporters (DAT), or norepinephrine transporters (NET) showed excellent binding affinity and selectivity for SERT (K(i) = 0.05, 3020, and 650 nM for SERT, DAT, and NET, respectively). For preparation of the [(18)F]ACF, the NH(2) group of the initially coupled adduct was converted to the trimethylammonium salt, which was replaced by [(18)F]fluoride in the presence of Kryptofix 222 and potassium carbonate. The final product, [(18)F]ACF, was obtained after a borane and stannous chloride reduction reaction. The combined two step reaction gave a radiochemical yield of 10-15% (EOB) and a radiochemical purity of >99%. Synthesis of the novel PET tracer, [(18)F]ACF, as a probe for binding to SERT in the brain was successfully achieved. The new tracer [(18)F]ACF showed excellent brain penetration and selective localization after an iv injection in rats (brain uptake at 2, 30, 60, 120, and 240 min was 3.27, 1.28, 0.69, 0.21, and 0.06% dose/organ, respectively). The hypothalamus/cerebellum ratio at 60 min post iv injection was 3.55. This specific localization in the hypothalamus was blocked by pretreatment of (+)McN5652. This novel ligand is a potential PET tracer for in vivo evaluation of SERT in the brain.     

Improved microvessel repair: laser welding with an anti-thrombotic solder

BACKGROUND AND OBJECTIVES: Concentrated protein solutions can be used as thermally polymerized solders in laser welding. Solders supplemented with biologically active chemicals may provide in situ drug delivery for localized therapeutics. These studies characterize a serum albumin (SA) solder containing heparin, designed to reduce microvascular thrombosis rates. STUDY DESIGN/MATERIALS AND METHODS: Samples of heparin added to 30% SA to obtain heparin-to-albumin molar ratios (HAMR) of 4:1 and 2:1 were thermally polymerized, and heparin release into saline was measured. Using a rat thrombosis model, patency was determined for suture, and 0 U/ml (control), 2.5 U/ml, 50 U/ml heparin solder repairs. RESULTS: Heparin release was five times higher for 4:1 than 2:1 HAMR solder acutely, but was equivalent after 2 days. Animal patency rates were: 50% suture, 0% control, 50% low heparin, 66% high heparin (P < 0.05 vs. control). CONCLUSIONS: Solders incorporating heparin should provide in situ anti-thrombotic therapy reducing the risk of microvascular thromboses.     

Radioiodinated styrylbenzene derivatives as potential SPECT imaging agents for amyloid plaque detection in Alzheimer's disease

Development of probes for β-amyloid (Aβ) plaques, a critical factor associated with Alzheimer’s disease (AD), provides important tools for studying their role in AD. Previously, we reported [¹²⁵I]IMSB and [¹²⁵I]ISB as excellent probes for Aβ plaque labeling. Despite their exquisite in vitro binding characteristics, low brain uptakes (likely due to two ionizable carboxylic acid groups) limited their potential as in vivo imaging agents. To improve brain penetration, we have successfully prepared a neutral radioiodinated probe [¹²⁵I]3. The improved probe displayed good binding affinity for Aβ aggregates (K_i=2.0 ± 0.2 using Aβ40 aggregates). In addition, the brominated counterpart displayed fluorescent-staining properties of Aβ plaques in postmortem AD brain sections similar to BSB, a fluoroscent probe reported previously. [¹²⁵I]3 gave excellent plaque labeling by film autoradiography of AD brain sections. Unlike [¹²⁵I]IMSB (which preferentially detects Aβ40 plaques), the improved radioioinated probe, [¹²⁵I]3, can readily detect plaques containing aggregates of both Aβ40 and Aβ42. The initial brain uptake of [¹²⁵I]3 in normal mice at 2 min p.i. was moderate (0.18% ID) and displayed a very slow washout from the brain (0.11 %.ID at 4 h p.i). Taken together, these data suggest that [¹²⁵I]3 is useful for in vitro plaque detection, it may not be suitable for in vivo monitoring of Aβ progression and deposition.     

Outcomes at 3 months after planned cesarean vs planned vaginal delivery for breech presentation at term: the international randomized Term Breech Trial

Context  The Term Breech Trial found a significant reduction in adverse perinatal outcomes without an increased risk of immediate maternal morbidity with planned cesarean delivery compared with planned vaginal birth. No randomized controlled trial of planned cesarean delivery has measured benefits and risks of postpartum outcomes months after the birth. Objective  To compare maternal outcomes of planned cesarean delivery and planned vaginal birth at 3 months post partum. Design  Follow-up study to the Term Breech Trial, a randomized controlled trial conducted between January 9, 1997, and April 21, 2000. Setting and Participants  A total of 1596 of 1940 women from 110 centers worldwide who had a singleton fetus in breech presentation at term responded to a follow-up questionnaire at 3 months post partum. Main Outcome Measures  Breastfeeding; infant health; ease of caring for infant and adjusting to being a new mother; sexual relations and relationship with husband/partner; pain; urinary, flatal, and fecal incontinence; depression; and views regarding childbirth experience and study participation. Results  Baseline information was similar for both the cesarean and vaginal delivery groups. Women in the planned cesarean delivery group were less likely to report urinary incontinence than those in the planned vaginal birth group (36/798 [4.5%] vs 58/797 [7.3%]; relative risk, 0.62; 95% confidence interval, 0.41-0.93). Incontinence of flatus was not different between groups but was less of a problem in the planned cesarean delivery group when it occurred (P = .006). There were no differences between groups in other outcomes. Conclusions  Planned cesarean delivery for pregnancies with breech presentation at term may result in a lower risk of incontinence and is not associated with an increased risk of other problems for women at 3 months post partum, although the effect on longer-term outcomes is uncertain.      

Simplified quantification of dopamine transporters in humans using [99mTc]TRODAT-1 and single-photon emission tomography

Quantification of dopamine transporters (DAT) using [99mTc]TRODAT-1 and single-photon emission tomography (SPET) requires full kinetic modeling of the data, using complex and invasive arterial blood sampling to provide an input function to the model. We have shown previously that a simpler reference tissue model provides accurate quantitative results, using a reference region devoid of DAT as the input to the model and thereby obviating the need for blood sampling. We now extend this work into humans, and develop further simplifications to make the imaging protocol much more practical as a routine procedure. Fourteen healthy subjects (age 29.8 +/- 8.4 years, range 18.7-45.5 years) underwent dynamic SPET for 6 h following injection of 752 +/- 28 MBq [99mTc]TRODAT-1. The kinetic data were analyzed using nonlinear regression analysis (NLRA) and Logan-Patlak graphical analysis. In addition, simple average ratios of striatal-to-background counts were obtained for three 1-h periods (3-4 h, 4-5 h, 5-6 h), and compared against the kinetic models. All methods gave an index of specific binding, proportional to the binding potential, known as the distribution volume ratio (DVR). The reference tissue NLRA gave mean values of k3=0.013 +/- 0.003 min(-1), k4=0.011 +/- 0.002 min(-1), and DVR=2.29 +/- 0.17. Graphical analysis gave a value of DVR=2.28 +/- 0. 16, and the three ratio values of DVR were: 3-4 h, 2.18 +/- 0.15; 4-5 h, 2.34 +/- 0.13; and 5-6 h, 2.46 +/- 0.19. Graphical analysis was highly correlated with NLRA (R2=0.91, slope=0.90 +/- 0.08). The ratio methods correlated well with NLRA (3-4 h, R2=0.71, slope= 0.73 +/- 0.13; 4-5 h, R2=0.86, slope=0.73 +/- 0.09; 5-6 h, R2=0.80, slope=1.00 +/- 0.15), and also with graphical analysis (3-4 h, R2=0.65, slope=0.74 +/- 0.16; 4-5 h, R2=0.85, slope=0.78 +/- 0.09; 5-6 h, R2=0.88, slope=1.11 +/- 0.12). The optimum equilibrium time point for obtaining a simple ratio was approximately 4.5-5.5 h. In conclusion, the simple ratio techniques for obtaining a quantitative measure of specific binding correlated well with the reference tissue kinetic models, using both NLRA and graphical analysis. The optimum time for obtaining a ratio appeared to be in the range 4.5-5.5 h. Earlier time points, while still relatively accurate, had a lower sensitivity and may not be optimized for measuring small changes in DAT concentrations.     

Raised maternal serum placenta growth factor concentration during the second trimester is associated with Down syndrome.

OBJECTIVES: To compare early second-trimester maternal serum placenta growth factor concentrations in Down syndrome pregnancies and those in normal pregnancies. METHODS: A case-control study was performed to evaluate the maternal serum placenta growth factor concentrations in 36 Down syndrome and 320 normal pregnancies with matched gestational age during the second trimester. For the detection of serum concentrations of placenta growth factor, a quantitative sandwich enzyme immunoassay technique (R & D Systems Inc., Minneapolis, Minnesota, USA) was performed. RESULTS: Using a multiple linear regression model, maternal serum placenta growth factor level was associated with gestational age (p<0.001) and the existence of Down syndrome pregnancy (p<0.001). After converting maternal serum placenta growth factor concentrations of each analyte to multiples of the appropriate gestational median (MoM), placenta growth factor MoM (p<0.001) was revealed to be an independent variable for Down syndrome pregnancies after adjusting for the effects of maternal age (p<0.001), free beta-hCG (p<0.001) and AFP (p=0.014) by multivariate logistic regression analysis. CONCLUSIONS: Maternal serum placenta growth factor concentration was elevated in Down syndrome pregnancies during the early second trimester. Placenta growth factor might be a novel marker for maternal serum Down syndrome screening.