Molecular pathology of tumor metastasis. II. Molecular staging and differential diagnosis

Molecular Pathology of Tumor Metastasis With the development of non-invasive methods, diagnosis of metastasis from various solid malignancies has become a routine task for diagnostic pathology. However, the differential diagnosis between primary and metastatic cancers and the precise identification of various metastatic cancer types requires the coordinated use of various morphological (light- and electron microscopic-), immunological and molecular techniques. The detection of the lymphatic spread of the primary tumor may now based on the sentinel lymph node technology while the identification of the hematogenous progression may be based on the analysis of the peripheral blood and the bone marrow. More and more frequently these techniques employ highly sensitive immunological and molecular techniques. Accordingly, clinical staging is now confronted with the results of molecular staging, where the only techniques which are able to detect cancer cells are immunocytochemistry or nucleic acid-based methodology. Although several clinical studies have provided evidences for the impact of the immunocytochemistry-based identification of micrometastases on the survival of patients with various type of cancers, none of these methods have become part of standard diagnostic protocols. Although more sensitive molecular techniques are being introduced to identify micrometastasis, their clinical significance is yet unknown. Multicentric clinical trials are now warranted to establish the clinical impact of molecular staging in various cancer types. Without the integration of these methods into the prognostic/predictive pathological protocols it is difficult to envision significant improvement in the results of cancer therapy.     

Juvenile rheumatoid arthritis of the knee: evaluation with contrast-enhanced color Doppler ultrasound

BACKGROUND: Contrast-enhanced color Doppler ultrasonography is a non-radiation-bearing tool that can be of value for assessment of inflammatory and vascular synovial changes in juvenile rheumatoid arthritis (JRA). OBJECTIVES: To evaluate the effect of contrast-enhanced color Doppler ultrasound (US) in the evaluation of synovial changes in the knees of children with JRA. MATERIALS AND METHODS: Sagittal color Doppler sonograms of 31 knees in 22 patients with JRA and of 10 knees in 5 control subjects were obtained before (at baseline) and after (at peak contrast phase) intravenous injection of SHU 508. Images were assessed for overall mean pixel intensity within the synovial tissue and for peak enhancement ratios [[(mean pixel intensity values at maximum contrast enhancement-unenhanced mean pixel intensity values)/unenhanced mean pixel intensity values] x 100]. The joints were classified into three groups by clinical/laboratory criteria: group A (active disease in the knee), n = 9; group B (quiescent disease with serum chemistry levels of active disease), n = 12 and group C (remission disease), n = 10. RESULTS: Mean color pixel intensity values were markedly increased by the use of US contrast agents in groups A (P = 0.004) and B (P = 0.0001), did not reach statistical significance in group C (P = 0.06) and remained essentially unchanged in the control group (P = 0.25). Enhancement ratios for the three groups of JRA patients were not different (P = 0.38) (mean +/- SD, 720% +/- 402 for group A, 731% +/- 703 for group B and 314% +/- 263 for group C). CONCLUSION: Contrast-enhanced color Doppler imaging holds promise for the detection of active synovial inflammatory disease in subclinical cases of JRA, thereby allowing earlier treatment and improved clinical outcome.     

ICSI and day 5 embryo transfers: higher implantation rates and lower rate of multiple pregnancy with prolonged culture

This retrospective review study, carried out in a private IVF clinic, compared pregnancy and implantation rates with day 3 versus day 5 embryo transfers in a selected group of patients. Participants were patients who failed to achieve pregnancy in at least one previous attempt with embryo transfer on days 2 or 3, and had more than five oocytes fertilized. A total of 296 patients who had undergone day 3 (group A) transfers were compared with 154 who had undergone day 5 transfers (group B). Interventions were intracytoplasmic sperm injection (ICSI), day 3 and day 5 embryo transfer. Outcome measures were pregnancy, implantation, multiple gestation and blastocyst formation rates. Overall, 86.4% of embryos were at the six- to eight-cell stage at 72 h and 30% developed to blastocyst by day 5. The mean number of embryos transferred was 4.0 on day 3 and 3.0 on day 5. Pregnancy and implantation rates were 34.8 and 11.5% in group A, versus 45.3 and 18.5% in group B. Multiple gestation rate was 47.1% in group A and 28.5% in group B. Prolonging embryo culture in vitro to day 5 improved embryo selection and implantation rates. A significant decrease in high order gestations was achieved by reducing the number of embryos transferred, without compromising the pregnancy rates.     

Antioxidative activity of Allium victorialis L. extracts

Allium victorialis L. (Liliaceae, "Hon-Gyoujya Nin-Niku" in Japanese) was successively extracted with hexane, acetone, methanol and 70% methanol and the extracts were further separated into a total of twenty-five fractions by silica gel and ODS column chromatographies. The biological activities of these four extracts and 25 column fractions were compared. The cytotoxic activity of all extracts and fractions against two oral tumor cell lines was significantly higher than that against normal human gingival fibroblasts, suggesting their tumor-specific action. Three methanol column fractions [M2, M3, M6] and a 70% methanol column fraction [70M6] most effectively reversed the multidrug resistance (MDR) against L5178 mouse T cell lymphoma. The electron spin resonance (ESR) spectroscopy showed that methanol column fractions and 70% methanol extracts produced the highest amount of radical(s) and most efficiently scavenging O2*-, generated by the hypoxanthine-xanthine reaction system, suggesting that the same substances in these fractions display both prooxidant and antioxidant properties. They showed no anti-human immunodeficiency virus (HIV) or anti-Helicobacterpylori activity. These data suggest the medicinal efficacy of Allium victorialis extract.     

The role of boost irradiation in the conservative treatment of stage I-II breast cancer

In this article, we review the current status, indication, technical aspects, controversies, and future prospects of boost irradiation after breast conserving surgery (BCS). BCS and radiotherapy (RT) of the conserved breast became widely accepted in the last decades for the treatment of early invasive breast cancer. The standard technique of RT after breast conservation is to treat the whole breast up to a total dose of 45 to 50 Gy. However, there is no consensus among radiation oncologists about the necessity of boost dose to the tumor bed. Generally accepted criteria for identification of high risk subgroups, in which boost is recommended, have not been established yet. Further controversy exists regarding the optimal boost technique (electron vs. brachytherapy), and their impact on local tumor control and cosmesis. Based on the results of numerous retrospective and recently published prospective trials, the European brachytherapy society (GEC-ESTRO), as well as the American Brachytherapy Society has issued their guidelines in these topics. These guidelines will help clinicians in their medical decisions. Some aspects of boost irradiation still remain somewhat controversial. The final results of prospective boost trials with longer follow-up, involving analyses based on pathologically defined subgroups, will clarify these controversies. Preliminary results with recently developed boost techniques (intraoperative RT, CT-image based 3D conformal brachytherapy, and 3D virtual brachytherapy) are promising. However, more experience and longer follow-up are required to define whether these methods might improve local tumor control for breast cancer patients treated with conservative surgery and RT.     

Transient synaptic activation of NMDA receptors leads to the insertion of native AMPA receptors at hippocampal neuronal plasma membranes.

The molecular mechanisms underlying long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus are not well understood. Transient depolarisation of cultured postnatal hippocampal neurones (3x1 s exposure to 90 mM K+) induces a form of LTP that is manifest primarily as an increase in mEPSC frequency. Site-directed antibodies that recognise an extracellular region of all AMPA receptor (AMPAR) subunits (GluR1-4) were used for the immunolabelling of living neurones. These antibodies were raised in two species to enable sequential immunofluorescent labelling of individual living neurones before and after the induction of LTP. High K+ treatment resulted in the appearance of new AMPAR clusters at sites on the neuronal surface that previously lacked detectable AMPARs. The appearance of new AMPAR clusters was NMDA receptor (NMDAR)-dependent since it was antagonised by the application of NMDAR antagonists. Our data indicate that the transient synaptic activation of NMDARs can lead to the insertion of native AMPARs at sites on the neuronal membrane that initially lacks AMPARs.     

Effect of X-ray tube parameters, iodine concentration, and patient size on image quality in pulmonary computed tomography angiography: a chest-phantom-study

OBJECTIVES: The aim of this phantom study was to evaluate the contrast-to-noise ratio (CNR) in pulmonary computed tomography (CT)-angiography for 300 and 400 mg iodine/mL contrast media using variable x-ray tube parameters and patient sizes. We also analyzed the possible strategies of dose reduction in patients with different sizes. MATERIALS AND METHODS: The segmental pulmonary arteries were simulated by plastic tubes filled with 1:30 diluted solutions of 300 and 400 mg iodine/mL contrast media in a chest phantom mimicking thick, intermediate, and thin patients. Volume scanning was done with a CT scanner at 80, 100, 120, and 140 kVp. Tube current-time products (mAs) varied between 50 and 120% of the optimal value given by the built-in automatic dose optimization protocol. Attenuation values and CNR for both contrast media were evaluated and compared with the volume CT dose index (CTDI(vol)). Figure of merit, calculated as CNR/CTDIvol, was used to quantify image quality improvement per exposure risk to the patient. RESULTS: Attenuation of iodinated contrast media increased both with decreasing tube voltage and patient size. A CTDIvol reduction by 44% was achieved in the thin phantom with the use of 80 instead of 140 kVp without deterioration of CNR. Figure of merit correlated with kVp in the thin phantom (r = -0.897 to -0.999; P < 0.05) but not in the intermediate and thick phantoms (P = 0.09-0.71), reflecting a decreasing benefit of tube voltage reduction on image quality as the thickness of the phantom increased. Compared with the 300 mg iodine/mL concentration, the same CNR for 400 mg iodine/mL contrast medium was achieved at a lower CTDIvol by 18 to 40%, depending on phantom size and applied tube voltage. CONCLUSIONS: Low kVp protocols for pulmonary embolism are potentially advantageous especially in thin and, to a lesser extent, in intermediate patients. Thin patients profit from low voltage protocols preserving a good CNR at a lower exposure. The use of 80 kVp in obese patients may be problematic because of the limitation of the tube current available, reduced CNR, and high skin dose. The high CNR of the 400 mg iodine/mL contrast medium together with lower tube energy and/or current can be used for exposure reduction.     

Impact of aneurysmal geometry on intraaneurysmal flow: a computerized flow simulation study

Introduction This study was performed to assess the effect of aneurysm geometry on parameters that may have an impact on the natural history of intracranial aneurysms, such as intraaneurysmal flow pressure and shear stress. Methods Flow was simulated in 21 randomly selected aneurysms using finite volume modeling. Ten aneurysms were classified as side-wall aneurysms, with either single-sided or circumferential involvement of the parent artery wall, and 11 as bifurcation aneurysms (symmetric or asymmetric), with an axis either perpendicular or parallel to the parent artery. The flow patterns were classified as either jet or vortex types (with regular or irregular vortex flow). Pressures and shear stresses were characterized as evenly or unevenly distributed over the aneurysm wall and neck. Results All side-wall and four of the bifurcation aneurysms with a perpendicular axis had a vortex type flow pattern and seven bifurcation aneurysms with a parallel axis (four symmetric and two asymmetric) had a jet flow pattern. Jet type flow was associated with an uneven pressure distribution in seven out of seven aneurysms. Vortex type flow resulted in an even pressure distribution in five out of six aneurysms with an irregular flow pattern and six out of eight with a regular flow pattern. No firm relationship could be established between any geometrical type and shear stress distribution. Only 1 of 14 aneurysms with a perpendicular axis, but 4 of 7 aneurysms with a parallel axis, had ruptured. Conclusion Aneurysm geometry does have an impact on flow conditions. Aneurysms with a main axis parallel to the parent artery have a tendency to have a jet flow pattern and uneven distribution of unsteady pressure. These aneurysms may have a higher rate of rupture as than those with a main axis perpendicular to the parent artery.