Effects of AZD2171 and vandetanib (ZD6474, Zactima) on haemodynamic variables in an SW620 human colon tumour model: an investigation using dynamic contrast-enhanced MRI and the rapid clearance blood pool contrast agent, P792 (gadomelitol).

The effect of two novel therapeutic agents on tumour haemodynamics was investigated using a fast dynamic contrast-enhanced (DCE)-MRI protocol (0.5 s/image) sensitive to signal changes in both the vascular input function and tumour during the administration of the macromolecular rapid clearance blood pool agent (MM-RCBPA), gadomelitol (P792, Vistarem). This enabled simultaneous measurement of the tumour blood flow per unit volume of tissue (F/V(T), mL/s/mL), the fractional plasma volume (V(p), %), and the permeability surface area product per unit volume of tissue (PSrho, s(-1)) in subcutaneous SW620 human colorectal tumour xenografts grown in nude rats before and after (at 0 and 22 h; imaging at 24 h) acute treatment with AZD2171 (3 mg/kg) and vandetanib (ZD6474, Zactima; 50 mg/kg), which have inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase. MRI was performed at 4.7 T using a single-slice, modified, T(1)-weighted, spoiled gradient-echo technique. Both compounds reduced gadomelitol uptake into the tumour. AZD2171 and vandetanib, respectively, (a) greatly reduced PSrho to 19.7 +/- 9.5% and 28.9 +/- 14.1% of baseline (P = 0.007 and P = 0.02), (b) markedly reduced V(p) to 31.2 +/- 19.1% and 54.8 +/- 21.2% of baseline (P = 0.015 and P = 0.09), and (c) had no significant effect on F/V(T). There was no significant difference between groups treated with AZD2171 and vandetanib when each variable was compared. The reductions in PSrho and V(p) are consistent with inhibition of VEGF signalling. AZD2171 (3 mg/kg) and vandetanib (50 mg/kg) were also found to produce a comparable chronic inhibition of SW620 tumour growth (89% for both). This study shows that DCE-MRI using an MM-RCPBA can be used to distinguish tumour vascular flow, volume, and permeability surface area product in a tumour model, and enables the acute effects of VEGF signalling inhibition to be examined in detail.

Should we resurface the patella in total knee replacement? Experience with the Nex Gen prothesis.

Patellar resurfacing is a controversial issue in primary total knee replacement. So, we took advantage of a large study to try and answer this question. An open prospective multicentric study was conducted about the outcome of the Nex Gen Total Knee prosthesis with clinical and radiological follow-up at regular intervals (1, 2 and 5 years). The data were centrally collected and analyzed by independent observers. A total of whole 5,915 cases were included (487 in the French group); incidences of patello-femoral pain were observed in both French and international groups and compared between cases with or without resurfaced patellae. Only osteoarthritic cases were selected for this particular study. Statistical analysis was performed using a Pearson's Chi-square test with a 95% confidence interval. The frequency of preoperative pain was significantly higher in the French group; 85.1% versus 66.6% (p<0.05). No patello-femoral pain appeared in preoperatively painless patients in the French group. The frequency of lateral patellar release was similar in both groups. 35.7% of the patellae were resurfaced in the international group versus 98.8% in the French one. At 2 years, patello-femoral pain was observed in 6.3% of cases in the former group versus 0.7% in the latter one. The risk of having patello-femoral pain was 9.45 times higher in the international group. When considering resurfaced cases in both groups the risk of having anterior knee pain was not significantly different (p=0.35). In the French group, one case out of nine (11.1%) with patello-femoral pain had not been resurfaced, while 129 cases out of 151 (85.4%) had not had a resurfacing in the international group. This emphasizes the effect of patellar implant on pain. Although patello-femoral pain is multifactorial, this analysis tool is powerful in getting rid of the "center effect " (cf Swedish register). Even if a longer follow-up for confirmation is needed, our data favor patellar resurfacing with this type of implant in spite of the fact that the trochlear design was considered as anatomical.

Reduced capillary perfusion and permeability in human tumour xenografts treated with the VEGF signalling inhibitor ZD4190: an in vivo assessment using dynamic MR imaging and macromolecular contrast media.

We describe the use of perfusion-permeability magnetic resonance imaging (ppMRI) to study hemodynamic parameters in human prostate tumor xenografts, following treatment with the vascular endothelial growth factor-A (VEGF) receptor tyrosine kinase inhibitor, ZD4190. Using a macromolecular contrast agent (P792), a fast MR imaging protocol and a compartmental data analysis, we were able to demonstrate a significant simultaneous reduction in tumor vascular permeability, tumor vascular volume and tumor blood flow (43%, 30% and 42%, respectively) following ZD4190 treatment (100 mg/kg orally, 24 h and 2 h prior to imaging). This study indicates that MR imaging can be used to measure multiple hemodynamic parameters in tumors, and that tumor vascular permeability, volume and flow, can change in response to acute treatment with a VEGF signaling inhibitor.

Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for treatment of primary infertility.

OBJECTIVE: Reports suggest that there is an increased incidence of preeclampsia after a previously normal pregnancy if there is a change in paternity. We hypothesize that there is a higher incidence of preeclampsia (proteinuric hypertension) in women conceiving by intrauterine insemination with donor sperm versus intrauterine insemination with partner sperm. STUDY DESIGN: This was a retrospective cohort study. In women with primary infertility all pregnancies achieved by either partner or donor intrauterine insemination carried to birth of a fetus (> 20 weeks) were identified. The medical records were examined for the maternal and pregnancy outcome data. The relative risk and 95% confidence interval were calculated for the risk of preeclampsia. The baseline data were compared with t tests, chi 2 analysis and Fisher's exact test where appropriate. RESULTS: Forty-four patients in the partner intrauterine insemination group and 37 in the donor insemination group were identified as having primary infertility. Three cases of mild preeclampsia were found in the partner insemination program and nine cases of preeclampsia (five severe, four mild) in the donor insemination program (relative risk 1.85, 95% confidence interval 1.20 to 2.85). CONCLUSIONS: There is a higher incidence of preeclampsia in women conceiving by intrauterine insemination with washed donor sperm compared with intrauterine insemination with washed partner sperm. This supports, indirectly, an immunologic basis for preeclampsia. The antigenic factor would appear to be located on the sperm as opposed to the seminal fluid itself.

[Monitoring after total hip prosthesis. Value of semi-quantitative D-dimer assay]. / Surveillance après prothèse totale de hanche. Intérêt du dosage semi-quantitatif du D-dimère.

Criteria for positive assay of the D-dimer were defined in order to establish its diagnostic value for phlebitis in the post-operative period. A retrospective study was carried out on the files of 94 patients who had received a total hip prosthesis in 1990. A semi-quantitative assay technique was used to measure the D-dimer because it is the only method giving immediate results. Three criteria were used to classify the results: criterium A: D-dimer greater than or equal to 2 micrograms/ml; criterium B: D-dimer greater than or equal to 4 times the preceding test; absence of both of these criteria. The results were compared to echo-doppler results and confirmed by phlebography when necessary. The incidence of proximal phlebitis was low (2 percent); criterium B showed a 100 percent negative predictability and a 29 percent positive predictability. None of the cases of phlebitis diagnosed with this test had been suspected clinically. This test provides a means of patient screening and spares the need for other explorations.

[T4 and T8 lymphocytic populations after total hip replacement]. / Etude des populations lymphocytaires CD 4 et CD 8 après chirurgie pour prothèse de hanche.

Immunosuppression is involved in the occurrence of sepsis after surgical trauma. A postoperative lymphocytopenia is a recognised fact. In the opposite, studies on T-lymphocytes helpers (CD 4) and suppressors (CD 8) resulted in conflicting results. The aim of this study was to assess the variations in these two T-lymphocyte sub-populations using strongly standardized conditions in order to minimize the risk of non specific variations: same surgeon, same surgical technique, blood samples collected just before induction, immediately and 24 hours after surgery, automatized measures (Technicon H1). The results confirmed the lymphocytopenia, 24 hours after surgery, but no differences on CD 4 and CD 8 percentages were noted. It is concluded that during the first 24 postoperative hours surgery does not change the relative proportions of T-helpers and T-suppressors. Their measurement is not more useful than total lymphocyte count for assessment of postoperative immunosuppression.