Overexpression of BclXL in a human ovarian carcinoma cell line: paradoxic effects on chemosensitivity in vitro versus in vivo

The effect of overexpressing the antiapoptotic protein BclXL in a human ovarian carcinoma cell line has been investigated in terms of sensitivity to the 2 major drugs used to treat this disease, paclitaxel and cisplatin. Stable transfection of BclXL into CH1 cells, which are relatively sensitive to cisplatin, resulted in around 2.7-fold higher expression in comparison with empty vector controls. However, this level of overexpression did not result in significant resistance in vitro to paclitaxel or cisplatin at the 50% inhibition level, using either short-term (4-day) growth inhibition or longer term colony-forming assays. By contrast, parallel subcutaneous xenograft models of these isogenic ovarian carcinoma cells in vivo, differing only in BclXL status, showed that this low-level BclXL overexpression conferred significant resistance to both paclitaxel and cisplatin in comparison with parent, nontransfected tumours. Whereas parent non-BclXL transfected tumours were highly responsive, with the disappearance of tumours for at least 50 days post treatment, tumours overexpressing BclXL grew back after 30 and 20 days after treatment with paclitaxel and cisplatin, respectively. These differences in responsiveness to paclitaxel in vivo were not attributable to any significant changes in the delivery of drug to the tumour. These data suggest that the responsiveness of ovarian cancer to paclitaxel and cisplatin in vivo, and therefore perhaps clinically, is influenced by levels of the antiapoptotic protein BclXL. Such effects may be missed in vitro when using short-term growth inhibition or clonogenic assays.     

Is there an increased maternal-infant prevalence of Factor V Leiden in association with severe pre-eclampsia?

Objective To compare the prevalence of the Factor V Leiden mutation in children and maternal–infant pairs in pregnancies affected by severe pre-eclampsia with unmatched normal controls.
Design Prospective cohort study.
Setting Department of Women's and Children's Health, The Canberra Hospital, Garran, ACT, Australia.
Sample Forty-eight maternal–infant pairs where the index pregnancy was affected by severe pre-eclampsia; 46 unmatched maternal–infant pairs where the index pregnancy was defined as normal.
Methods DNA analysis of cheek swab samples obtained from maternal–infant pairs for the Factor V Leiden mutation.
Main outcome measure The prevalence of the Factor V Leiden mutation in mothers, infants and maternal–infant pairs in association with severe pre-eclampsia compared with unmatched controls.
Results No difference was detected in the prevalence of Factor V Leiden mutation between the women and children of both groups, nor the maternal–infant pairs from each group.
Conclusions No evidence was found of an increased prevalence of the Factor V Leiden mutation in either the mothers or children in association with severe pre-eclampsia. This result argues against a Factor V Leiden fetal or maternal contribution to the development of severe pre-eclampsia.     

Anilinoquinazoline inhibitors of fructose 1,6-bisphosphatase bind at a novel allosteric site: synthesis,in vitro characterization,and X-ray crystallography

The synthesis and in vitro structure-activity relationships (SAR) of a novel series of anilinoquinazolines as allosteric inhibitors of fructose-1,6-bisphosphatase (F16Bpase) are reported. The compounds have a different SAR as inhibitors of F16Bpase than anilinoquinazolines previously reported. Selective inhibition of F16Bpase can be attained through the addition of appropriate polar functional groups at the quinazoline 2-position, thus separating the F16Bpase inhibitory activity from the epidermal growth factor receptor tyrosine kinase inhibitory activity previously observed with similar structures. The compounds have been found to bind at a symmetry-repeated novel allosteric site at the subunit interface of the enzyme. Inhibition is brought about by binding to a loop comprised of residues 52-72, preventing the necessary participation of these residues in the assembly of the catalytic site. Mutagenesis studies have identified the key amino acid residues in the loop that are required for inhibitor recognition and binding.     

Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials

OBJECTIVE: To investigate the optimum number of cycles of controlled ovarian hyperstimulation and intrauterine insemination in the treatment of unexplained infertility. DESIGN: Observational prospective study. SETTING: In vitro fertilization embryo transfer center. PATIENT(S): Five hundred ninety-four couples with unexplained infertility. INTERVENTION(S): Controlled ovarian hyperstimulation (COH), intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Cycle fecundity. RESULT(S): One to 3 cycles of COH/IUI were performed in 594 patients (group A) undergoing 1,112 cycles (mean, 1.9 cycles/patient). Up to 3 further trials (cycles 4-6) of COH/IUI were then performed in 91 of these women (group B), a total of 161 cycles (mean, 1.8 cycles/patient). A historical comparison group C consisted of 131 patients with 3 failed cycles of COH/IUI who underwent 1 cycle of IVF and ICSI at our center. In group A, 182 pregnancies occurred, with a cycle fecundity of 16.4% and a cumulative pregnancy rate (PR) of 39.2% after the first 3 cycles. In group B, 9 pregnancies occurred in cycles 4-6, with a cycle fecundity of 5.6%, significantly lower than that of group A (P<.001). The cumulative PR rose to 48.5% by cycle 6, a further increase of only 9.3%. In the women undergoing IVF and ICSI in group C, 48 pregnancies occurred, with a cycle fecundity of 36.6% per cycle, significantly higher than that of group B (P<.001). CONCLUSION(S): In unexplained infertility, the cycle fecundity in the first three trials of COH and IUI was higher than in cycles 4-6, with a statistically significant difference. Patients should be offered IVF or ICSI if they fail to conceive after three trials of COH and IUI.     

Neuroendocrine tumors of the thymus: a clinicopathological and prognostic study

BACKGROUND: Neuroendocrine tumors of the thymus are rare, histologically diverse neoplasms with an unpredictable clinical behavior. This study provides a useful clinicopathological classification and determines the relevance of specific prognostic factors. METHODS: Ten neuroendocrine tumors of the thymus were analyzed for specific clinical and pathological features. Prognostic factors of these cases and 71 previously published cases were evaluated by Kaplan-Meier survival curves and Cox multivariate hazard model. RESULTS: There were 7 males and 3 females, with ages ranging from 26 to 77 years. Cases were classified as carcinoid tumor (2), atypical carcinoid tumor (6), and small cell carcinoma (2). An advanced clinical stage was evident in all instances with frequent recurrence (4) and metastases (8), and a short disease-free survival. Overall mortality was 60%. Statistical analysis of current and previously published cases (n = 81 total) revealed that unresectability (p = 0.0001), extent of surgical resection (p = 0.0002), and advanced clinical stage at presentation (p = 0.03) were associated with higher mortality. By multivariate Cox regression analysis, unresectability (p = 0.02) and advanced clinical stage (p = 0.03) were associated with decreased survival. CONCLUSIONS: Neuroendocrine tumors of the thymus can be classified into distinct clinicopathological entities, and specific factors have prognostic relevance.     

Short stay carotid surgery for veterans: an emerging standard

We have taken the short stay approach to carotid artery surgery to our VA setting over the past 5 to 6 years. Retrospectively, we reviewed the efficacy and safety of that approach in 201 consecutive carotid operations over the recent 4-year period (January 1, 1996-December 31, 1999). In 1996 we had already begun the transition to an algorithm to (1) utilize carotid color flow Doppler duplex exams for diagnosis, (2) same-day admission (SDA), (3) intensive care unit (ICU) only when deemed medically necessary, and (4) next-day discharge. Results of this approach have been a decrease in the utilization of diagnostic arteriograms and utilization of the ICU from 100% previous to the onset of this approach to 17 and 22%, respectively. SDA increased from 24 to 89%. Mean LOS decreased from 5.13+/-0.9 to 1.97+/-0.4 days. The percentage of patients completing the algorithm went from 15 to 72%. Stroke and/or death varied from 0 to 3.7% each year and was only 2.4% over the 4-year period. In conclusion, this approach to short stay carotid surgery in the veteran population has proven both efficacious and safe with results similar to those in university and community practices.     

Ultrasound assessment of the spring ligament complex

This study was conducted to document the normal ultrasound anatomy of the spring ligament in asymptomatic subjects and to prospectively determine the frequency of ultrasound abnormality of the spring ligament in patients with suspected posterior tibial tendinopathy. The superomedial calcaneonavicular ligament (CNL) of 10 healthy volunteers was examined by ultrasound. Nineteen patients with a clinical diagnosis of suspected posterior tibial tendinopathy and/or chronic pain along the course of the tendon were examined by ultrasound. The superomedial CNL thickness was measured. Normal anatomy of the superomedial CNL could be demonstrated in all the volunteers. The mean of the combined proximal measurements was 4 mm and of the distal measurements 3.6 mm. Sixteen patients with posterior tibial tendinopathy had increased thickness of the spring ligament, which was more evident on its distal portion over the talar head. One patient had superomedial CNL insufficiency with normal posterior tibial tendon. The mean proximal measurement in the study group was 5.1 mm and the distal measurement 6.1 mm. The differences between the measurements in the study group and controls were highly significant (proximal site P < 0.01, distal site P < 0.001). Spring-ligament laxity or tear is characterised by thickening. There is a strong association between posterior tibial tendinopathy and abnormality of the spring ligament.     

Breast cancer in Tunisia in 2004: a comparative clinical and epidemiological study

The aim of this study was to determine the epidemiological, clinical and anatomopathological aspects of breast cancer in Tunisia. We censored and analyzed all cases of breast cancer newly diagnosed in Tunisia during the year 2004. During that year, 1437 new cases of invasive breast cancer were diagnosed and 35 cases of non invasive breast cancer. There were 1408 women and 29 men. The accrual incidence was 27.1 and the standardized incidence was 28.5. The mean age for women was 51 years. The mean tumour size was 40.8 mm (32.3 mm and 42.5 mm for private and public sectors respectively). Tumour stage was T1 in 12.2% cases, T2 in 46.9% cases, T3 in 11.2% cases and T4 in 24.7% cases. Invasive ductal carcinoma was the most frequent (86,6%) with SBR II grade representing 54.5%. 27.7% of the patients had undergone conservative treatment. There was an unexpected increase of the incidence since 1994 where the standardized incidence was 16.9. We have noticed a moderate decrease of the tumour size of 8 mm during the last decade. This national epidemiological study on breast cancer showed an increase in the incidence of this cancer with a moderate decrease in the clinical tumour size. The relative young mean age of our patients may be explained by the age distribution in our population or by risk factors that may be particular to our country.     

Impact of telemedicine on pediatric neuro-oncology in a developing country: the Jordanian-Canadian experience

BACKGROUND: Telemedicine is widely used in industrialized countries for educational purposes. Twinning experiences using telemedicine between institutions in industrialized and developing countries (DC) have been limited. Pediatric neuro-oncology is a complex multidisciplinary discipline that is underserved in most of DC and provides a model to test the feasibility of such tool for twinning purposes. METHODS: A computer, an EMLO visual presenter HV-7600SX document camera, and a TANDBERG 6000 model videoconference unit were used to present data. For connectivity, we used a six-channel ISDN telephone line. Each channel is 64 megabytes/sec. RESULTS: Between December 2004 and May 2006, 20 sessions of videoconference were held between King Hussein Cancer Center and the Hospital for Sick Children to discuss 72 cases of 64 patients with various brain tumors (5 patients were discussed twice and 1 patient four times). In 23 patients (36%), major changes from original plan were recommended on different aspects of the care. In 21 patients (91%), those recommendations were followed, with potentially significant positive impact on patients' care. CONCLUSIONS: Videoconferencing is a feasible and practical twinning tool in pediatric neuro-oncology with a potentially major impact on patient care.