Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17

Background: MA.17 evaluated letrozole or placebo after 5 yearsof tamoxifen and showed significant improvement in disease-freesurvival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008].The trial was unblinded and placebo patients were offered letrozole. Patients and methods: An intent-to-treat analysis of all outcomes,before and after unblinding, on the basis of the original randomizationwas carried out. Results: In all, 5187 patients were randomly allocated to thestudy at baseline and, at unblinding, 1579 (66%) of 2383 placebopatients accepted letrozole. At median follow-up of 64 months(range 16–95), 399 recurrences or contralateral breastcancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-yearDFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95%confidence interval (CI) 0.55–0.83, P = 0.0001] and showedsuperiority for letrozole in both node-positive and -negativepatients. Corresponding 4-year distant DFS was 96.3% and 94.9%(HR 0.80, 95% CI 0.62–1.03, P = 0.082). Four-year overallsurvival was 95.1% for both groups. The annual rate of CLBCwas 0.28% for letrozole and 0.46% for placebo patients (HR 0.61,95% CI 0.39–0.97, P = 0.033). Conclusions: Patients originally randomly assigned to receiveletrozole within 3 months of stopping tamoxifen did better thanplacebo patients in DFS and CLBC, despite 66% of placebo patientstaking letrozole after unblinding. Key words: extended adjuvant therapy, intent-to-treat, letrozole Received for publication September 19, 2007. Revision received November 20, 2007. Accepted for publication November 22, 2007.     

Acculturation and perinatal health outcomes among rural women of Mexican descent

Research has shown that health outcomes for urban women of Mexican descent are related to acculturation. The purpose of this research was to compare perinatal outcomes of 773 women of Mexican descent who gave birth in three rural northern California hospitals, in relation to acculturation measured three different ways: by place of birth, by language spoken, and by the two factors combined as an Acculturation Index (AI). The prenatal and birth records of 773 Mexico-born or U.S.-born women of Mexican descent were reviewed. Results showed that language spoken was a less useful indicator of acculturation associated with perinatal complications than place of birth or the AI. The categorization of acculturation with the AI enhanced understanding of more specific groups of rural women and their particular health outcomes.     

Effects of rocking on neuromuscular development in the premature

It has been postulated that motion stimulation accelerates postnatal development. To test this hypothesis, 26 premature infants participated in a randomized controlled study of the effects of rocking on body weight gain and measures of neuromuscular development. Treatment infants were exposed to 15-min sessions of sinusoidal oscillation about the longitudinal axis, three times a day for 2 weeks. Infants were evaluated at the beginning and end of the 2-week treatment period and 2 weeks later. Neuromuscular development at these three times was measured with the comprehensive Dubowitz examination. Following treatment, large as compared with small premature infants showed a marked, but not statistically significant increase in weight gain. Duration of treatment appears to be a critical factor in influencing weight gain. All infants exposed to motion stimulation showed significant gains over controls in overall neuromuscular development. Passive muscle tone (posture, arm recoil and popliteal angle) and active motility (arm traction, head lag and ventral suspension) showed significant improvement in the treatment group at posttest. Similar results were recorded with auditory and visual orientation, alertness and defensive reaction. These specific areas of behavior have been recognized to be delayed in premature infants not exposed to a program of sensory stimulation.     

Bcl-2 and GDNF delivered by HSV-mediated gene transfer after spinal root avulsion provide a synergistic effect

Proximal spinal nerve injury results in the death of motor neurons in ventral horn. We have previously demonstrated this cell death can be prevented by HSV-mediated transfer of the gene coding for the antiapoptotic peptide Bcl-2 7 days prior to injury, but that expression of Bcl-2 does not preserve ChAT expression in the lesioned cells. In the current study, we examined two related issues: whether Bcl-2 delivered by HSV-mediated gene transfer 30 min after injury could similarly protect motor neurons from cell death, and whether the additional HSV-mediated expression of the glial cell derived neurotrophic factor (GDNF) could improve the result. At 30 min after avulsion of the L4, L5, and L6 spinal nerves, replication defective genomic HSV-based vectors coding for Bcl-2, GDNF, a reporter transgene (lacZ), or the Bcl-2 and GDNF vectors together were injected into spinal cord. Transduction of motor neurons with either the Bcl-2-expressing vector or the GDNF-expressing vector resulted in a substantial increase in the number of surviving motor neurons, and coinjection of the two vectors together resulted in cell survival that was similar to the result obtained with either vector alone. Neither the Bcl-2-expressing vector nor the GDNF-expressing vector delivered alone protected choline acetyltransferase (ChAT) expression in lesioned neurons. However, simultaneous injection of the Bcl-2- and the GDNF-expressing vectors together resulted in a substantial increase in the number of ChAT in cells in the lesioned ventral horn. Together, these findings suggest an approach to improving cell survival and regeneration following proximal root injury.     

The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases

Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. This review describes the history of clinical trials, clinical trials networks, and the goals of such networks in the United States. The Cystic Fibrosis Therapeutics Development Network, a network that represents the paradigm for genetic and orphan diseases, is described in detail. This network has been extremely successful in its first 3.5 years of existence conducting 18 different clinical trials in patients with Cystic Fibrosis. Unique aspects of the network include the use of internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to Cystic Fibrosis, and the development of infrastructure necessary for expediting protocol development. In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.     

Maintenance of the celiac trunk with the left-sided liver allograft for in situ split-liver transplantation

BACKGROUND: It has been shown that in situ split-liver transplantation (SLT) expands the cadaveric donor pool, decreases recipient waiting time, and decreases pretransplant morbidity. However, the technique as previously described requires a microvascular left hepatic artery anastomosis. In an attempt to decrease the incidence of hepatic artery thrombosis and to increase collaboration among transplant teams, in the current report, we describe a modification of the in situ SLT technique that maintains the celiac trunk with the left-sided liver allograft. METHODS: Twelve in situ split-liver procurements resulted in 24 segmental liver allografts; 11 right trisegments, 11 left lateral segments, 1 right lobe, and 1 left lobe. The common bile duct and main portal vein were maintained with the right-sided liver allograft in all cases. The right hepatic artery was divided, and the celiac trunk was maintained with the left-sided liver allograft in nine cases. In one case the left hepatic artery was divided and the celiac trunk was maintained with the right-sided allograft. Two of the 12 donors had a completely replaced left hepatic artery originating from the left gastric artery, which was divided at its origin from the celiac trunk. When the celiac trunk was maintained with the left-sided allografts, arterial reconstruction of the right-sided allograft was performed with an external iliac arterial interposition graft. Nineteen of the 24 split-liver allografts were transplanted at our center. The remaining five liver allografts were shared with regional liver transplant centers. RESULTS: In this series, 1-year actuarial patient and allograft survival rates are 100% and 96%, respectively. Hepatic artery thrombosis (HAT) did not occur in any patient receiving a left-sided split allograft in which the celiac trunk or left gastric artery was maintained; in addition, HAT did not occur in any of the right-sided allografts. HAT did occur immediately after transplantation in the one patient who was transplanted with a left lateral segment without the celiac trunk. This allograft was salvaged by early thrombectomy and interposition grafting. One patient required retransplantation, owing to portal vein thrombosis. Hepatic venous outflow obstruction did not occur in any of the patients. Two patients required reexploration in the posttransplant period because of arterial anastomotic site bleeding, and one of the left lateral segment allograft recipients had a cut-surface bile leak, which was managed nonoperatively. All of the patients are alive and well, including the five patients who received their transplants at other centers, with a median follow-up of 10 months (range, 1-27 months). CONCLUSIONS: In summary, our data demonstrate that maintaining the celiac trunk with the left-sided allograft in SLT provides excellent early survival results with low complication rates. This technical modification obviates the need for a left hepatic artery microvascular anastomosis and should lower the incidence of hepatic artery thrombosis in the small-caliber left hepatic artery. We have also shown that this technique allows sharing among liver transplant centers without compromise in patient or allograft survival rates. It is hoped that this modification in SLT will increase the number of livers split, and will promote sharing among transplant centers to truly optimize the number of liver allografts available from the cadaveric pool.     

Gender comparison of RPE at absolute and relative physiological criteria

PURPOSE: The effect of gender on ratings of perceived exertion for the overall body (RPE-O), chest (RPE-C), legs (RPE-L), and arms (RPE-A (ski)) was determined. METHODS: Comparisons were made at, a) absolute oxygen uptake (VO2, L x min(-1); mL x kg(-1) x min(-1)) and heart rate (HR, b x min(-1)) and b) relative VO2 (%VO2max/peak) and HR (% HRmax/peak) reference criteria. Nine male and 10 female subjects were compared using a perceptual estimation paradigm for treadmill (weight bearing), simulated ski (partial weight bearing), and cycle (nonweight bearing) exercise. RPE was determined by the Borg 15-category scale. RESULTS: For each exercise mode, RPE-O, RPE-L, RPE-A (ski), and RPE-C were higher (P < 0.05) in the female than male cohort when compared at submaximal absolute VO2 criteria. RPE did not differ between female and male cohorts when compared at mode specific relative VO2 criteria. Differences in RPE-O, RPE-L, RPE-A (ski), and RPE-C were not found between female and male subjects when comparisons were made at both absolute and relative HR. Responses were consistent for the three exercise modes. CONCLUSION: RPE did not differ between gender when comparisons were made at relativized VO2 and HR reference criteria at exercise intensities between 70 and 90% of mode specific maximal/peak values.     

Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration

Previous studies have demonstrated that either the neurotrophin glial-derived neurotrophic factor (GDNF) or the antiapoptotic peptide Bcl-2 delivered into striatum by a viral vector protects dopaminergic neurons of the substantia nigra in vivo from degeneration induced by the administration of the neurotoxin 6-hydroxydopamine (6-OHDA). In this study we used recombinant, replication-incompetent, genomic herpes simplex virus-based vectors to deliver the genes coding for Bcl-2 and GDNF into rat substantia nigra (SN) 1 week prior to 6-OHDA injection into the striatum. Vector-mediated expression of either Bcl-2 or GDNF alone each resulted in a doubling in cell survival as measured by retrograde labeling with fluorogold (FG) and a 50% increase in tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the lesioned SN compared to the unlesioned side. Gene transfer of Bcl-2 and GDNF were equivalent in this effect. Coadministration of the Bcl-2-expressing vector with the GDNF-expressing vector improved the survival of lesioned SN neurons as measured by FG labeling by 33% and by the expression of TH-IR by 15%. These results suggest that the two factors delivered together act in an additive fashion to improve DA cell survival in the face of 6-OHDA toxicity.     

Herpes simplex virus vector-mediated expression of Bcl-2 protects spinal motor neurons from degeneration following root avulsion

Proximal axotomy in adult animals results in delayed death of motor neurons. Features characteristic of both necrosis and apoptosis have been described in motor neurons of the spinal cord following proximal avulsion of the ventral roots. We have previously demonstrated that a genomic herpes simplex virus (HSV)-based vector expressing the anti-apoptotic peptide Bcl-2 protects dopaminergic neurons of the substantia nigra from neurotoxin-induced apoptotic cell death and preserves the neurotransmitter phenotype of those cells. In this study we examined whether the same vector could protect adult rat lumbar motor neurons from cell death following proximal ventral root avulsion. Injection of the Bcl-2-expressing vector 1 week prior to root avulsion increased the survival of lesioned motor neurons, determined by retrograde Fluorogold labeling, by 50%. The Bcl-2-expressing vector did not preserve choline acetyltransferase neurotransmitter phenotype of the lesioned cells. These results shed light on the mechanism of cell death following axonal injury, and have implications for developing an effective treatment for the clinical problem of proximal root avulsion.     

Survey of Australian and New Zealand Oral and Maxillofacial Surgery trainees and recent specialists--workforce issues

This study examined Oral and Maxillofacial Surgeon (OMS) workforce issues in relation to current training in Australia and New Zealand. Earlier findings identified that there was a requirement of approximately 6 additional OMS specialists per year in Australia and one per year in New Zealand to maintain an adequate level of supply in the profession. It was found in this study that through to the early part of the next decade the number of OMS entering the Australian workforce is appropriate (5.9 per annum), but there would appear to be concerns about the sufficiency of the number entering the New Zealand workforce (0.7 per annum). In addition, the study also found possible maldistribution in the location of intended future practices, with possible shortages outside of the metropolitan areas.