Maternal vitamin D, DNA methylation at imprint regulatory regions and offspring weight at birth, 1 year and 3 years.

BACKGROUND/OBJECTIVE: Vitamin D deficiency during pregnancy is associated with poor birth outcomes in some studies, but few have examined weight beyond birth. In addition, little is known about how vitamin D influences DNA methylation of regulatory regions known to be involved in growth, as possible mediators to weight status in offspring. SUBJECTS/METHODS: We conducted linear regressions to assess maternal plasma 25-hydroxyvitamin D (25(OH)D) by quartile and birth weight for gestational age z-score, 1-year weight-for-length z-score and 3-year body mass index (BMI) z-score among 476 mother/infant dyads from a prospective cohort. We assessed maternal 25(OH)D and infant DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes with known functions in fetal growth, including H19, IGF2, MEG3, MEG3-IG, MEST, NNAT, PEG3, PLAGL1 and SGCE/PEG10. RESULTS: Mean (standard deviation, s.d.) maternal 25(OH)D was 41.1 (14.2) nmol l-m at a mean (s.d.) of 13.2 (5.5) weeks gestation. After adjustment for potential confounders, the first (Q1) and second (Q2) quartiles of 25(OH)D, compared to the fourth (Q4), were associated with lower birth weight for gestational age z-scores (-0.43 units; CI: -0.79, -0.07; P=0.02 for Q1 and -0.56 units; CI: -0.89, -0.23; P=0.001 for Q2). Q1 compared to Q4 was associated with higher 1-year weight-for-length z-scores (0.78 units; 0.08, 1.54; P=0.04) and higher 3-year BMI z-scores (0.83 units; 0.11, 0.93; P=0.02). We did not observe associations between maternal 25(OH)D and methylation for any of the nine DMRs after correcting for multiple testing. CONCLUSIONS: Reduced maternal 25(OH)D was associated with lower birth weight for gestational age z-scores but higher 1-year weight-for-length and 3-year BMI z-scores in offspring. However, 25(OH)D does not appear to be operating through the regulatory sequences of the genomically imprinted genes we examined.

Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect?

INTRODUCTION: Although antifibrinolytic agents are used to prevent and treat hemorrhage, there are concerns about a potential increased risk for peripartum venous thromboembolism. We sought to determine the impact of tranexamic acid and ɛ-aminocaproic acid on in vitro clotting properties in pregnancy. METHODS: Blood samples were obtained from healthy pregnant, obese, and preeclamptic pregnant women (n = 10 in each group) prior to delivery as well as from healthy non-pregnant controls (n = 10). Maximum clot firmness (MCF) and clotting time (CT) were measured using rotation thromboelastometry in the presence of tranexamic acid (3, 30, or 300 µg/mL) or ɛ-aminocaproic acid (30, 300, or 3000 µg/mL). ANOVA and regression analyses were performed. RESULTS: Mean whole blood MCF was significantly higher in healthy pregnant vs. non-pregnant women (66.5 vs. 57.5 mm, p < 0.001). Among healthy pregnant women, there was no significant difference between mean MCF (whole blood alone, and with increasing tranexamic acid doses = 66.5, 66.1, 66.4, 66.3 mm, respectively; p = 0.25) or mean CT (409, 412, 420, 424 sec; p = 0.30) after addition of tranexamic acid. Similar results were found using ɛ-aminocaproic acid. Preeclamptic women had a higher mean MCF after the addition of ɛ-aminocaproic acid and tranexamic acid (p = 0.05 and p = 0.04, respectively) compared to whole blood alone. CONCLUSIONS: Pregnancy is a hypercoagulable state, as reflected by an increased MCF compared to non-pregnant women. Addition of antifibrinolytic therapy in vitro does not appear to increase MCF or CT for non-pregnant, pregnant, and obese women. Whether antifibrinolytics are safe in preeclampsia may require further study.

Intraoperative factors associated with stranded source placement accuracy in low-dose-rate prostate brachytherapy.

PURPOSE: The quality of a low-dose rate prostate brachytherapy implant depends on the accurate placement of sources in their planned locations. This study investigates intraoperative factors that potentially contribute to stranded source placement inaccuracy in prostate brachytherapy. METHODS AND MATERIALS: Intraoperative video images of the brachytherapist's hand motions and needle insertions during the implant procedure were acquired for analysis. Using video analysis software, maximum and average needle insertion velocities were determined. The number of needle insertion attempts and the use of the brachytherapist's other hand to manipulate the needle direction were also recorded. Sources misplacements were analyzed using an ultrasound-based method described elsewhere. RESULTS: Fifteen patients agreed to undergo this study; 1619 125I seeds were inserted using 357 needles; 1197 seeds were confidently identified using ultrasound images and included in the analysis. The mean overall misplacement was 0.49 cm (0-2 cm, 95% CI = 0.47-0.51); 614 seeds were delivered with a single pass and 583 seeds with >1 passes (range 2-6). The mean maximum needle velocity was 12.34 cm s-1 (range 4-28 cm s-1) and mean average velocity was 4.76 cm s-1 (range 0.4-17.4 cm s-1); 747 seeds were delivered with manipulation of the needle. The generalized linear model test was used to analyze factors contributing to seed misplacement, and it was found that a maximum speed <12 cm s-1 was associated with a decrease in seed misplacement by 0.049 cm vs. a maximum speed >12 cm s-1, p = 0.0121). Other evaluated factors were found to have no statistically significant correlation with seed misplacement: average speed (p = 0.4947), manual manipulation of needle (p = 0.9264), and number of needle passes (p = 0.8907). CONCLUSIONS: This study identified that needles inserted with lower maximum velocity were associated with less seed misplacement. Manual manipulation of the needle, number of passes, and average speed did not show statistically significant correlation with seed misplacement.

Obstetric hemorrhage survey: Attitudes and practices of maternal-fetal medicine fellows.

OBJECTIVE: To evaluate experiences related to obstetric hemorrhage and suspected abnormal placentation among first year maternal-fetal medicine fellows. STUDY DESIGN: A cross-sectional anonymous survey was administered at the Society for Maternal-Fetal Medicine fellow retreat in March 2013. Fellows were asked about management strategies that reflected both their individual and institutional practices. RESULTS: There was a 56% response rate (55/98). In cases of postpartum hemorrhage due to uterine atony, there was variable use of the uterine tamponade device. The median incremental time for balloon deflation was every 5 hours (IQR = 2-12). Compared to the east coast, fellows from the west coast performed more hysterectomies (mean±SD; 2.9±2.4 vs. 1.2±1.2, p = 0.004). During a peripartum hysterectomy, 29% of fellows used a handheld cautery device such as Ligasure® or Gyrus®. Fifty-six percent responded that their institution never recommend planned delayed hysterectomies for abnormal placental implantation. CONCLUSION: There is wide variation in practice among first year maternal-fetal medicine fellows in management of peripartum hysterectomy and postpartum hemorrhage.

Acute toxicity of hypofractionated intensity-modulated radiotherapy for prostate cancer.

BACKGROUND: Dose-escalated hypofractionated radiotherapy (hfrt) using intensity-modulated radiotherapy (imrt), with inclusion of the pelvic lymph nodes (plns), plus androgen suppression therapy (ast) in high-risk prostate cancer patients should improve patient outcomes, but acute toxicity could limit its feasibility. METHODS: Our single-centre phase ii prospective study enrolled 40 high-risk prostate cancer patients. All patients received hfrt using imrt with daily mega-voltage computed tomography imaging guidance, with 95% of planning target volumes (ptv68 and ptv50) receiving 68 Gy and 50 Gy (respectively) in 25 daily fractions. The boost volume was targeted to the involved plns and the prostate (minus the urethra plus 3 mm and minus 3 mm from adjacent rectal wall) and totalled up to 75 Gy in 25 fractions. Acute toxicity scores were recorded weekly during and 3 months after radiotherapy (rt) administration. RESULTS: For the 37 patients who completed rt and the 3-month follow-up, median age was 65.5 years (range: 50-76 years). Disease was organ-confined (T1c-T2c) in 23 patients (62.1%), and node-positive in 5 patients (13.5%). All patients received long-term ast. Maximum acute genitourinary (gu) and gastrointestinal (gi) toxicity peaked at grade 2 in 6 of 36 evaluated patients (16.6%) and in 4 of 31 evaluated patients (12.9%) respectively. Diarrhea and urinary frequency were the chief complaints. Dose-volume parameters demonstrated no correlation with toxicity. The ptv treatment objectives were met in 36 of the 37 patients. CONCLUSIONS: This hfrt dose-escalation trial in high-risk prostate cancer has demonstrated the feasibility of administering 75 Gy in 25 fractions with minimal acute gi and gu toxicities. Further follow-up will report late toxicities and outcomes.

Newborns of obese parents have altered DNA methylation patterns at imprinted genes.

BACKGROUND: Several epidemiologic studies have demonstrated associations between periconceptional environmental exposures and health status of the offspring in later life. Although these environmentally related effects have been attributed to epigenetic changes, such as DNA methylation shifts at imprinted genes, little is known about the potential effects of maternal and paternal preconceptional overnutrition or obesity. OBJECTIVE: We examined parental preconceptional obesity in relation to DNA methylation profiles at multiple human imprinted genes important in normal growth and development, such as: maternally expressed gene 3 (MEG3), mesoderm-specific transcript (MEST), paternally expressed gene 3 (PEG3), pleiomorphic adenoma gene-like 1 (PLAGL1), epsilon sarcoglycan and paternally expressed gene 10 (SGCE/PEG10) and neuronatin (NNAT). METHODS: We measured methylation percentages at the differentially methylated regions (DMRs) by bisulfite pyrosequencing in DNA extracted from umbilical cord blood leukocytes of 92 newborns. Preconceptional obesity, defined as BMI ⩾30 kg m(-2), was ascertained through standardized questionnaires. RESULTS: After adjusting for potential confounders and cluster effects, paternal obesity was significantly associated with lower methylation levels at the MEST (ß=-2.57; s.e.=0.95; P=0.008), PEG3 (ß=-1.71; s.e.=0.61; P=0.005) and NNAT (ß=-3.59; s.e.=1.76; P=0.04) DMRs. Changes related to maternal obesity detected at other loci were as follows: ß-coefficient was +2.58 (s.e.=1.00; P=0.01) at the PLAGL1 DMR and -3.42 (s.e.=1.69; P=0.04) at the MEG3 DMR. CONCLUSION: We found altered methylation outcomes at multiple imprint regulatory regions in children born to obese parents, compared with children born to non-obese parents. In spite of the small sample size, our data suggest a preconceptional influence of parental life-style or overnutrition on the (re)programming of imprint marks during gametogenesis and early development. More specifically, the significant and independent association between paternal obesity and the offspring's methylation status suggests the susceptibility of the developing sperm for environmental insults. The acquired imprint instability may be carried onto the next generation and increase the risk for chronic diseases in adulthood.

Midregional pro-adrenomedullin plasma concentrations are blunted in severe preeclampsia.

Levels of the peptide hormone adrenomedullin (AM) are elevated during normal pregnancy, but whether this differs during complications of pregnancy remains unresolved. AM can be quantified by measuring its pre-prohormone byproduct, midregional pro-adrenomedullin (MR-proADM). MR-proADM has shown prognostic value as a biomarker of heart failure, sepsis, and community-acquired pneumonia. Given the relevance of AM to pregnancy, we tested the hypothesis that MR-proADM provides a biomarker for preeclampsia. We find that MR-proADM plasma concentrations are blunted in severe preeclampsia and that MR-proADM is similarly effective as established biomarkers endoglin and placental growth factor at discriminating patients with severe preeclampsia from controls.

Progesterone receptor membrane component 1 (PGRMC1) expression in fetal membranes among women with preterm premature rupture of the membranes (PPROM).

PGRMC1 function is implicated in maintaining fetal membrane (FM) integrity. PGRMC1 was detectable primarily in the cytoplasm of FM cells and was actively regulated in FMs and relevant for PGRMC1-mediated progesterone action. By cell type, PGRMC1 expression was higher in amnion and chorion compared with decidua. By clinical phenotype, PGRMC1 expression was higher among preterm-no-labor and term-no-labor subjects compared to PPROM. PGRMC1 expression appears to be diminished in PPROM subjects.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring.

OBJECTIVES: Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations. METHODS: Between 2009-2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions. RESULTS: After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (ß-coefficient=-132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (ß-coefficient=-135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight. CONCLUSION: We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations.

Quality-of-life outcomes in high-risk prostate cancer patients treated with helical tomotherapy in a hypofractionated radiation schedule with long-term androgen suppression.

PURPOSE: We examined the impact of hypofractionated radiation therapy and androgen suppression therapy (AST) on quality of life (QOL) in high-risk prostate cancer patients. METHODS: Between March 2005 and March 2007, 60 patients with high-risk prostate cancer were enrolled in a prospective phase ii study. All patients received 68 Gy (2.72 Gy per fraction) to the prostate gland and 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes in 25 fractions over 5 weeks. Of the 60 patients, 58 received ast. The University of California-Los Angeles Prostate Cancer Index questionnaire was used to prospectively measure QOL at baseline (month 0) and at 1, 6, 12, 18, 24, 30, and 36 months after radiation treatment. The generalized estimating equation approach was used to compare the QOL scores at 1, 6, 12, 18, 24, 30, and 36 months with those at baseline. RESULTS: We observed a significant decrease in QOL items related to bowel and sexual function. Several QOL items related to bowel function were significantly adversely affected at both 1 and 6 months, with improvement toward 6 months. Although decreased QOL scores persisted beyond the 6-month mark, they began to re-approach baseline at the 18- to 24-month mark. Most sexual function items were significantly adversely affected at both 1 and 6 months, but the effects were not considered to be a problem by most patients. A complete return to baseline was not observed for either bowel or sexual function. Urinary function items remained largely unaffected, with overall urinary function being the only item adversely affected at 6 months, but not at 1 month. Urinary function returned to baseline and remained unimpaired from 18 months onwards. CONCLUSIONS: In our study population, who received hypofractionated radiation delivered using dynamic intensity-modulated radiotherapy with inclusion of the pelvic lymph nodes, and 2-3 years of ast prescription, QOL with respect to bowel and sexual function was significantly affected; QOL with respect to urinary function was largely unaffected. Our results are comparable to those in other published studies.

Cervical dilation as a predictor of pregnancy outcome following emergency cerclage.

OBJECTIVE: To determine whether cervical dilation at the time of physical examination indicated cerclage placement can predicts latency and gestational age at delivery. METHODS: A retrospective cohort study of all women who underwent physical examination indicated cerclage placement from 1996 to 2011 at Duke University Hospital (DUH) was performed. Physical examination indicated cerclage was defined as cerclage placement after 16 weeks in women with a cervical length of less than 2.5 cm and/or cervical dilation greater than or equal to 1 cm at time of procedure. Subjects were divided into two groups depending on cervical dilation at time of procedure (2 cm, <2 cm) for comparison. A multivariate linear regression model for the outcome gestational age of delivery was constructed, controlling for confounding variables. RESULTS: A total of 110 women with complete data were available for analysis. Median gestational age at cerclage placement was similar between the two groups (20.3 vs. 20.3 weeks, p = 0.8). Women with cervical dilatation ≥ 2 cm dilation delivered at an earlier median gestational age than women with cervical dilation <2 cm (27.0 vs. 35.6 weeks, p < 0.001). Cervical dilation at the time of cerclage placement independently predicted gestational age at delivery while controlling for use of intracervical Foley balloon catheter for membrane reduction, cerclage suture type, history of prior preterm birth, race, insurance status, and tobacco use. CONCLUSIONS: Women who receive a rescue cerclage are more likely to deliver at an earlier gestational age when cervical dilation is ≥ 2 cm at the time of procedure.

Bleeding per vaginam is associated with funisitis in women with preterm prelabour rupture of the fetal membranes.

OBJECTIVE: To evaluate the risk of funisitis among women with preterm prelabour rupture of the membranes (PPROM) and subsequent bleeding per vaginam. DESIGN: Prospective cohort study. SETTING: A University Hospital in the USA. POPULATION: A total of 157 women with PPROM, divided into those with bleeding per vaginam during the hospital admission (n = 46) and those without bleeding per vaginam (n = 111). METHODS: Pathologist blinded to bleeding status assessed placental pathology for funisitis. MAIN OUTCOME MEASURES: Funisitis. RESULTS: Women with bleeding per vaginam were more likely to have funisitis (67.4% versus 36%, P < 0.001) compared with those without bleeding. Logistic regression demonstrated that bleeding per vaginam predicted funisitis after controlling for gestational age at admission, latency period and gestational age at delivery. CONCLUSIONS: Among women with PPROM, those with bleeding per vaginam are more likely to have funisitis than those without bleeding per vaginam.

The effects of depression and use of antidepressive medicines during pregnancy on the methylation status of the IGF2 imprinted control regions in the offspring.

In utero exposures to environmental factors may result in persistent epigenetic modifications affecting normal development and susceptibility to chronic diseases in later life. We explored the relationship between exposure of the growing fetus to maternal depression or antidepressants and DNA methylation at two differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Aberrant DNA methylation at the IGF2 and neighboring H19 DMRs has been associated with deregulated IGF2 expression, childhood cancers and several chronic diseases during adulthood. Our study population is comprised of pregnant mothers and their newborns (n = 436), as part of the Newborn Epigenetics Study (NEST). A standardized questionnaire was completed and medical record data were abstracted to ascertain maternal depression and antidepressive drug use. DMR methylation levels in umbilical cord blood leukocytes were quantified using pyrosequencing. From the 436 newborns, laboratory data were obtained for 356 individuals at the IGF2 DMRs, and for 411 individuals at the H19 DMRs; about half of each group was African American or Caucasian. While overall no association between depression and methylation profiles was found, we observed a significant hypermethylation of the H19 DMRs in newborns of African American (n = 177) but not Caucasian (n = 168) mothers who reported the use of antidepressive drugs during pregnancy (ß = +6.89, p = 0.01). Of note, our data reveal a race-independent association between smoking during pregnancy and methylation at the IGF2 DMR (+3.05%, p = 0.01). In conclusion, our findings suggest a race-dependent response related to maternal use of antidepressants at one of the IGF2 DMRs in the offspring.

Poster - Thurs Eve-17: Stand alone software for deforming delivered dose distributions to account for daily anatomical variations in prostate patients treated on the TomoTherapy Hi-Art II system.

The acquisition of daily megavoltage (MV)-CT images provides an invaluable tool in the delivery of adaptive radiotherapy (ART) on the TomoTherapy Hi-ART II system. Using TomoTherapy's Planned Adaptive software, delivery sinograms can be applied to pre-treatment MVCT images to generate daily delivered dose distributions, allowing for the potential comparison of planned and delivered doses. However, daily patient anatomical variations complicate the task and accurate comparison requires that daily doses be evaluated in the same references frame as the planned dose. Each anatomical point in daily MVCT images must be mapped to its corresponding point in the patient planning CT and that deformation map must be applied to the daily dose distribution. Stand alone software has been developed for the comparison of planned and delivered doses for TomoTherapy prostate patients. Software inputs are the planning CT, planning structure data, planned dose distribution, daily MVCT and delivered dose distribution. The software uses an in-house developed automatic voxel-based deformable registration algorithm designed and optimized specifically for the registration of prostate CT images to achieve anatomical correspondence between MVCT and planning images. The resultant deformation map is applied to the daily dose distribution and the software outputs the deformed daily dose distribution in the planning CT's reference frame, as well as a delivered DVH for each of the planning CT's ROI. The software allows for a number of potential research opportunities, in particular, the calculation of the cumulative dose delivered over the course of treatment for prostate patients treated on the Hi-Art II system.

Prognostic significance of serial magnetic resonance spectroscopies over the course of radiation therapy for patients with malignant glioma.

BACKGROUND: The standard treatment of high grade gliomas (HGG) involves maximal neuro-surgical debulking, followed by post-operative radiotherapy, with or without concurrent chemotherapy, depending on histologic grade. Despite this aggressive strategy, there are few long-term survivors. Proton magnetic resonance spectroscopy (MRS) is a non-invasive imaging method that can monitor metabolic changes in brain tumours. To date there is little data concerning the prognostic significance of the evolving spectral alterations during a course of radiotherapy. MATERIALS: We report herein a prospective study of patients with HGGs undergoing post-operative radiotherapy. Fourteen consecutively eligible patients with a confirmed histologic diagnosis of malignant glioma and completion of all required MRS imaging were included in this study. All patients had MRS imaging prior to radiotherapy, at week 4 of radiotherapy, and 2 months post-treatment. T1 and T2 weighted images as well as post-gadolinium multi-voxel proton MRS images were obtained. Normalized (tumour metabolite/normal brain metabolite) levels of choline, NAA, creatine, lipid and lactate were calculated. Kaplan-Meier (KM) curves of progression-free and overall survival were constructed based on the evolving patterns of metabolite changes over the course of the images. RESULTS: The mean tumour choline/NAA ratio decreased over the course of therapy, with a reduction observed between the baseline and post-radiotherapy studies (1.91 vs. 1.29, P=0.049). A similar decrease was identified with the mean normalized choline ratio, with a highly significant difference observed between the baseline and post-radiation images (1.61 vs. 0.96, P=0.001). Patients who exhibited more than 40% decrease in normalized choline between the week 4 and post-radiotherapy studies were associated with unfavourable survival (logrank test, P=0.003) and disease progression (logrank test, P=0.012). The Lactate/NAA ratio at the 4th week of radiotherapy and the change in normalized choline/creatine between baseline and week 4 of radiotherapy were also predictive of outcome suggesting the possibility of adaptive, response-based radiation treatment. Patients with two or more poor prognostic MRS indices had a significantly shorter progression-free survival compared with those with zero or one poor indices, with 15% and 68% at 1 year, respectively (logrank test, P=0.045). CONCLUSION: The evolving pattern of spectral changes over the course of radiotherapy, in particular those associated with choline-containing compounds, appears to be prognostic of tumour response and outcome. Based on our data, a decision point may exist in the mid course of radical radiotherapy, at which time consideration of the choline levels could indicate the extent of radiotherapeutic response, thus allowing for individualized treatment modification.

A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma.

PURPOSE: To determine the response rate, time to disease progression, survival, and toxicity of intravenous carboplatin and chronic oral high-dose tamoxifen in patients with recurrent malignant gliomas. PATIENTS AND METHODS: Patients with histological confirmation of recurrent malignant gliomas were eligible for this multicenter phase II trial. Treatment consisted of 400 mg/m2 carboplatin intravenously every 4 weeks and oral high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men). RESULTS: Twenty seven patients met the eligibility criteria and were evaluable for response. The histological subtypes were: 16 (59%) glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient). Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No complete responses were observed, 4 patients (15%) achieved a partial response, and 14 patients (52%) had stable disease. Median time to progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was 14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a sustained partial response and is progression free 81 months since starting treatment. Another patient with mixed malignant oligoastrocytoma also had a prolonged partial response (lasting 63 months) and is alive 84 months after treatment for recurrence. The most frequently reported grade 3 or 4 toxicities were fatigue (19%), nausea (11%) and anorexia (11%). CONCLUSIONS: Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. Long-lasting periods of disease free survival in some patients (particularly those with malignant mixed oligo astrocytomas) were found.

Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.

PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.

Apoptosis in the chorion laeve of term patients with histologic chorioamnionitis.

OBJECTIVE: The balance between cell survival and cell death (apoptosis) is critical during development and may affect organ function. Apoptosis is accelerated in the presence of infection and inflammation in a variety of organ systems. The objective of this investigation was to determine if apoptosis was increased in the chorion laeve of term patients with and without histologic chorioamnionitis. METHODS: Records of placental pathology were reviewed with respect to the presence/absence of histologic chorioamnionitis. Sections from formalin-fixed, paraffin-embedded fetal membrane rolls were stained using the TUNEL method. The proportion of apoptotic nuclei was calculated in seven high-powered fields/section. Those with and without histologic chorioamnionitis were compared. Data were analyzed using the Mann-Whitney U test, with significance defined as p < 0.05. RESULTS: There was no significant difference in demographic or clinical characteristics between the two groups. The chorion laeve from subjects with histologic chorioamnionitis had significantly more apoptotic nuclei when compared to those without chorioamnionitis (11.2% vs. 5%, p = 0.02). CONCLUSION: Apoptosis is more prevalent in the chorion laeve of fetal membranes with histologic chorioamnionitis. This finding suggests that infection/inflammation may impact cell survival within fetal membranes. The implications of these findings warrant further investigation.

Muscle-invasive transitional cell carcinoma of the urinary bladder: a population-based study of patterns of care and prognostic factors.

PURPOSE: Population-based cancer registries can permit the study of the survivorship of all patients with a particular diagnosis regardless of patterns of referral and practice within a specific geographic distribution. The purpose of this study is to describe the patterns of care, outcome, and prognostic factors for bladder cancer in the northern region of the province of Alberta, Canada, between 1984 and 1993. METHODS AND MATERIALS: Between 1984 and 1993, 184 patients from northern Alberta were identified from the Alberta Cancer Registry as having undergone curative treatment for biopsy-proven muscle-invasive transitional cell carcinoma of the bladder. Data were obtained, by retrospective chart review, regarding the staging, pathology, treatment, and outcome of patients treated in the northern Alberta cities of Edmonton, Grande Prairie, and Red Deer, regardless of the responsible treating institution. The prognostic significance of patient-, tumor-, and treatment-related variables were tested using univariate and multivariate analysis using the Cox proportional-hazard model. RESULTS: As the primary treatment modality, 74 patients (40%) received radical radiotherapy (RT) without surgery; surgery was used alone in 81 patients (44%), and was combined with preoperative or postoperative radiotherapy in 29 patients (16%). Seventy-three (40%) patients also received concurrent, neoadjuvant, or adjuvant chemotherapy. The Kaplan-Meier estimate of median survival was 2.2 years, and the 5-year overall survival was 30%. Univariate analysis demonstrated the prognostic significance of T classification (p < 0.001), lymph node involvement (p < 0.001), complete response to RT (p = 0.001), hydronephrosis (p = 0.017), and vascular/lymphatic involvement (p = 0.035). Multivariate analysis revealed the following to have a significant association with survival: T classification (p = 0.001), lymph node involvement (p = 0.004), complete response to RT (p = 0.054), hydronephrosis (p = 0.019), and use of chemotherapy in the treatment regimen (p = 0.025). CONCLUSION: The strongest prognostic factors in this study were tumor related, and no significant differences in survival were detected between patients treated with primary surgery vs. organ-preservation approaches. A survival advantage associated with the incorporation of chemotherapy into the management schema was detected on multivariate, but not univariate, analysis. Stratification of patients based on tumor characteristics is imperative in clinical trials for invasive bladder cancer. Novel treatment approaches are required to improve survival further in patients with apparently localized disease.