Cheryl C. Saenz

Effect of predelivery diagnosis in 99 consecutive cases of placenta accreta.

OBJECTIVE: To estimate the effects of prenatal diagnosis and delivery planning on outcomes in patients with placenta accreta. METHODS: A review was performed of all patients with pathologically confirmed placenta accreta at the University of California, San Diego Medical Center from January 1990 to April 2008. Cases were divided into those with and without predelivery diagnosis of placenta accreta. Patients with prenatal diagnosis of placenta accreta were scheduled for planned en bloc hysterectomy without removal of the placenta at 34–35 weeks of gestation after betamethasone administration. Maternal and neonatal outcomes were assessed. RESULTS: Ninety-nine women with placenta accreta were identified, of whom 62 were diagnosed before delivery and 37 were diagnosed intrapartum. Comparing women with predelivery diagnosis with those diagnosed at the time of delivery, there were fewer units of packed red blood cells transfused (4.7±2.2 compared with 6.9±1.8 units, P=.02) and a lower estimated blood loss (2,344±1.7 compared with 2,951±1.8 mL, P=.053), although this trend did not reach statistical significance. Comparison of neonatal outcomes demonstrated a higher rate of steroid administration (65% compared with 16%, P≤.001), neonatal admission to the neonatal intensive care unit (NICU) (86% compared with 60%, P=.005), and longer neonatal hospital stays (10.7±1.9 compared with 6.9±2.1 days, P=.006). Length of NICU stay, rates of respiratory distress syndrome, and surfactant administration did not differ between the groups. CONCLUSION: Predelivery diagnosis of placenta accreta is associated with decreased maternal hemorrhagic morbidity. Planned delivery at 34–35 weeks of gestation in this cohort did not significantly increase neonatal morbidity. LEVEL OF EVIDENCE: II

Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide.

Advanced-stage peritoneal carcinomatosis is resistant to current chemotherapy treatment and, in the case of metastatic ovarian cancer, results in a devastating 15%–20% survival rate. Therapeutics that restore genes inactivated during oncogenesis are predicted to be more potent and specific than current therapies. Experiments with viral vectors have demonstrated the theoretical utility of expressing the p53 tumor suppressor gene in cancer cells. However, clinically useful alternative approaches for introducing p53 activity into cancer cells are clearly needed. It has been hypothesized that direct reactivation of endogenous p53 protein in cancer cells will be therapeutically beneficial, but few tests of this hypothesis have been carried out in vivo. We report that a transducible D-isomer RI-TATp53C′ peptide activates the p53 protein in cancer cells, but not normal cells. RI-TATp53C′ peptide treatment of preclinical terminal peritoneal carcinomatosis and peritoneal lymphoma models results in significant increases in lifespan (greater than 6-fold) and the generation of disease-free animals. These proof-of-concept observations show that specific activation of endogenous p53 activity by a macromolecular agent is therapeutically effective in preclinical models of terminal human malignancy. Our results suggest that TAT-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to malignant cells in vivo.

Cardiovascular disease is the leading cause of death among endometrial cancer patients

OBJECTIVE To evaluate the causes of death among women with endometrial cancer. METHODS SEER registries from 1973-1988 were queried to perform a retrospective cohort study of women with invasive epithelial endometrial cancer. Causes of death were compared according to grade and stage. RESULTS 33,232 women with incident cases of endometrial cancer had died at the time of last follow up. Overall, women were most likely to die from cardiovascular disease (35.9%, 95% CI 35.3-36.3%), followed by other causes, other malignancies, and endometrial cancer. Women with low grade localized cancer were most likely to die of cardiovascular disease, while women with high grade advanced cancer were least likely to die of cardiovascular disease and most likely to die of endometrial cancer. For the entire population, risk of death from cardiovascular causes surpasses the risk of death from endometrial cancer 5 years after diagnosis. CONCLUSIONS Higher risk of cardiac death among endometrial cancer patients likely reflects the high probability of curative cancer treatment and the prevalence of cardiac disease and risk factors. As the probability of dying of endometrial cancer decreases with time, the probability of dying of cardiovascular disease increases. Interventions and investigations aimed at addressing risk factors for cardiovascular disease may have the greatest potential to improve survival for women diagnosed with endometrial cancer and should feature prominently in treatment and survivorship plans.

Relocalized p27Kip1 Tumor Suppressor Functions as a Cytoplasmic Metastatic Oncogene in Melanoma

The p27 tumor suppressor negatively regulates G1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membrane-confined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non-cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss.

Prospective Study of Functional Bone Marrow-Sparing Intensity Modulated Radiation Therapy With Concurrent Chemotherapy for Pelvic Malignancies

PURPOSE To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). METHODS AND MATERIALS We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. RESULTS In gynecologic cancer patients, the mean functional BM V(10) (volume receiving ≥10 Gy) and V(20) (volume receiving ≥20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. CONCLUSIONS IMRT can reduce dose to BM subregions identified by (18)F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial.

Evaluation of intra- and inter-fraction movement of the cervix during intensity modulated radiation therapy

BACKGROUND AND PURPOSE To assess the degree of intra- and inter-fraction cervical motion throughout a course of intensity modulated radiation therapy (IMRT) for cervical cancer patients. MATERIALS AND METHODS A retrospective study of 10 women with stage 1B1-3B cervical cancer diagnosed from September 2007 to July 2008 was conducted. All patients were treated with chemoradiation using IMRT followed by intracavitary brachytherapy. Pretreatment, patients had 2 seeds placed at a depth of 10mm into the cervix. On-Board Imaging (OBI) was used to obtain anterior/posterior (AP) and lateral X-rays before and after each treatment. OBI images were rigidly aligned to baseline digitally reconstructed radiographs (DRRs), and movement of cervical seeds was determined in the lateral, vertical, and AP directions. Mean differences in cervical seed position and standard error of the mean (SEM) were calculated. RESULTS A total of 922 images were reviewed, with approximately 90 images per patient. The mean intra-fractional movement in cervical seed position in the lateral, vertical, and AP directions were 1.6mm (SD±2.0), 2.6mm (SD±2.4), and 2.9mm (SD±2.7), respectively, with a range from 0 to 15mm for each direction. The mean inter-fractional movement in the lateral, vertical, and AP directions were 1.9mm (SD±1.9), 4.1mm (SD±3.2), and 4.2mm (SD±3.5), respectively, with a range from 0 to 18mm for each direction. CONCLUSIONS This is the first study to assess intra- and inter-fractional movement of the cervix using daily imaging before and after each fraction. Within and between radiation treatments, cervical motion averages approximately 3mm in any given direction. However, maximal movement of the cervix can be as far as 18mm from baseline. This wide range of motion needs to be accounted for when generating planning treatment volumes.

High Vegetable and Fruit Diet Intervention in Premenopausal Women with Cervical Intraepithelial Neoplasia

OBJECTIVE To examine whether diet intervention can promote increased vegetable and fruit intake, as reflected in increased plasma carotenoid and decreased plasma total homocysteine concentrations, in premenopausal women with cervical intraepithelial neoplasia, a precancerous condition. DESIGN Randomized controlled diet intervention study. SUBJECTS Fifty-three free-living premenopausal women who had been diagnosed with cervical intraepithelial neoplasia, were randomly assigned to an intervention (n = 27) or a control (n = 26) group. INTERVENTION Individualized dietary counseling to increase vegetable and fruit intake. MAIN OUTCOME MEASURES Diet was assessed by food frequency questionnaire. Plasma carotenoids and total homocysteine were measured at enrollment and at 6 months follow up. ANALYSIS Associations between baseline plasma concentrations of carotenoids and homocysteine and influencing factors were examined with multiple regression analysis. Repeated measures analysis of variance was used to test for group by time effects in these plasma concentrations. Plasma carotenoids at baseline and 6 months in the study groups, and differences in homocysteine concentrations from baseline to 6 months, were compared with independent sample t tests. RESULTS Repeated measures analysis of variance showed significant group by time effects (P<.01) in plasma carotenoid and homocysteine concentrations. In the intervention group, total plasma carotenoids increased by an average of 91%, from 2.04+/-0.13 (mean+/-standard error of the mean) to 3.90+/-0.56 micromol/L and plasma total homocysteine was reduced by 11%, from 9.01+/-0.40 to 8.10+/-0.44 micromol/L (P<.003). Neither changed significantly in the control group. APPLICATIONS Individualized dietary counseling can effectively promote increased vegetable and fruit intake in premenopausal women. This dietary pattern may reduce risk for cancer and other chronic diseases and also promote an improvement in folate status.

Preoperative intravascular balloon catheters and surgical outcomes in pregnancies complicated by placenta accreta: a management paradox

OBJECTIVE The objective of the study was to compare outcomes between patients who did and did not receive preoperative uterine artery balloon catheters in the setting placenta accreta. STUDY DESIGN This was a retrospective case-control study of patients with placenta accreta from 1990 to 2011. RESULTS Records from 117 patients with pathology-proven accreta were reviewed. Fifty-nine patients (50.4%) had uterine artery balloons (UABs) placed preoperatively. The mean estimated blood loss (EBL) was lower (2165 mL vs 2837 mL; P = .02) for the group that had UABs compared with the group that did not. There were more cases with an EBL greater than 2500 mL and massive transfusions of packed red blood cells (>6 units) in the group that did not have UABs. Percreta was diagnosed more often on final pathology in the group with UABs. Surgical times did not differ between the 2 groups. Two patients (3.3%) had complications related to the UABs. CONCLUSION Preoperative placement of UABs is relatively safe and is associated with a reduced EBL and fewer massive transfusions compared with a group without UABs.

Comparison of computed tomography and magnetic resonance imaging in cervical cancer brachytherapy target and normal tissue contouring.

Objective: To evaluate the differences between target and normal tissue delineation between magnetic resonance imaging (MRI) and computed tomography (CT) in cervical cancer patients and to explore the differences in dosimetry after brachytherapy planning. Methods: High-dose-rate brachytherapy was performed on 11 patients. Planning CT and MRI were performed with tandem and ring in place. The radiation oncologist contoured the rectum, the bladder, the sigmoid, and the high-risk clinical target volume (HR-CTV) on CT and MRI. The values compared between CT and MRI included D90 and D100 to HR-CTV; coronal, sagittal, and axial measurements of HR-CTV; and minimum dose to most irradiated 0.1-, 0.5-, 1.0-, and 2.0-cm3volumes for the organs at risk (OAR). Doses were converted to the equivalent dose in 2 Gy by applying the linear quadratic model. Volume optimization was also performed, and the above parameters were evaluated. Results: Magnetic resonance imaging showed a significantly greater HR-CTV length in the sagittal plane (P = 0.006), with CT showing a greater length in the coronal plane (P = 0.004). The equivalent dose in 2 Gy to 2.0 cm3 for the bladder was greater on CT than MRI (P = 0.041). The remainder of the dose volume histogram values for the OAR were similar between CT and MRI. With volume optimization, no significant differences were seen between HR-CTV dose parameters or doses to OAR. Conclusions: The CT- and MRI-based brachytherapy tissue delineation seems adequate for evaluation of OAR and target tissues, although the shapes of HR-CTV and OAR do differ. When adopting volume-based prescription, these differences may lead to altered target dosing. The clinical impact of these differences seems to be small and may demonstrate that planning with CT, if combined with one MRI, may be sufficient.

Bariatric surgery decreases the risk of uterine malignancy.

OBJECTIVE To describe the risk of uterine malignancy among women who have had weight loss surgery. METHODS We performed a retrospective cohort study among inpatient admissions of women 18years, or older, registered in the University HealthSystem Consortium (UHC) dataset. The rate of uterine malignancy per hospital admission was calculated. Rates were compared according to whether diagnoses at the time of discharge included history of bariatric surgery, and further, according to whether there was a diagnosis of obesity. RESULTS In admissions of patients who did not have a history of prior bariatric surgery, the rate of uterine malignancy was 599/100,000 (95% CI 590 to 610). Among obese women who had not previously undergone bariatric operations, the rate was 1409/100,000 (95% CI 1380 to 1440). Of women admitted who had a history of bariatric surgery, the rate of uterine malignancy was 408/100,000 (95% CI 370 to 450). The relative risk of uterine malignancy in all admissions for women who had prior bariatric surgery, compared to obese women who had not had bariatric surgery, was 0.29 (95% CI 0.26-0.32). Among women who had bariatric surgery and were not currently obese, the relative risk of uterine malignancy was 0.19 (95% CI 0.17-0.22) compared to obese women who had not undergone bariatric surgery. CONCLUSION A history of bariatric surgery is associated with a 71% reduced risk for uterine malignancy overall, and an 81% reduced risk if normal weight is maintained after surgery. This finding suggests that obesity may be a modifiable risk factor related to development of endometrial cancer.