Laila Dahmoush

Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes : a comparative study

OBJECTIVE To determine pharmacokinetic and endometrial effects of vaginally delivered micronized P. DESIGN Functionally agonadal estrogen-replacement recipients received either micronized P administered vaginally or bi-daily IM injections of P. Hourly blood samples were obtained, from baseline to 6 hours after the initial dose of P and again on simulated cycle day 21 when transvaginal ultrasound (US) measurements and tissue samples of the endometrium were performed. Blood and tissue samples were assayed for P. Endometrial histology, estrogen receptor (ER) and P receptor (PR) contents were evaluated. SETTING University of Southern California School of Medicine, Los Angeles, California. PARTICIPANTS Twenty functionally agonadal and four normally ovulating women. MAIN OUTCOME MEASURE Delivery differences were assessed by [1] endometrial P concentrations; [2] USs; [3] histologic datings; [4] ER and PR contents, and [5] serum P levels. RESULTS Endometrial P concentrations were higher with vaginally administered P than endometrial concentrations observed in normal ovulatory women or women who consistently had the highest serum P after IM administration (11.50 +/- 2.60 versus 1.40 +/- 0.40 versus 0.30 +/- 0.10 ng/mg protein [36.56 +/- 8.27 versus 4.45 +/- 1.27 versus 0.95 +/- 0.32 nmol/L], respectively). After 7 days of P, no differences between either treatment regimen and control groups were detected by histologic, ultrasonographic, or immunocytochemical receptor analyses. CONCLUSION Vaginal micronized P enhances P delivery to the uterus compared with a standard IM regimen and results in a synchronous secretory endometrial histology in agonadal women preparing for embryo donation.

Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients

Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (β=-0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: β=-0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer.

Social Influences on Clinical Outcomes of Patients With Ovarian Cancer

PURPOSE Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance. PATIENTS AND METHODS Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records. RESULTS In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates. CONCLUSION Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.

Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: Relationships with depression, fatigue, and disability

Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at 6 months, and at 1 year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At 6 months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at 1 year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by 1 year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients.

The prevalence of renal cell carcinoma diagnosed at autopsy.

To compare the rate of renal cell carcinoma (RCC) detected only at autopsy, from two periods, to determine if the apparent recent increase in RCC in the USA is a true increase or mainly a result of improved imaging techniques, as a true increase in the clinical incidence of RCC should not affect the number of previously undiscovered RCC found only at autopsy.

Evaluating the effect of age on endometrial responsiveness to hormone replacement therapy: A histologic ultrasonographic, and tissue receptor analysis

ObjectiveOur objective was to characterize the endometria of women of various ages placed on similar estrogen/progesterone replacement regimens prior to attempted donor embryo transfer using histologic, ultrasonographic, and steroid receptor markers in order to determine if advancing age has a detrimental effect on uterine responsiveness to pharmacologic sex steroid replacement therapy.Study DesignThis was a prospective open clinical trial. Functionally agonadal women aged 25 to 60 years receiving hormone replacement therapy underwent transvaginal ultrasound examination of the uterus followed by a timed endometrial biopsy on artificial cycle day 21. Endometrial histology and estrogen and progesterone receptors were analyzed from biopsy material. Subjects were assigned to three groups according to age: Group I, aged 25 to 39 years (n =48); Group II, aged 40 to 49 years (n =61); and Group III, aged 50 to 60 years (n =13). Endometrial preparation was accomplished in all patients using the same sequential regimen consisting of oral micronized estradiol and intramuscular progesterone.ResultsSimilar histologic, ultrasonographic, and steroid receptor characteristics were noted in all groups of patients regardless of age. A normal appearing midluteal secretory endometrium was demonstrated histologically in 85% of biopsies. However, 15% of biopsies exhibited intraluminal papillary excrescences within the glands and/or an increase in the normal gland-to-stroma ratio. Three patients, one from each group, did not initially respond to replacement therapy and required further treatment.ConclusionFunctionally agonadal women exhibit normal or near-normal endometrial responses to sex steroid replacement therapy designed to imitate the natural cycle through the sixth decade of life.

Sleep disturbance, distress, and quality of life in ovarian cancer patients during the first year after diagnosis

Sleep disturbance is a common clinical complaint of oncology patients and contributes to substantial morbidity. However, because most sleep studies have been cross‐sectional, associations between sleep quality and distress in patients with ovarian cancer over time remain unclear. This prospective longitudinal study examined rates of sleep disturbance; contributions of depression, anxiety, and medication use in sleep disturbance; and associations between sleep quality and quality of life (QOL) during the first year after diagnosis among women with ovarian cancer.

Diurnal cortisol and survival in epithelial ovarian cancer

Introduction Hypothalamic-pituitary-adrenal (HPA) deregulation is commonly observed in cancer patients, but its clinical significance is not well understood. We prospectively examined the association between HPA activity, tumor-associated inflammation, and survival in ovarian cancer patients prior to treatment. Materials and Methods Participants were 113 women with ovarian cancer who provided salivary cortisol for three days prior to treatment for calculation of cortisol slope, variability, and night cortisol. Cox proportional hazard regression analyses were used to examine associations between cortisol and survival in models adjusting for disease stage, tumor grade, cytoreduction and age. On a subsample of 41 patients with advanced disease ascites fluid was assayed for levels of interleukin-6 (IL-6) and correlated with cortisol variables. Results Each cortisol measure was associated with decreased survival time, adjusting for covariates (all p<.041). A one standard deviation increase in night cortisol was associated with a 46% greater likelihood of death. Patients in the high night cortisol group survived an estimated average of 3.3 years compared to 7.3 years for those in the low night cortisol group. Elevated ascites IL-6 was associated with each cortisol measure (all r >.36, all p<.017). Discussion Abnormal cortisol rhythms assessed prior to treatment are associated with decreased survival in ovarian cancer and increased inflammation in the vicinity of the tumor. HPA abnormalities may reflect poor endogenous control of inflammation, dysregulation caused by tumor-associated inflammation, broad circadian disruption, or some combination of these factors. Nocturnal cortisol may have utility as a non-invasive measure of HPA function and/or disease severity.

Mitotic activity and apoptosis in endocervical glandular lesions.

To evaluate the significance of mitotic activity and apoptosis in the differential diagnosis of endocervical glandular lesions, we examined the frequency of mitoses and apoptosis in 89 endocervical glandular lesions from 78 patients, which consisted of benign reactive changes (7 cases), lobular or diffuse laminar endocervical glandular hyperplasia (4), microglandular hyperplasia (3), tunnel clusters (7), nabothian cysts (2), mesonephric remnants (3), tubal metaplasia (3), endocervical glandular dysplasias (including atypical tubal metaplasia) (EGD) (7), adenocarcinoma in situ (AIS) (31), microinvasive adenocarcinoma (7), frankly invasive adenocarcinoma (12), and minimal deviation adenocarcinoma (3). Mitotic index (MI; mitotic figures per 1000 cells) was significantly higher in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma than any other lesions examined. Microinvasive adenocarcinoma showed the highest MI. Apoptosis was detected consistently and frequently in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma. AIS showed the highest apoptotic index (AI; apoptoses per 1000 cells). Frequent apoptotic bodies and mitotic figures are a common feature of endocervical glandular malignancies (except for minimal deviation adenocarcinoma) and are an important feature that can facilitate their differentiation from benign and borderline lesions. High MI in microinvasive adenocarcinoma might aid the distinction of microinvasive adenocarcinoma from AIS. Although both MI and AI of EGD were between those of benign reactive changes and of AIS, MI and AI alone are not sufficient to differentiate EGD from benign reactive changes. MI and AI are not helpful in the differential diagnosis between minimal deviation adenocarcinoma and its benign mimics.

Symposium Part 3: Should Pathologists Diagnose Endocervical Preneoplastic Lesions “less Than” Adenocarcinoma in Situ ?: Point

The insufficient state of knowledge concerning the biology of endocervical glandular lesions is compounded by the lack of universal diagnostic criteria for recognizing endocervical glandular dysplasia. This study addressed the issue of diagnostic reproducibility of noninvasive endocervical glandular lesions and tested the proposed new scoring scheme designed to improve this reproducibility. We have shown that the application of this scheme has significantly improved interobserver agreement in all diagnostic categories. Moreover, the results of this study lend support to the recommendation not to diagnose endocervical glandular dysplasia in the clinical setting, although this category can be still reliably separated out for research purposes. Application of our scoring scheme will bring uniformity to the diagnosis of noninvasive endocervical glandular lesions and allow the study of a precursor to endocervical adenocarcinoma in situ.