Use of aromatase inhibitors in menopausal deep endometriosis: a case report and literature review.

We report and review the clinical effectiveness of aromatase inhibitors in a patient with refractory, recurrent and infiltrating endometriosis. We demonstrate excellent clinical, radiological and endoscopic responses after failure of multiple other modalities. Our case and the literature show that single-agent letrozole is capable to treat deep infiltrative endometriosis involving the rectum and the urinary tract. The use of aromatase inhibitor treatment of endometriosis in postmenopausal women makes sense, is safe and is well tolerated. Difficult cases of deep infiltrative endometriosis might require use of combined surgical and medical treatment modalities. Multidisciplinary involvement of the gynecologist, bowel surgeon, urologist and invasive radiologist might be needed. Aromatase inhibitors should be considered to be an integral part of the armamentarium in the management of women with endometriosis, especially in refractory cases that have failed conventional therapeutic modalities.

Characterization of the endometrial, cervicovaginal and anorectal microbiota in post-menopausal women with endometrioid and serous endometrial cancers.

OBJECTIVE: To characterize the microbiota of postmenopausal women undergoing hysterectomy for endometrioid (EAC) or uterine serous cancers (USC) compared to controls with non-malignant conditions. METHODS: Endometrial, cervicovaginal and anorectal microbial swabs were obtained from 35 postmenopausal women (10 controls, 14 EAC and 11 USC) undergoing hysterectomy. Extracted DNA was PCR amplified using barcoded 16S rRNA gene V4 primers. Sequenced libraries were processed using QIIME2. Phyloseq was used to calculate α- and ß- diversity measures. Biomarkers associated with case status were identified using ANCOM after adjustment for patient age, race and BMI. PICRUSt was used to identify microbial pathways associated with case status. RESULTS: Beta-diversity of microbial communities across each niche was significantly different (R2 = 0.25, p < 0.001). Alpha-diversity of the uterine microbiome was reduced in USC (Chao1, p = 0.004 and Fisher, p = 0.007) compared to EAC. Biomarkers from the three anatomical sites allowed samples to be clustered into two distinct clades that distinguished controls from USC cases (p = 0.042). The USC group was defined by 13 bacterial taxa across the three sites (W-stat>10, FDR<0.05) including depletion of cervicovaginal Lactobacillus and elevation of uterine Pseudomonas. PICRUSTt analysis revealed highly significant differences between the USC-associated clades within the cervicovaginal and uterine microbiota. CONCLUSIONS: The microbial diversity of anatomic niches in postmenopausal women with EAC and USC is different compared to controls. Multiple bacteria are associated with USC case status including elevated levels of cervicovaginal Lactobacillus, depletion of uterine Pseudomonas, and substantially different functional potentials identified within cervicovaginal and uterine niches.

Low molecular weight serum cell-free DNA concentration is associated with clinicopathologic indices of poor prognosis in women with uterine cancer.

BACKGROUND: Serum cell-free DNA (cfDNA) holds promise as a non-invasive cancer biomarker. The objective of this study was to evaluate the association of cfDNA concentration with clinicopathologic variables of poor prognosis and overall survival among women with uterine cancer compared to benign cancer-free controls. METHODS: cfDNA was extracted from the serum of 91 women with multiple uterine cancer histologies and 22 post-menopausal controls without cancer. Low molecular weight (LMW) cfDNA was separated from contaminating genomic high molecular weight cfDNA using paramagnetic bead purification and its concentration was measured using fluorometric quantification. Clinicopathologic data was abstracted from the electronic medical record. The association between serum cfDNA concentration, clinicopathologic variables, and overall survival was assessed using linear regression modelling, Cox proportional hazards modelling, and the Kaplan-Meier method. RESULTS: Median total serum cfDNA concentration for the cohort was 69.2 ng/mL (IQR 37.4, 132.3) and median LMW cfDNA concentration was 23.8 ng/mL (IQR 14.9, 44.4). There were no significant differences in total serum cfDNA concentration with any clinicopathologic variables. However, LMW cfDNA concentration was significantly higher in serum of women with cancer (25.8 ng/mL IQR 16.0, 49.6) compared to benign controls (15.5 ng/mL IQR 9.3, 25.8 ng/mL) (p < 0.01). It is also significantly higher among women with early stage cancer than benign controls (p < 0.01). There were also significant associations between LMW cfDNA concentration and stage of cancer (p = 0.01) and histology (p = 0.02). Patients with leiomyosarcoma and carcinosarcoma had higher cfDNA concentrations than those with endometrioid cancer. Over a median follow-up of 51.9 months, 75th percentile for overall survival for women with cancer was 24.0 months. Higher LMW cfDNA concentrations is associated with lower survival among women with cancer (p < 0.01). CONCLUSIONS: Serum LMW cfDNA concentration is associated with overall survival in women with uterine cancer, and it is higher among women with uterine cancer compared to those of controls.

The association of sexual dysfunction with race in women with gynecologic malignancies.

Gynecologic cancer survivors report sexual health among their highest concerns. The aim of this study was to identify the prevalence of sexual dysfunction (SD) in survivors of gynecologic malignancies and to evaluate the association of sexual function with race, ethnicity and treatment modality. In this study, survivors of endometrial, cervical, vaginal, and vulvar cancer who presented to the gynecologic oncology practice were asked to self-administer the Female Sexual Function Index (FSFI) survey to evaluate their sexual function. The prevalence of SD was estimated and its association with demographic and clinical co-variates was analyzed. Of the 155 participants, the prevalence of SD was 44.5% (95%CI: 36.7-52.7). Patients were significantly more likely to report SD if they did not currently have a partner (69% vs 22% p < .01). Abstinence within six months of their cancer diagnosis was also associated with SD (72% vs 26% p < .01). Patients who self-identified as black race compared to white race were three times more likely to have SD (OR = 3.9, 95% CI 1.1-14.3). Patients who received adjuvant chemotherapy and radiation therapy compared to those who did not among the entire cohort had an increased risk of SD (OR = 3.4, 95% CI 1.2-9.6). In our diverse population, almost half of our patients were identified to have SD. Black as compared to white race reported significantly higher sexual dysfunction. An increased risk for sexual dysfunction was observed among those women who received chemotherapy and radiation with or without surgery. PRECIS: Survivorship is an important issue for women with gynecologic malignancies. This study addresses the high rates of sexual dysfunction in a racially diverse patient population.

Readability assessment of online gynecologic oncology patient education materials from major governmental, non-profit and pharmaceutical organizations.

OBJECTIVE: Patients are increasingly using online materials to learn about gynecologic cancer. Providers can refer patients to online educational materials produced by a number of different major medical organizations and pharmacology companies. The National Institutes of Health (NIH) and the American Medical Association (AMA) recommend that patient educational materials (PEMs) are written between a sixth and eighth grade reading level. In this study, we assess the readability of online PEMs published by major medical organizations and industry partners. METHODS: Websites from twelve websites providing educational materials for gynecologic oncology patients were surveyed. Online PEMs were identified and analyzed using seven validated readability indices. One-way ANOVA and Tukey's Honestly Significant Difference (HSD) post-hoc analysis were performed to detect differences in readability between publishers. RESULTS: Two-hundred and sixty PEMs were included in this analysis. Overall, PEMs were written at a mean 11th±0.6 grade reading level. Only 6.5% of articles were written at the AMA/NIH recommended reading grade level of 6th to 8th grade or below. ANOVA demonstrated a significant difference in readability between publishing associations (p<0.01). PEMs from the Centers for Disease Control had a mean 9th±1.2 grade reading level and were significantly lower than all other organizations. PEMs from The Foundation for Women's Cancer had a mean 13th±1.8 grade reading level and were significantly higher than most other organizations. PEMs from pharmaceutical companies (mean readability=10.1±1.1, N=30) required the lowest reading grade level and were significantly more readable than those from governmental organizations (11.1±1.7, p<0.05) and nonprofit medical associations (12.4±1.7, p<0.01) in ANOVA and Tukey-Kramer post hoc analysis. CONCLUSIONS: Gynecologic oncology PEMs available from twelve major organization websites are written well above the recommended sixth to eighth grade reading difficulty level.

Utilizing the Patient Reported Outcomes Measurement Information System (PROMIS®) to increase referral to ancillary support services for severely symptomatic patients with gynecologic cancer.

OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS®) Network has developed a comprehensive repository of electronic patient reported outcomes measures (ePROs) of major symptom domains that have been validated in cancer patients. Their use for patients with gynecologic cancer has been understudied. Our objective was to establish feasibility and acceptability of PROMIS ePRO integration in a gynecologic oncology outpatient clinic and assess if it can help identify severely symptomatic patients and increase referral to supportive services. METHODS: English-speaking patients with a confirmed history of gynecologic cancer completed PROMIS ePROs on iPads in the waiting area of an outpatient gynecologic oncology clinic. Symptom scores were calculated for each respondent and grouped using documented severity thresholds. Response data was compared with clinicopathologic characteristics across symptom domains. Severely symptomatic patients were offered referral to ancillary services and asked to complete post-exposure surveys assessing acceptability of the ePRO. RESULTS: Of the 336 patients who completed ePROs, 35% had active disease and 19% had experienced at least one disease recurrence. Sixty-nine percent of the cohort demonstrated moderate to severe physical dysfunction (60%), pain (36%), fatigue (28%), anxiety (9%), depression (8%), and sexual dysfunction (32%). Thirty-nine (12%) severely symptomatic patients were referred to services such as psychiatry, palliative care, pain management, social work or integrative oncology care. Most survey respondents identified the ePROs as helpful (78%) and easy to complete (92%). CONCLUSIONS: Outpatient PROMIS ePRO administration is feasible and acceptable to gynecologic oncology patients and can help identify severely symptomatic patients for referral to ancillary support services.

Mediation of oxidative stress in hypothalamic ghrelin-associated appetite control in rats treated with phenylpropanolamine.

Phenylpropanolamine (PPA)-induced appetite control is associated with oxidative stress in the hypothalamus. This study explored whether hypothalamic antioxidants participated in hypothalamic ghrelin system-associated appetite control in PPA-treated rats. Rats were given PPA daily for 4 days, and changes in food intake and the expression of neuropeptide Y (NPY), the cocaine- and amphetamine-regulated transcript (CART), superoxide dismutase, catalase, ghrelin, acyl ghrelin (AG), ghrelin O-acyltransferase (GOAT) and the ghrelin receptor (GHSR1a) were examined and compared. Results showed that both food intake and the expression of NPY and ghrelin/AG/GOAT/GHSR1a decreased in response to PPA treatment with maximum decrease on Day 2 of the treatment. In contrast, the expression of antioxidants and CART increased, with the maximum increase on Day 2, with the expression opposite to that of NPY and ghrelin. A cerebral infusion of either a GHSR1a antagonist or reactive oxygen species scavenger modulated feeding behavior and NPY, CART, antioxidants and ghrelin system expression, showing the involvement of ghrelin signaling and oxidative stress in regulating PPA-mediated appetite control. We suggest that hypothalamic ghrelin signaling system, with the help of antioxidants, may participate in NPY/CART-mediated appetite control in PPA-treated rats.

Central dopamine action modulates neuropeptide-controlled appetite via the hypothalamic PI3K/NF-κB-dependent mechanism.

Hypothalamic neuropeptides, including neuropeptide Y (NPY) and proopiomelanocortin (POMC), have been found to control the appetite-suppressing effect of amphetamine (AMPH). In this study, we have examined whether dopamine receptor (DAR), phosphatidylinositol 3-kinase (PI3K) and nuclear factor-kappaB (NF-κB) are involved in AMPH's action. We administered AMPH to rats once a day for 4 days and assessed and compared changes in hypothalamic NPY, melanocortin receptor 4 (MC4R), PI3K, pAkt and NF-κB expression. We found that the inhibition of DAR increased NPY, but decreased MC4R, PI3K and NF-κB expression, compared with AMPH-treated rats. Moreover, MC4R, PI3K, pAkt and NF-κB increased with the maximum response on Day 2, which was consistent with the response of feeding behavior, but was opposite to the expression of NPY. Furthermore, we found that the intracerebroventricular infusion of the PI3K inhibitor or NF-κB antisense could attenuate AMPH-induced anorexia, and partially reverse the expression of NPY, MC4R, PI3K, Akt and NF-κB back toward a normal level. We, therefore, suggest that DAR-PI3K-NF-κB signaling in the hypothalamus plays functional roles in the modulation of NPY and POMC neurotransmissions and in the control of AMPH-evoked appetite suppression.

Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone.

BACKGROUND: We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. PATIENTS AND METHODS: Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter. RESULTS: Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity. CONCLUSION: The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

Evidence for the involvement of dopamine D(1) and D(2) receptors in mediating the decrease of food intake during repeated treatment with amphetamine.

Repeated treatment with amphetamine (AMPH), a well-known anorectic agent, into animals could induce anorexia on day 1 and produce a gradual reversion of food intake (tolerant anorexia) on the following days. It is unknown whether these feeding changes are related to dopamine (DA) and/or noradrenergic neurotransmission. Thus, the present study investigated the subtype of receptor mediating AMPH-induced anorexia. Daily food intake was measured after various drugs were given. Pretreatment with haloperidol, an antagonist of DA receptors, may lead to inhibition of AMPH-induced anorexia. However, pretreatment with the alpha-adrenoceptor antagonist phentolamine, and the beta-adrenoceptor antagonist propranolol, failed to modify the action of AMPH, suggesting the involvement of DA receptors but not adrenoceptors in the action of AMPH-induced anorexia. Furthermore, pretreatment with SCH 23390 at a dose sufficient to block D(1) receptors or pimozide at a dose sufficient to inhibit D(2) receptors blocked AMPH-induced anorexia, indicating the involvement of D(1) and D(2) receptors. In a study of tolerant anorexia, repeated treatment with the D(1)/D(2) agonist apomorphine, but not the D(1) agonist SKF 38393 or D(2) agonist quinpirole, induced an AMPH-like tolerant feeding response, providing evidence for conjoint action of D(1) and D(2) receptors in the effect. The present results suggest that both D(1) and D(2) receptors are involved in anorexia and tolerant anorexia induced by chronic intermittent administration of AMPH.

Bullous pemphigoid masquerading as acute radiation dermatitis: case report.

We report the first case of bullous pemphigoid complicating radiation therapy for vulvar cancer. Shortly after completion of postoperative radiation therapy for a TIN1 vulvar carcinoma, the patient presented with a rash that started within, but continued to extend, well beyond the radiation field. A biopsy of the lesions confirmed the diagnosis of bullous pemphigoid, and she had prompt clinical resolution with systemic tetracycline and steroids.

Role of hypothalamic neuropeptide Y (NPY) in the change of feeding behavior induced by repeated treatment of amphetamine.

Neuropeptide Y (NPY), an orexigenic peptide, is involved in the control of food intake. Repeated administration of amphetamine (AMPH), an anorectic agent, results in an anorectic effect on day 1 and a tolerant anorectic effect on the followings. In an attempt to know the role of hypothalamic NPY in these effects of AMPH, contents of hypothalamic NPY were determined by radioimmunoassay at first. In AMPH-treated groups, the contents of hypothalamic NPY decreased rapidly on day 1 but restored gradually to the normal level on the following days as observed in repeated AMPH. An involvement of hypothalamic NPY in the feeding change of repeated AMPH can thus be considered. Moreover, daily injection of NPY antisense oligonucleotide into brain (10 microg/10 microl/day, i.c.v.) to inhibit the gene expression of hypothalamic NPY were performed at 1 hour before daily 2 mg/kg AMPH. The reversion of food intake from the anorectic level to the normal level (tolerant anorexia) was abolished by this antisense pretreatment. It is suggested that hypothalamic NPY may play a role in the change of feeding behavior induced by repeated AMPH administration.

Ovarian carcinoid: management of primary and recurrent tumors.

We present a case of Stage I ovarian carcinoid tumor recurrent in the peritoneal cavity and review the pertinent literature concerning the management of this disease. Based on the data in the gynecologic and general surgery literature, it appears that primary complete cytoreductive surgery usually affords a high cure rate. Reexploration and attempt at complete resection of this slow-growing tumor appears to provide significant and prolonged palliation and is indicated for recurrent disease.

Nicotine-induced hyperlocomotion is not modified by the estrous cycle, ovariectomy and estradiol replacement at physiological level.

The present study was designed to investigate whether nicotine's effect on locomotion might be modulated by the ovarian hormone at physiological level. Rats at normal cycling of estrus and diestrus were selected for the comparison of nicotine-induced hyperlocomotion based on the document that the release of striatal dopamine was greatest at the estrous phase. Ovariectomized rats primed with or without estrogen at physiological level were also selected for comparison. Increase in spontaneous locomotion by nicotine was statistically significant at the doses of 0.15 and 0.3 mg/kg (p < 0.001). The stimulating effect of nicotine led the locomotor response to almost the same magnitude in all hormonal groups studied. Nicotine-induced hyperlocomotion appeared to be mediated by central nicotinic receptor because it was blocked by mecamylamine (0.5 and 1.0 mg/kg, i.p.). Also it was blocked by haloperidol (0.04 and 0.08 mg/kg, i.p.) indicating the involvement of dopaminergic neurotransmission. These effects were similar in all groups regardless of the estrous cycle or ovariectomy. The observed data provided behavioral evidence to suggest that the effect of nicotine on locomotion-related dopaminergic neurons might not be modified by the physiological action of estrogen.

Dermatofibrosarcoma protuberans of the vulva: a rare tumor presenting during pregnancy in a teenager.

OBJECTIVES: We report a case of a young patient with dermatofibrosarcoma protuberans of the vulva diagnosed during pregnancy. We also provide a review of the literature on this topic. MATERIALS AND METHODS: This patient's case was reviewed retrospectively. A current literature search was performed and findings were reported. RESULTS: This rare malignancy was diagnosed during pregnancy in a teenager. CONCLUSIONS: Dermatofibrosarcoma protuberans of the vulva, a rare vulvar neoplasm mostly associated with older patients and never before reported during pregnancy, should be considered as part of the differential diagnosis for any vulvar mass and cannot be excluded on the basis of the patient's age or pregnancy status.

Effects of nicotine on spontaneous and amphetamine-induced motor behaviors: the differences between nicotine tolerant and nontolerant rats.

This study was designed to investigate the effect of nicotine on spontaneous and amphetamine (AMP)-induced motor activity in rats with or without tolerance to nicotine. Tolerance were induced by treating the rats with nicotine (0.3 mg/kg, s.c.) 2 hr before receiving challenge doses. Motor activity including locomotion and stereotypy was monitored automatically by videocamera every 15 min for 90 min. The results indicated that: (1) Nicotine increased spontaneous locomotion at 0.15 or 0.3 mg/kg (s.c.) in naive rats and at 0.6 mg/kg in tolerant rats. Nicotine also slightly affected AMP-induced locomotion at 0.15, 0.3 or 0.6 mg/kg in both naive and tolerant rats, and (2) Nicotine increased spontaneous stereotypy at 0.3 or 0.6 mg/kg in naive rats only and showed no effect on AMP-induced stereotypy in either naive or tolerant rats. Comparing the results of spontaneous motor activity between naive and tolerant rats, it revealed behavioral desensitization in locomotion at low doses (0.15 or 0.3 mg/kg) and hyperlocomotion at higher dose (0.6 mg/kg), and revealed desensitization in stereotypy at 0.3 or 0.6 mg/kg. Moreover, nicotine had temporary (at 0-15 min interval) attenuating effect on AMP-induced locomotion in naive rats but showed a potentiating effect on AMP-induced locomotion in tolerant rats. The present results indicated that acute tolerance modified the action of nicotine in both spontaneous and AMP-induced locomotion, while stereotypy was changed only in the spontaneous one but not in the AMP-induced one. In other words, acute tolerance modified the effect of nicotine on locomotion-related dopaminergic system, and it affected the stereotypy-related dopaminergic system only in the spontaneous one but not in the AMP-induced one.

Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.

The treatment of advanced ovarian cancer with taxol is hindered by the development of drug resistance. The cellular target for taxol is the microtubule that is stabilized by the drug. Taxol preferentially binds to the beta subunit of tubulin of which there are six distinct isotypes in mammalian cells. We have used highly specific oligonucleotides and polymerase chain reaction to analyze expression of all six beta-tubulin genes. Human lung cancer cells (A549) were selected in 12 and 24 nM taxol resulting in cell lines that were 9- and 17-fold resistant, respectively. These cells displayed an altered ratio of classes I, II, III, and IVa beta-tubulin isotypes. Ovarian tumors, seven untreated primary and four taxol- resistant tumor-bearing ascites, displayed significant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), and IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appears to be related to the resistance phenotype, as the basal levels of the class III and IVa isotypes in the untreated tumors were extremely low. This is the first report of altered expression of specific beta-tubulin genes in taxol-resistant ovarian tumors and we propose that the latter may play a role in clinical resistance to taxol.

Endometrioid adenocarcinoma of the ovary and long-term tamoxifen therapy: a coincidence or a cause for concern?

In recent years, the extensive usage of tamoxifen in patients with breast cancer has led us to acquire a great deal of knowledge of its effects on various organs in the gynecological system, especially the effect on the endometrium and the increased risk of endometrial cancer. Information on the possible potential carcinogenic effect of tamoxifen on the ovary, however, has been limited, mainly because of the overall low incidence of ovarian carcinoma. In addition, there is the confounding variable posed by the diverse here-ditary breast and ovarian cancer syndromes which tend to occur in a younger age group. Here, we present a case of a postmenopausal woman who was treated for six years with tamoxifen for breast cancer before being diagnosed with endometrioid carcinoma of the ovary. We believe that given the age of the patient and the duration of tamoxifen use, the occurrence of ovarian endometrioid carcinoma may be associated with long-term tamoxifen use.

Analysis of MDR1 expression in normal and malignant endometrium by reverse transcription-polymerase chain reaction and immunohistochemistry.

The purpose of this study was to quantitate the expression of human MDR1 mRNA levels in normal endometrium and in endometrial carcinoma and to determine the association of MDR1 levels with prognostic indicators. Endometrial samples from 43 postmenopausal patients with endometrial carcinoma and 38 patients (controls) with benign disease undergoing hysterectomy were snap-frozen. MDR1 levels were determined by quantitative reverse transcription-PCR (RT-PCR) and compared to sensitive and resistant cell lines. Immunohistochemistry was done with MM4.17, an anti-MDR1 antibody, on paraffin sections, and the results were compared to those obtained from RT-PCR. Data was analyzed using the Kruskal-Wallis and Bonferroni tests, setting the P value at 0.05. In both postmenopausal endometrial tissue and tumors, MDR1 expression was localized to the epithelial cell layer. Comparison of immunohistochemistry and RT-PCR results demonstrated a correlation of 80%. In control patients, MDR1 expression was significantly higher in postmenopausal endometrium (n = 15) than in the proliferative premenopausal endometrium (n = 15; P = 0.0024). MDR1 expression in all tumors was lower than that measured in the postmenopausal controls. Between each tumor group, there was no significant difference in the MDR1 levels observed. MDR1 expression was significantly lower in patients with high nuclear grade (n = 18) tumors when compared to patients with low nuclear grade (n = 14; P = 0.04) tumors. Comparison of MDR1 levels with multiple prognostic indicators for endometrial cancer was only significant for nuclear grade. The data indicate that MDR1 expression is not a major component of the drug resistance observed in primary endometrial tumors.