Ascertainment and validation of major bleeding events in a primary care database.

PURPOSE: The purpose of the study is to evaluate the impact of validation on the identification of major bleeding events in The Health Improvement Network (THIN) database in patients receiving anticoagulant therapy. METHODS: Patients aged 2 to 89 years with a first prescription for an anticoagulant (rivaroxaban or warfarin) between 2012 and 2015 were identified in THIN. Major bleeding events, defined as bleeding events necessitating hospitalization or referral to accident and emergency services or a specialist clinic, were identified using a 2-step ascertainment process based on read codes only, and then validated using a 2-step process requiring manual review of patients' records. RESULTS: The positive predictive value for the ascertainment of major intracranial (IC) bleeds using only read codes was 96.9%, compared with 70.4% for gastrointestinal (GI) bleeds and 64.1% for urogenital (UG) bleeds. The incidence rate of major IC bleeding events was therefore similar when it was calculated before and after validation (0.32 per 100 person-years and 0.31 per 100 person-years, respectively). The incidence rate of major GI bleeds identified using read codes alone was reduced following validation from 2.05 to 0.94 per 100 person-years, and that of major UG bleeds decreased from 2.45 to 1.11 per 100 person-years. CONCLUSIONS: Major GI and UG bleeding events ascertained from THIN using read codes require validation using additional information to prevent outcome misclassification. The absence of validation may lead to overestimated incidence rates of major bleeding for GI and UG bleeds.

Missing documentation in breast cancer survivors: genitourinary syndrome of menopause.

OBJECTIVE: Breast cancer survivors often take hormonal treatments to prevent the recurrence of breast cancer, particularly aromatase inhibitors that can worsen the symptoms of genitourinary syndrome of menopause (GSM) such as dyspareunia, dysuria, and urinary incontinence, all of which may adversely affect survivors' quality of life. Few breast cancer survivors experiencing GSM receive adequate assessment or treatment. METHODS: In this descriptive study, we reviewed medical records for documented GSM and any treatments administered or referrals for treatment in 800 female patients who visited the Breast Cancer Survivorship Clinic at a comprehensive cancer center between July 1, 2010 and June 30, 2011, either at least 5 years after completion of treatment for invasive breast cancer or at least 6 months after completion of treatment for ductal carcinoma in situ. RESULTS: Of the 279 patients with documented symptoms of vaginal atrophy, only 111 (39.8%) had documentation of having received any form of treatment or referral. Of the 71 patients with documented symptoms of urinary tract atrophy, only 33.8% had documentation of having received treatment or referral for treatment. CONCLUSION: Breast cancer survivors often experience GSM due to lack of estrogen. The worrisome lack of documentation of assessment or treatment for GSM in a large breast cancer survivorship practice reveals missed opportunities to improve quality of life. Dissemination of recent progress in the development of GSM assessment tools, patient handouts, and new treatments to providers who care for breast cancer survivors is needed to improve this process.

Local hormone therapy for genitourinary syndrome of menopause in breast cancer patients: is it safe?

The genitourinary syndrome of menopause (GSM) is a frequent complaint among breast cancer (BC) survivors that lead to an important affection of their quality of life (QoL). Lifestyle measures such as smoking cessation or regular sexual activity are usually insufficient to significantly improve GMS and although therapies such as lubricants and polycarbophil moisturized gels are considered first-line therapies to alleviate symptoms of vulvovaginal atrophy, these non-hormonal options are not able to reverse atrophy once it occurs. Instead, this complaint is corrected by local estrogens. The estrogen vaginal treatment usually used to treat GSM, is an issue of concern in this group due to the possible negative effect over the BC outcomes. On the other hand, the worsening of QoL in these patients due to symptoms related to GSM can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly. The goal of this review is to contribute to health care professionals to make an informed decision to care for their BC patients.

A systematic evaluation of chemicals in hydraulic-fracturing fluids and wastewater for reproductive and developmental toxicity.

Hydraulic-fracturing fluids and wastewater from unconventional oil and natural gas development contain hundreds of substances with the potential to contaminate drinking water. Challenges to conducting well-designed human exposure and health studies include limited information about likely etiologic agents. We systematically evaluated 1021 chemicals identified in hydraulic-fracturing fluids (n=925), wastewater (n=132), or both (n=36) for potential reproductive and developmental toxicity to triage those with potential for human health impact. We searched the REPROTOX database using Chemical Abstract Service registry numbers for chemicals with available data and evaluated the evidence for adverse reproductive and developmental effects. Next, we determined which chemicals linked to reproductive or developmental toxicity had water quality standards or guidelines. Toxicity information was lacking for 781 (76%) chemicals. Of the remaining 240 substances, evidence suggested reproductive toxicity for 103 (43%), developmental toxicity for 95 (40%), and both for 41 (17%). Of these 157 chemicals, 67 had or were proposed for a federal water quality standard or guideline. Our systematic screening approach identified a list of 67 hydraulic fracturing-related candidate analytes based on known or suspected toxicity. Incorporation of data on potency, physicochemical properties, and environmental concentrations could further prioritize these substances for future drinking water exposure assessments or reproductive and developmental health studies.

Management of Hormone Deprivation Symptoms After Cancer.

Cancer survivors often experience symptoms related to hormone deprivation, including vasomotor symptoms, genitourinary symptoms, and sexual health concerns. These symptoms can occur due to natural menopause in midlife women, or they can be brought on by oncologic therapies in younger women or men. We searched PubMed for English-language studies from January 1990 through January 2016 to identify relevant articles on the management of hormone deprivation symptoms, including vasomotor, genitourinary, and sexual symptoms in patients with cancer. The search terms used included hormone deprivation, vasomotor symptoms, hot flash, vaginal dryness, sexual dysfunction, and breast cancer. This manuscript provides a comprehensive description of data supporting the treatment of symptoms associated with hormone deprivation.

Genitourinary Syndrome of Menopause in Breast Cancer Survivors: Are We Facing New and Safe Hopes?

Breast cancer survivors (BCSs) often suffer from menopausal symptoms induced by systemic treatments, with a consequent negative effect on quality of life. Since the introduction of aromatase inhibitors as the standard therapy for hormone-dependent tumors, genitourinary syndrome of menopause (GSM) has become a main problem for BCSs. This new terminology refers to the wide range of vaginal and urinary symptoms related to menopause, which can be relieved by estrogen therapy. Unfortunately, systemic hormone therapy is contraindicated for BCSs and also vaginal estrogens at standard dosage might influence the risk of recurrence because they cause a significant increase of circulating estrogens. Nonhormonal vaginal moisturizers or lubricants are the first choice for BCSs but only have limited and short-term efficacy. New strategies of management of GSM are now available, including: (1) low-dose or ultra low-dose vaginal estrogens; (2) oral selective estrogen receptor modulators (ospemifene); (3) androgen therapy; (4) physical treatment with vaginal laser; and (5) psychosocial interventions. In this review we discuss and analyze these different options.

Profile of sexual and genitourinary treatment-emergent adverse events associated with atomoxetine treatment: a pooled analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder that begins in childhood. Atomoxetine is a selective inhibitor of the presynaptic norepinephrine transporter. Several studies have demonstrated the safety and efficacy of atomoxetine in the treatment of ADHD. OBJECTIVE: The objective of this analysis was to provide additional information on the frequency, time to onset and time to resolution of sexual and genitourinary (GU) treatment-emergent adverse events (TEAEs) reported during atomoxetine treatment in clinical trials. METHODS: Data from all adult atomoxetine placebo-controlled ADHD trials were pooled for this analysis, for a total of 3,314 patients (atomoxetine, n = 1,738; placebo, n = 1,576). Additionally, data from all adolescent patients (baseline age ≥13 to <18 years) within all ADHD placebo-controlled trials were pooled for analysis, for a total of 538 patients (atomoxetine, n = 329; placebo, n = 209). Rates of sexual and GU TEAEs were summarized by sex for each age group. Time to onset and resolution of sexual and GU TEAEs were summarized and compared using Kaplan-Meier methods. RESULTS: Overall, the baseline characteristics of randomized patients in the atomoxetine and placebo groups were similar. Profiles of sexual and GU TEAEs for atomoxetine appeared clinically similar to placebo in female patients and in adolescent male patients. Adult male patients reported relatively more sexual and GU TEAEs when taking atomoxetine compared with placebo, with libido decreased (4.6 vs. 3.0 %), dysuria (3.7 vs. 1.5 %), urinary hesitation (6.9 vs. 2.4 %), urine flow decreased (2.5 vs. 0.6 %), ejaculation disorder (2.8 vs. 1.1 %) and erectile dysfunction (8.0 vs. 1.9 %) being the most common. The time to onset of the most common TEAEs in adult male patients tended to occur relatively early in dosing: within the first 2 weeks for GU TEAEs, and during the second and third week of dosing for erectile and ejaculation issues. The median time to resolution for these events ranged from around 3-8 weeks after event onset, depending on the event. While the common sexual and GU TEAEs showed numerically higher percentages of discontinuations in atomoxetine-treated patients compared with placebo, most incidences of the sexual and GU TEAEs were not considered severe. CONCLUSIONS: The sexual and GU TEAE profiles of patients taking atomoxetine were generally similar to those of patients taking placebo in the female and adolescent male populations, with greater frequency of TEAEs reported in adult males taking atomoxetine compared with placebo. The time to onset of the TEAEs tended to be shorter, and time to resolution tended to be longer in adult male patients treated with atomoxetine compared with those receiving placebo. The conclusions must be interpreted with caution because the TEAEs were likely underreported.

Urinary symptoms and impaired quality of life in female ketamine users: persistence after cessation of use.

OBJECTIVE: To compare the urinary symptoms and quality of life in ex-ketamine abusers and controls. DESIGN: Prospective observational study. SETTING: A hospital in Hong Kong. PATIENTS: Female ex-ketamine abusers admitted to a local drug rehabilitation centre and age-matched controls attending a general gynaecology clinic between December 2009 and April 2010. MAIN OUTCOME MEASURES: Evaluation of urinary symptoms based on a 3-day bladder diary, and responses to the Urogenital Distress Inventory Short Form (UDI-6) and the Incontinence Impact Questionnaire Short Form (IIQ-7). The study group had repeat measurements 3 months later. RESULTS: Overall, 90% of ex-ketamine abusers had active urinary symptoms. On average, they had increased 24-hour urinary frequency (10.0 vs 5.8; P=0.001) and lower maximum voided volume (253.3 mL vs 401.9 mL; P<0.001) compared to controls. Correspondingly, the median functional bladder capacity was smaller (195.3 mL vs 261.2 mL; P=0.011) and the mean UDI-6 and IIQ-7 scores were higher (P<0.001). Among those who abused ketamine for 2 years or more, the mean UDI-6 and IIQ-7 scores were higher (P=0.03, P=0.02 respectively). When they stopped abusing ketamine for 3 months or more, their mean 24-hour urinary frequency had decreased (P=0.03), the maximum voided volume had increased (P=0.03) and the mean UDI-6 and IIQ-7 scores had decreased (P=0.04, P=0.02 respectively), although they were still higher than in controls. After 3 more months, in the ex-ketamine abusers there had been a further decrease in 24-hour urinary frequency (P=0.01) and a further improvement in quality of life based on mean UDI-6 scores (P=0.04) but nevertheless poorer than the control group (P<0.01). CONCLUSION: Female ex-ketamine abusers had significant urinary symptoms affecting their quality of life when studied at a mean of 8 (range, 0.5-48) months after cessation of use. The symptom severity was inversely correlated with the duration of cessation; though they improved with time, some still persisted.

Spectrum of medication-induced complications in the abdomen: role of cross-sectional imaging.

OBJECTIVE: This article provides a comprehensive review of the role of MDCT and MRI in the diagnosis of drug-induced complications in the abdomen and pelvis in adults. A systematic organ-based review of these complications is presented, including but not limited to hepatic changes after chemotherapy, renal complications such as tumor lysis syndrome and lithium nephropathy, gastrointestinal manifestations, various opportunistic infections and secondary neoplasms, mycotic aortic aneurysm from intravesical bacille Calmette-Guérin, complications of anticoagulant therapy, and oral contraceptives. CONCLUSION: Advancements in imaging have led to recognition of radiologic features of previously unsuspected diseases. Occasionally, imaging may also identify effects of treatments instituted for these diseases. Consequently, imaging plays a critical role in the accurate diagnosis of a broad spectrum of drug-induced complications in the abdomen, both in emergent and nonemergent settings. Knowledge of the natural history, clinical manifestations, and salient imaging features of these entities is crucial to facilitate accurate clinical diagnosis in a timely fashion.

A phase I randomized placebo controlled trial of the safety of 3% SPL7013 Gel (VivaGel®) in healthy young women administered twice daily for 14 days.

OBJECTIVE: To assess the safety of VivaGel® used vaginally twice daily for 14 days among healthy, sexually-abstinent women, aged 18-24 years in the USA and Kenya. DESIGN: Randomized placebo controlled trial. METHODS: Participants were randomized 2∶1, VivaGel to placebo. Safety was assessed by comparing genitourinary (GU) adverse events (AEs), colposcopy findings, vaginal lactobacilli and laboratory abnormalities by arm. RESULTS: Fifty-four women were enrolled; 35 in the VivaGel arm and 19 in the placebo arm. Twenty-six (74%) and 10 (53%) women reported taking all doses of VivaGel and placebo, respectively. No grade 3 or 4 AEs, or serious AEs occurred. Twenty-five (71%) participants in the VivaGel arm compared to 10 (53%) participants in the placebo arm had at least one grade 1 or 2 GU AE associated with product use (RR = 1.4, 95% CI 0.8-2.2). All seven grade 2 GU AEs associated with product use occurred among four women in the VivaGel arm. Vulvar and cervical erythema, cervical lesions, symptomatic BV, urinary frequency and metrorrhagia were more common in the VivaGel arm than the placebo arm. Twenty-nine (83%) participants in the VivaGel arm had a colposcopic finding compared to 10 (53%) participants in the placebo arm (RR = 1.6, 95%CI = 1.0-2.5). Two women in the VivaGel arm prematurely discontinued product use themselves due to a reported GU AE. Persistence of H2O2-producing and non-producing lactobacilli did not differ by study arm. CONCLUSIONS: GU AEs and colposcopic findings consistent with mild epithelial irritation and inflammation occurred more commonly among women in the VivaGel arm. TRIAL REGISTRATION: ClinicalTrials.gov NCT003311032.

Vaginal estriol to overcome side-effects of aromatase inhibitors in breast cancer patients.

OBJECTIVE: Aromatase inhibitors are essential as endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients. Menopausal symptoms are often aggravated during endocrine treatment. We investigated whether vaginal estriol is a safe therapeutic option to overcome the urogenital side-effects of aromatase inhibitors. Serum hormone levels were used as the surrogate parameter for safety. METHODS: Fasting serum hormone levels of ten postmenopausal breast cancer patients receiving aromatase inhibitors were prospectively measured by electro-chemiluminescence immunoassays and gas chromatography/mass spectrometry before and 2 weeks after daily application of 0.5 mg vaginal estriol (Ovestin® ovula), respectively. RESULTS: Two weeks of daily vaginal estriol treatment did not change serum estradiol or estriol levels. However, significant decreases in levels of serum follicle stimulating hormone (p = 0.01) and luteinizing hormone (p = 0.02) were observed. Five out of six breast cancer patients noticed an improvement in vaginal dryness and/or dyspareunia. CONCLUSIONS: The significant decline in gonadotropin levels, indicating systemic effects, has to be kept in mind when offering vaginal estriol to breast cancer patients receiving an aromatase inhibitor.

CT findings of chemotherapy-induced toxicity: what radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity.

Cancer chemotherapy has evolved from cytotoxic agents and now includes several new agents that target specific molecules responsible for the regulation of cell growth, nutrient supply, and differentiation. These molecularly targeted therapies have a different mechanism of action than do classic cytotoxic agents, which predominantly attack rapidly proliferating cells. Not surprisingly, therefore, the toxicity of targeted and cytotoxic agents may differ in both clinical and radiologic presentation. Many of the toxicities of targeted therapies are not cumulative or dose dependent, some are asymptomatic, and others may first manifest radiologically. It is imperative that radiologists be aware of these toxicities and that they learn to recognize the relevant findings so that they can provide a complete differential diagnosis and thus play an important role in patient care.

Prevalence and severity of urogenital symptoms in postmenopausal women receiving endocrine therapy for breast cancer.

BACKGROUND: Data from randomized trials in postmenopausal women receiving endocrine therapy for breast cancer would suggest that the incidence of significant urogenital symptoms is around 40%. As there are inherent reporting biases associated with clinical trials, we sought to assess the prevalence, severity, and effect of urogenital side effects of endocrine therapy in the non-trial setting. PATIENTS AND METHODS: A cross-sectional survey study was undertaken and questionnaires used to assess vulvovaginal and urinary tract symptoms in a group of postmenopausal women receiving endocrine therapy for breast cancer. RESULTS: A total of 251 women were surveyed. Sixty-three percent (158) reported urogenital symptoms. Vaginal dryness was the most common vaginal symptom, occurring in 121 women (48%). This was rated as severe or very severe in 56 of 121 (46%). Thirty-one of 251 (12%) women experienced urinary symptoms. A total of 68 women (27%) had used some form of treatment for vaginal symptoms. Nine women (4%) had considered discontinuing treatment because of urogenital side effects. CONCLUSION: Urogenital side effects are common and often severe in women receiving endocrine therapy for breast cancer. The prevalence in this study was 63%, which is higher than that reported in the clinical trial literature. Less than one third of patients had used some form of treatment for these symptoms. This highlights the need for increased recognition and management of the urogenital side effects of estrogen deprivation therapy and raises the concern of the risk of non-compliance with potentially curative adjuvant therapy.

The effect of tamoxifen on the genital tract.

Tamoxifen is a selective estrogen receptor modulator (SERM) that is widely used in the treatment of patients with breast cancer and for chemoprophylaxis in high risk women. Tamoxifen results in a spectrum of abnormalities involving the genital tract, the most significant being an increased incidence of endometrial cancer and uterine sarcoma. This article reviews the effects of tamoxifen on the genital tract and the strengths and weaknesses of various imaging modalities for evaluating the endometrium.

High dose zinc increases hospital admissions due to genitourinary complications.

PURPOSE: Zinc is a common dietary supplement that is widely believed to have beneficial health effects. To assess the impact of high dose supplemental zinc on genitourinary diseases we analyzed a recent randomized trial comparing zinc, antioxidants and their combination to placebo for complications related to the genitourinary tract. MATERIALS AND METHODS: In a further analysis of the recent Age-related Eye Disease Study we examined the data pool for primary International Classification of Diseases, 9th revision codes given for hospital admissions related to urological problems. The Age-Related Eye Disease Study randomized 3,640 patients with age related macular degeneration to 1 of 4 study arms, including placebo, antioxidants (500 mg vitamin C, 400 IU vitamin E and 15 mg beta-carotene), 80 mg zinc and antioxidant plus zinc. Statistical analyses using Fisher's exact test were performed. RESULTS: We found a significant increase in hospital admissions due to genitourinary causes in patients on zinc vs nonzinc formulations (11.1% vs 7.6%, p = 0.0003). The risk was greatest in male patients (RR 1.26, 95% CI 1.07-1.50, p = 0.008). In the study group of 343 patients requiring hospital admission the most common primary International Classification of Diseases, 9th revision codes included benign prostatic hyperplasia/urinary retention (benign prostatic hyperplasia), urinary tract infection, urinary lithiasis and renal failure. When comparing zinc to placebo, significant increases in urinary tract infections were found (p = 0.004), especially in females (2.3% vs 0.4%, RR 5.77, 95% CI 1.30-25.66, p = 0.013). Admissions for urinary lithiasis approached significance in men on zinc compared to placebo (2.0% vs 0.5%, RR = 4.08, 95% CI 0.87-19.10). There was no increase in prostate or other cancers with zinc supplementation. A significant decrease in prostate cancer diagnoses was seen in patients receiving antioxidants vs placebo (RR = 0.6, 95% CI 0.49-0.86, p = 0.049). Subgroup analysis revealed that this finding was significant in men who smoked but not in nonsmokers. CONCLUSIONS: Zinc supplementation at high levels results in increased hospitalizations for urinary complications compared to placebo. These data support the hypothesis that high dose zinc supplementation has a negative effect on select aspects of urinary physiology.