Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study
OBJECTIVES: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.
BACKGROUND: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.
METHODS: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.
RESULTS: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.
CONCLUSIONS: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.
OBJECTIVES: Unplanned pregnancy is a public health problem in the United States, including in rural areas. Primary care physicians are the main providers of health care to women in rural areas and are uniquely positioned to help reduce unplanned pregnancy in rural women. This study documents provision of contraception by rural primary care physicians, focusing on the most effective, long acting methods, intrauterine devices (IUDs) and contraceptive implants.
METHODS: We surveyed all primary care physicians practicing in rural areas of Illinois and Wisconsin. Bivariate analysis was performed using chi squared and Fisher's exact test, and multivariable analysis was performed with logistic regression to determine factors associated with provision.
RESULTS: The response rate was 862 out of 2312 physicians (37%). Nine percent of respondents place implants and 35% place IUDs. Eighty-seven percent of physicians had not had training in implant placement, and 41% had not had training in IUD placement. In multivariable analysis, factors associated with placement of long acting contraception include provision of maternity care, and female gender of the physician. The most common reasons for not providing the methods were lack of training and perceived low demand from patients.
CONCLUSIONS: Many rural primary care providers do not place long acting contraceptive devices due to lack of training. Female physicians and those providing maternity care are the most likely to place these devices. Increased training for primary care physicians both during and after residency would help increase access to these options for women in rural areas.
Vulvar carcinoma is an uncommon tumor that is seen most often in older women. Subtle symptoms such as pruritus should prompt examination and targeted biopsy in all women as this disease can be successfully treated even in elderly, frail individuals. Vulvar cancer has a bimodal age distribution and is seen in both young and older women with risk factors including human papillomavirus (HPV) infection, smoking, and vulvar skin diseases (i.e., lichen sclerosus). This cancer is staged surgically, with an update in 2009 incorporating prognostic factors. The treatment of vulvar carcinoma has evolved to include more conservative surgical techniques that provide improved cure rates with emphasis on minimizing morbidity. Advanced and metastatic lesions are now treated with chemoradiation which produces substantial cure rates with decreased morbidity. Promising areas of research in vulvar cancer include refinement of sentinel lymph node biopsy, prevention of lymphedema, and preservation of sexual function following treatment.
BACKGROUND: Hypothetical choice studies suggest that physicians often take more risk for themselves than on their patient's behalf.
OBJECTIVE: To examine if physicians recommend more screening tests than they personally undergo in the real-world context of breast cancer screening.
DESIGN: Within-subjects survey.
PARTICIPANTS: A national sample of female obstetricians and gynecologists (N = 135, response rate 54%) from the United States. In total, they provided breast care to approximately 2,800 patients per week.
MEASURES: Personal usage history and patient recommendations regarding mammography screening and breast self-examination, a measure of defensive medicine practices.
RESULTS: Across age groups, female physicians were more likely to recommend mammography screening than to have performed the procedure in the past 5 years (86% vs. 81%, p = .10). In respondents aged 40-49 this difference was significant (91% vs. 82%, p < .05), whereas no differences were detected for younger or older physicians. Among respondents in their 40s, 18% had undergone annual screenings in the past 5 years, compared to 48% of their colleagues above 50. Respondents were as likely to practice breast self-examination (98%) as to recommend it (93%), a pattern that was consistent across age groups. A logistic regression model of personal use of mammography significantly predicted recommending the procedure to patients (OR = 15.29, p = .001). Similarly, number of breast self-examinations performed over the past 2 years positively predicted patient recommendations of the procedure (OR = 1.31, p < .001).
CONCLUSIONS: Obstetricians and gynecologists tended to recommend early mammography screening to their patients, though their personal practices indicated later start than their own recommendations and lower frequency of screening than peers in recent studies have recommended.
Patient-focused websites related to stress urinary incontinence and pelvic organ prolapse: a DISCERN quality analysis
INTRODUCTION AND HYPOTHESIS: The quality of information related to pelvic floor disorders is varied and understudied. Using a validated instrument we evaluated the quality of selected websites addressing treatment options for pelvic organ prolapse (POP) and stress urinary incontinence (SUI).
METHODS: English-language, patient-focused professional, governmental, and consumer websites related to POP and SUI were identified using the International Urogynecology Association (IUGA) list of continence societies worldwide, search terms, and provider nomination. Websites were evaluated by 10 providers at an academic medical center, representing urogynecology (6), urology (3), and general gynecology (1). Quality assessment utilized the DISCERN instrument, a validated instrument consisting of 16 questions addressing the quality of consumer health information.
RESULTS: Websites of 13 organizations met inclusion criteria and were assessed, 12 relating to SUI and 8 to POP. The websites with the highest mean total DISCERN score for POP were those of the IUGA, the American Society of Colon and Rectal Surgeons, and the American Urogynecologic Association, and for SUI, the National Association For Continence, the American Urological Association, and the IUGA. High correlations were obtained for the total DISCERN score and the overall quality scores for POP (0.76) and SUI (0.82). The most commonly omitted components of the DISCERN instrument were a clear statement of the content objectives, references or sources of the content, and a discussion of what patients could expect if they opted for no intervention.
CONCLUSIONS: Available English-language professional websites written to inform patients about management choices for SUI and POP miss key components of quality patient information.
Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia
Angiogenic biomarkers, including soluble fms-like tyrosine kinase 1 (sFlt1), are thought to be predictors of preeclampsia onset; however, improvement is needed before a widespread diagnostic test can be utilized. Here we describe the development and use of diagnostic monoclonal antibodies specific to the two main splice variants of sFlt1, sFlt1-1 and sFlt1-14. These antibodies were selected for their sensitivity and specificity to their respective sFlt1 isoform in a capture ELISA format. Data from this pilot study suggest that sFlt1-1 may be more predictive of preeclampsia than total sFlt1. It may be possible to improve current diagnostic platforms if more specific antibodies are utilized.
On a day-to-day basis, doctors must decide which treatments are most beneficial for their patients, and which make the most sense in terms of costs. In medical decision making, factors such as efficiency and cost-effectiveness can be particularly challenging to navigate because many of the most expensive procedures encountered in medical practice are also high-stake treatments for patients. One-hundred-six obstetricians-gynecologists (Obs/Gyns) completed a survey asking them to allocate the following resources in scenarios in which they are scarce: human papilloma virus (HPV) vaccinations, mammograms, and in vitro fertilization (IVF) treatments. Additional questions focused on how fairness and cost-effectiveness factored into the allocation decisions of each group. Results indicated that Obs/Gyns were more efficient in their distribution of HPV vaccinations and mammograms than in their distribution of IVF treatments. More efficient responding was associated with placing less emphasis on fairness in decision making. This study demonstrates the differences that exist in the emphasis that physicians place on medical evidence, cost, outcomes, and perceptions of fair (equal) allocation when faced with different costs and health impacts.
The increasing use of point-of-care (POC) ultrasound presents a challenge in providing efficient training to POC ultrasound users for whom formal training is not readily available. In response to this need, we developed an affordable compact laptop-based obstetric ultrasound training simulator. It offers a realistic scanning experience, task-based training, and performance assessment. The position and orientation of the sham transducer are tracked with 5 DoF on an abdomen-sized scan surface with the shape of a cylindrical segment. On the simulator, user interface is rendered a virtual torso whose body surface models the abdomen of the pregnant scan subject. A virtual transducer scans the virtual torso by following the sham transducer movements on the scan surface. A given 3-D training image volume is generated by combining several overlapping 3-D ultrasound sweeps acquired from the pregnant scan subject using a Markov random field-based approach. Obstetric ultrasound training is completed through a series of tasks, guided by the simulator and focused on three aspects: basic medical ultrasound, orientation to obstetric space, and fetal biometry. The scanning performance is automatically evaluated by comparing user-identified anatomical landmarks with reference landmarks preinserted by sonographers. The simulator renders 2-D ultrasound images in real time with 30 frames/s or higher with good image quality; the training procedure follows standard obstetric ultrasound protocol. Thus, for learners without access to formal sonography programs, the simulator is intended to provide structured training in basic obstetrics ultrasound.
Absence or Presence of High-Grade Squamous Intraepithelial Lesion in Cervical Conization Specimens: A Clinicopathologic Study of 540 Cases
OBJECTIVES: To explore the implications of cervical conization specimens lacking the targeted high-grade squamous intraepithelial lesions (negative cone).
METHODS: We studied 540 conization procedures: 400 positive cones and 140 negative cones. Clinicopathologic features and 2-year follow-up results were reported.
RESULTS: Negative cones comprised 22% of procedures triggered by CIN2 or higher biopsies. Procedures triggered by cytology produced much higher percentages of negative cones (37% high-grade squamous intraepithelial lesion [HSIL], 46% atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion [ASC-H], and 76% low-grade squamous intraepithelial lesion-cannot exclude high-grade squamous intraepithelial lesion [LSIL-H]). Upon reviewing negative excision-triggering biopsy and cytology, we downgraded 24 (24%) CIN2 biopsies, three (14%) HSIL, five (83%) ASC-H, and 12 (92%) LSIL-H. One-third of our negative cones can be attributed to overdiagnosis either on biopsy or cytology. Patients with negative cones were older and had smaller excisions, negative colposcopic findings, and negative/equivocal high-risk human papillomavirus (HR-HPV). Within 2 years, 35 (25%) women with negative cones experienced ASCUS or LSIL. Only one (0.7%) recurred as CIN3, a significantly lower percentage than women with positive cones (13%).
CONCLUSIONS: We advocate careful review of all excision-triggering biopsy and cytology, especially in cases of LSIL-H. Patients with negative cones should be surveyed with cytology and HR-HPV testing.
FGF2 and insulin signaling converge to regulate cyclin D expression in multipotent neural stem cells
The ex vivo expansion of stem cells is making major contribution to biomedical research. The multipotent nature of neural precursors acutely isolated from the developing central nervous system has been established in a series of studies. Understanding the mechanisms regulating cell expansion in tissue culture would support their expanded use either in cell therapies or to define disease mechanisms. Basic fibroblast growth factor (FGF2) and insulin, ligands for tyrosine kinase receptors, are sufficient to sustain neural stem cells (NSCs) in culture. Interestingly, real-time imaging shows that these cells become multipotent every time they are passaged. Here, we analyze the role of FGF2 and insulin in the brief period when multipotent cells are present. FGF2 signaling results in the phosphorylation of Erk1/2, and activation of c-Fos and c-Jun that lead to elevated cyclin D mRNA levels. Insulin signals through the PI3k/Akt pathway to regulate cyclins at the post-transcriptional level. This precise Boolean regulation extends our understanding of the proliferation of multipotent NSCs and provides a basis for further analysis of proliferation control in the cell states defined by real-time mapping of the cell lineages that form the central nervous system.
OBJECTIVE: To implement a customizable checklist in an interdisciplinary, team-based plastic surgery setting to reduce surgical complications.
METHODS: We examined the effects on patient outcomes and documentation of a customizable, office-based surgical safety checklist. On the basis of the World Health Organization Surgical Safety Checklist, we developed a 28-element, perioperative checklist for use in the office-based surgical setting. The checklist was implemented in an office-based plastic surgery practice with an already high standard of care. We recorded baseline, prechecklist rates for each checklist item and postoperative adverse outcomes via a retrospective chart review of 219 cases. After an education program and 30-day run-in period, a prospective, post-checklist implementation chart review was initiated (n = 184), with outcome data compared to the baseline.
RESULTS: The total number of complications per 100 patients decreased from 15.1 to 2.72 after checklist implementation (P < .0001), for an absolute risk reduction of 12.4. The proportion of patients with one or more complications decreased from 11.9% to 2.72% (P = .0006). Site and side marking increased from 69.9% prechecklist to 97.8% (P < .0001). Medical optimization increased from 90.9% to 99.5% (P < .0001). Emergency medical services (EMS) policy confirmation, case-specific equipment availability, anticipation of estimated blood loss, and verbal confirmation of local anesthetic toxicity precautions increased from 0% to 90.0% (P < .0001), 92.4% (P < .0001), 82.1% (P < .0001), and 91.3% (P < .0001), respectively. Assessment of patient satisfaction increased from 57.1% to 90.8% (P < .0001).
CONCLUSIONS: Implementation of a customizable checklist was associated with a reduction in surgical complications in an office-based plastic surgery practice with an already high standard of care.
Patterns in immunohistochemical usage in extended core prostate biopsies: comparisons among genitourinary pathologists and nongenitourinary pathologists
CONTEXT: Immunohistochemical (IHC) stains have known utility in prostate biopsies and are widely used to augment routine staining in difficult cases. Patterns in IHC utilization and differences based on pathologist training and experience is understudied in the peer-reviewed literature.
OBJECTIVES: To compare the rates of IHC usage between specialized (genitourinary; [GU]) and nonspecialized (non-GU) pathologists in extended core prostate biopsies (ECPBs) and the effects of diagnosis; and in cancer cases Gleason grade, disease extent, and perineural invasion on the rate.
DESIGN: Consecutive ECPBs from 2009-2011 were identified and billing data were used to determine the number of biopsies and IHC stains per case. Diagnoses were mapped and in cancer cases, Gleason grade, extent of disease, and perineural invasion were recorded. Pathologists were classified as GU or non-GU on the basis of training and experience.
RESULTS: A total of 618 ECPBs were included in the study. Genitourinary pathologists ordered significantly fewer IHC tests per case and per biopsy than non-GU pathologists. The rate of ordering was most disparate for biopsies of cancerous and benign lesions. For biopsies of cancerous lesions, high-grade cancer, bilateral disease, and perineural invasion decreased the rate of ordering in both groups. In cancer cases, GU pathologists ordered significantly fewer stain tests for highest Gleason grade of 3 + 3 = 6, for patients with focal disease and for patients with multiple positive bilateral cores. The effect of the various predictors on IHC ordering rates was similar in both groups.
CONCLUSIONS: Genitourinary pathologists ordered significantly fewer IHC stain tests than non-GU pathologists in ECPBs. Guidelines to define when IHC workup is necessary and not necessary may be helpful to guide workups.
BACKGROUND: Stress cardiomyopathy (SCM) is a peculiar form of reversible left ventricular dysfunction seen predominantly in women and occurs in response to emotional or physical stress. Because dysfunction in SCM is reversible and that of acute myocardial infarction (MI) is not, we hypothesized that these fundamental mechanistic differences between SCM and MI would be associated with different systolic and diastolic properties.
METHODS AND RESULTS: We examined 3 groups, all women: patients with SCM (n=24; mean age, 63+/-12 years), those with left anterior (LAD) ST-segment-elevation MI (n=36; mean age, 63+/-10 years), and referent control subjects (n=30; mean age, 62+/-8 years). All underwent angiography, ventriculography, and pressure measurements within 48 hours of presentation. Left ventricular volumes, diastolic pressures, and diastolic stiffness were higher in SCM and LAD MI patients than in control subjects but no different from each other. Similarly, left ventricular diastolic pressures and diastolic stiffness were elevated in the SCM and LAD MI groups compared with the control group. Left ventricular ejection fraction in SCM and LAD MI were 40.8+/-12.3% and 49.6+/-5.6%, respectively, versus 70.4+/-9.4% in control subjects (P < 0.001), and stroke work less than half the value of control subjects. Indexes of contractility and ventricular-arterial coupling were similarly abnormal in SCM and LAD MI.
CONCLUSIONS: SCM and LAD MI show severe diastolic dysfunction. At similar left ventricular volumes, their diastolic pressures are more than twice as high as in control subjects, and systolic dysfunction is equally reduced in SCM and LAD MI. Despite a completely different pathophysiology in terms of systolic and diastolic function, SCM is indistinguishable from acute LAD-territory MI.
Numerous techniques have been described for the treatment of pilonidal disease, yet there remains no consensus on the optimal management of recurrent pilonidal disease. Pilonidal wounds often lack the structural integrity to heal over and Integra provides a scaffold for the regrowth of an autogenous dermis from the patient's own fibroblasts and collagen. Postoperative negative pressure wound therapy (NPWT) may speed vascularisation of Integra, re-epithelialisation, and wound closure. This case report concerns two patients with chronic pilonidal sinuses who underwent wide excision and placement of Integra with postoperative NPWT. Postoperatively, the patients were assessed for complications and recurrence. Both patients went on to heal and did not require further surgical treatment after a median follow-up of 29 months. Integra may help prevent pocket or cyst formation during the closure process and provides a neodermis, allowing for full re-epithelialisation. More research and a longer follow-up are needed to evaluate the role of Integra and NPWT in recurrent pilonidal disease.
Determining cochlear implant users' true noise tolerance: use of speech reception threshold in noise testing
OBJECTIVE: The speech perception abilities of cochlear implant (CI) recipients have significantly improved over the past decade. At the same time, clinical test batteries to measure their performance in noise remain mostly unchanged, resulting in ceiling-level performance for the most successful recipients. The goal of this study is to determine the true noise tolerance abilities of CI recipients using adaptive speech reception threshold (SRT) in noise testing.
STUDY DESIGN: Prospective clinical study.
SETTING: Tertiary care hospital; CI program.
PATIENTS: Ten CI users, either unilateral or bilateral, with HINT scores that equaled or exceeded 80% when administered with a fixed +10 dB signal-to-noise (SNR) ratio (i.e., HINT(+10dB)).
INTERVENTION: The HINT with adaptive SNR levels and QuickSIN test were administered to measure noise tolerance at speech thresholds where 50% of the stimuli were correctly perceived.
MAIN OUTCOME MEASURE(S): SRTs were measured for both the adaptive SNR HINT (i.e., HINT(50%)) and the QuickSIN test. These SRTs were compared with the fixed noise level HINT(+10dB) scores as well as to CNC monosyllable word perception scores.
RESULTS: Despite small variance in performance levels on the HINT(+10dB), results of the HINT(50%) ( approximately 16 dB range) and QuickSIN ( approximately 12 dB range) tests demonstrate significant differences in noise tolerance levels among these CI recipients.
CONCLUSION: For excellent CI users, use of adaptive speech threshold tests in noise better defines a user's actual ability to perceive speech than do fixed SNR level tests. SRT-in-noise tests have the advantage of being quick to administer, and the same stimuli can be used over a very wide range of performance levels. The use of adaptive SRT-in-noise tests should be considered a viable and valuable replacement of fixed SNR tests in the CI clinical test battery.
Consumer-oriented interventions for evidence-based prescribing and medicines use: an overview of systematic reviews
BACKGROUND: Numerous systematic reviews exist on interventions to improve consumers' medicines use, but this research is distributed across diseases, populations and settings. The scope and focus of reviews on consumers' medicines use also varies widely. Such differences create challenges for decision makers seeking review-level evidence to inform decisions about medicines use. OBJECTIVES: To synthesise the evidence from systematic reviews on the effects of interventions which target healthcare consumers to promote evidence-based prescribing for, and medicines use, by consumers. We sought evidence on the effects on health and other outcomes for healthcare consumers, professionals and services. METHODS: We included systematic reviews published on the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects. We identified relevant reviews by handsearching both databases from start date to Issue 3 2008. We screened and ranked reviews based on relevance to consumers' medicines use, using criteria developed for this overview. Standardised forms were used to extract data, and reviews were assessed for methodological quality using the AMSTAR instrument. We used standardised language to summarise results within and across reviews; and a further synthesis step was used to give bottom-line statements about intervention effectiveness. Two review authors selected reviews, extracted and analysed data. We used a taxonomy of interventions to categorise reviews. MAIN RESULTS: We included 37 reviews (18 Cochrane, 19 non-Cochrane), of varied methodological quality.Reviews assessed interventions with diverse aims including support for behaviour change, risk minimisation, skills acquisition and information provision. No reviews aimed to promote systems-level consumer participation in medicines-related activities. Medicines adherence was the most commonly reported outcome, but others such as clinical (health and wellbeing), service use and knowledge outcomes were also reported. Reviews rarely reported adverse events or harms, and the evidence was sparse for several populations, including children and young people, carers, and people with multimorbidity.Promising interventions to improve adherence and other key medicines use outcomes (eg adverse events, knowledge) included self-monitoring and self-management, simplified dosing and interventions directly involving pharmacists. Other strategies showed promise in relation to adherence but their effects were less consistent. These included reminders; education combined with self-management skills training, counselling or support; financial incentives; and lay health worker interventions.No interventions were effective to improve all medicines use outcomes across all diseases, populations or settings. For some interventions, such as information or education provided alone, the evidence suggests ineffectiveness; for many others there is insufficient evidence to determine effects on medicines use outcomes. AUTHORS' CONCLUSIONS: Systematically assembling the evidence across reviews allows identification of effective or promising interventions to improve consumers' medicines use, as well as those for which the evidence indicates ineffectiveness or uncertainty.Decision makers faced with implementing interventions to improve consumers' medicines use can use this overview to inform these decisions and also to consider the range of interventions available; while researchers and funders can use this overview to determine where research is needed. However, the limitations of the literature relating to the lack of evidence for important outcomes and specific populations, such as people with multimorbidity, should also be considered.
OBJECTIVE: Stent-assisted coiling of intracranial aneurysms is performed by placing a microcatheter through a stent's interstices or jailing the microcatheter between the stent and the artery. Both approaches impede manipulation of the microcatheter during coiling. We describe a modified jailing technique that improves catheter maneuverability and report the safety and efficacy of the method for the treatment of complex, wide-necked aneurysms.
METHODS: The semi-jailing technique involves the partial deployment of a retrievable stent, bridging part of the aneurysm neck while leaving space to maneuver the microcatheter. Twenty-two complex, wide-necked aneurysms, including 3 ruptured and 5 dissecting, were treated using the semi-jailing technique (15 women; mean age, 55.2 years).
RESULTS: The semi-jailing technique was successfully applied in all cases. Immediate posttreatment angiograms showed total occlusion of the aneurysm in 17 cases (77%), neck remnant in 3 cases (14%), and aneurysm dome filling in 2 cases (9%). Follow-up angiography available in 10 patients at an average of 8.5 months showed progressive occlusion in 1 aneurysm and 7 remained occluded. In 2 cases of dissecting aneurysms, retreatment was required. No permanent periprocedural morbidity was encountered. One patient died of complications secondary to intracranial hemorrhage 6 days after treatment. In 2 cases (9%), thromboembolic events after final stent placement were successfully treated with intraarterial thrombolysis. No delayed stent migration was seen.
CONCLUSION: Semi-jailing is a safe and effective stent-assisted coiling technique that facilitates treatment of complex, wide-necked aneurysms.