Pathologic and clinical tumor size discordance in early-stage cervical cancer: Does it matter?

OBJECTIVE: The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes. METHODS: This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size >4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method. RESULTS: Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p < .001) or preoperative tumor sizes ≤2 cm (p < .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11). CONCLUSIONS: Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors <2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

Randomized controlled trials define shape of dose response for Pollinex Quattro Birch allergoid immunotherapy.

BACKGROUND: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. METHODS: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency. RESULTS: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. CONCLUSION: Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.

Work-related health advice in primary care.

BACKGROUND: The dangers of long-term sickness absence and worklessness are well recognized. In the UK, the occupational health (OH) community was challenged to seek new partners to support health in working age people. A National Health Service OH service and Leicestershire general practice set up a pilot clinic to provide work-related health advice in primary care. AIMS: To recruit 100 patients to an OH clinic in general practice and record their demographic characteristics, diagnoses and occupational outcomes. METHODS: Pre-booked 30 min appointments for work-related health consultations in general practice were offered over 12 months. Consultations were recorded electronically and questionnaire feedback invited 3-6 months later. The main outcome was subjective reporting of benefit and workplace adjustments. RESULTS: Ninety-six patients attended OH appointments in general practice, 86 were in employment: 49 on sick leave at the time of their consultation and 10 were workless. Mental health and musculoskeletal problems accounted for the most common diagnoses. Following their consultation, 29% of patients reported workplace adjustments which were beneficial to them. None of the workless reported a return to employment. CONCLUSIONS: Patients will access work-related health advice in primary care. Extended OH consultations by general practitioners can achieve positive self-reported outcomes for patients in employment.

Sex- and menopause-associated changes in body-fat distribution.

We investigated sex- and menopause-related differences in body composition and regional fat distribution, using dual-energy X-ray absorptiometry (DEXA) in nonobese healthy volunteers. Men (n = 103) had a 50% greater lean tissue mass (P less than 0.001) but a 13% lower fat mass (P less than 0.001) than the women (n = 131). Postmenopausal (n = 70) women had a 20% greater fat mass (P less than 0.001) than premenopausal (n = 61) women. The proportion of android (upper body) fat was greatest in men (48.6%, P less than 0.001) but was significantly lower in premenopausal (38.3%) than in postmenopausal (42.1%) women (P less than 0.001). The reverse was found for gynoid (lower body) fat (P less than 0.001). DEXA measurements thus clearly demonstrated that sex differences in total fat mass were opposite those of android fat, and that marked menopausal changes in fat mass and its distribution existed. Body mass indices did not demonstrate that men had less total fat than women whereas postmenopausal women had more total fat than did premenopausal women. Our findings suggest that DEXA measurements of fat distribution may be useful for studies related to obesity-associated disease risk.

Relationships between insulin metabolism, serum lipid profile, body fat distribution and blood pressure in healthy men.

Insulin resistance and hyperinsulinaemia may be important in a cluster of coronary heart disease-related metabolic disturbances known as the insulin resistance syndrome. Whether the relationships between insulin and other features of the syndrome are independent of the amount and distribution of body fat is uncertain. We have investigated these relationships in 103 healthy males, using dual-energy X-ray absorptiometry to measure body fat directly. Volunteers underwent an intravenous glucose tolerance test (IVGTT), from which insulin sensitivity, secretion and elimination were determined by mathematical modelling analysis. Independently of adiposity and body fat distribution, serum triglyceride concentration was correlated with fasting C-peptide concentration and second-phase intravenous glucose tolerance test insulin concentration (r = 0.42, P < 0.001; r = 0.28, P < 0.05). High density lipoprotein subfraction 2 (HDL2) cholesterol was correlated with fasting C-peptide, first-phase IVGTT insulin concentration, and the hepatic insulin throughout index (r = -0.15 -0.20, -0. 20 respectively, all P < 0.05). The association of HDL2 cholesterol with the hepatic throughput index was additionally independent of serum triglyceride concentration (r = -0.18, P < 0.05). Our results suggest that relative hyperinsulinaemia leads to elevated triglyceride concentration, independently of body fat mass and distribution. Furthermore, the independent association of HDL2 cholesterol with hepatic insulin throughput confirms that hepatic insulin processing may may directly influence lipoprotein metabolism.

Body fat distribution, rather than overall adiposity, influences serum lipids and lipoproteins in healthy men independently of age.

PURPOSE: We investigated the relationships between the amount and distribution of body fat and fasting serum lipids and lipoproteins to explore whether coronary artery disease (CAD) risk may be mediated through effects on the serum lipid profile. PATIENTS AND METHODS: We determined serum total cholesterol and triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and HDL subfractions 2 and 3 in 103 healthy men, aged 21 to 77 years (mean 48.7). The amount and distribution of fat were determined directly by dual energy X-ray absorptiometry. Adiposity was determined as the ratio between total body fat tissue and total body lean tissue, while fat distribution was taken as the ratio between the mass of fat tissue in the android (central) and gynoid (hip and thigh) regions. RESULTS: Univariate analysis showed both adiposity and fat distribution to be correlated with total serum cholesterol and triglyceride concentrations (adiposity r = .20, .21; both P < 0.05: fat distribution r = .25, .38; P < 0.05, P < 0.001, respectively). Fat distribution was also negatively correlated with HDL2 cholesterol (r = -.20, P < 0.05). In multiple linear regression analysis, neither age nor adiposity was significantly correlated with any serum lipid or lipoprotein concentration, while increasing android-to-gynoid ratio was independently associated with elevated total serum triglyceride (r = .40, P < 0.01) and decreased HDL2 (r = -.25, P < 0.05) concentrations. CONCLUSIONS: The association of both age and overall adiposity with the fasting serum lipid profile are mediated via their correlations with body fat distribution. In men, the distribution, rather than the amount, of body fat is related to adverse changes in serum lipids and lipoproteins, and hence potentially to increased CAD risk.

Increased blood pressure following pupillary dilation with 2.5% phenylephrine hydrochloride in preterm infants.

Heart rate and blood pressure changes following 0.5% tropicamide and 2.5% phenylephrine hydrochloride were evaluated in seven ill preterm infants (birth weight, 910 to 2,060 gm; gestational age, 26 to 36 weeks) during the first day of life. Each infant was monitored continuously for 30 minutes before and for 75 minutes after, instillation of the pupillary dilators. There were no significant changes in the heart rate, whereas a significant increase in systolic, diastolic, and mean arterial blood pressure was found. The increase in arterial blood pressure was detected at two minutes, peaked at eight minutes, and remained at significantly higher levels for 30 minutes after instillation. Because of the potential relationship between increased blood pressure and intraventricular hemorrhage, arterial blood pressure must be monitored during instillation of mydriatic drugs in the preterm infant.

Bone density and endometriosis.

To establish whether there is evidence of low bone density in women with endometriosis, we compared bone density between 48 women with laparoscopically proven endometriosis and 48 age-matched normal controls. Bone density of the lumbar spine (L2-4), proximal femur (femoral neck, Ward's triangle, and trochanteric region), and total body were measured by dual energy roentgenogram absorptiometry. After adjusting for physical and lifestyle differences, bone density was not significantly different between the groups in any site. Bone density measurements were not related to the severity of endometriosis. These results do not confirm evidence of low bone density in women with endometriosis.

Changes in body composition with danazol therapy.

Whole body lean and fat mass measurements by dual energy x-ray absorptiometry were performed in 14 premenopausal women undergoing danazol treatment for endometriosis. After 6 months, there was a significant increase in lean tissue mass. Body fat decreased but this was significantly less in the android (upper body segment) region than in the gynoid (lower body segment) region. Danazol thus has both anabolic and androgenic effects on body composition. Dual energy x-ray absorptiometry provides a new, noninvasive, and rapid means of studying body composition.

Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial.

OBJECTIVE: To determine whether treatment of endometriosis with a GnRH analogue (GnRH-a; goserelin) combined with continuous estrogen and progestogen hormone replacement therapy (HRT) would prevent the hypoestrogenic effects, including loss of bone density, while maintaining efficacy for treatment of endometriosis. DESIGN: Randomized controlled trial. PATIENTS: Fifty premenopausal women with laparoscopically diagnosed endometriosis (revised American Fertility Score for endometriosis implants equal to four or greater) and significant symptoms of dysmenorrhoea, dyspareunia, and other pelvic pain. INTERVENTION: Patients were randomized to receive either goserelin alone, 3.6 mg SC depot every 4 weeks for 24 weeks, or goserelin, 3.6 mg SC depot every 4 weeks for 24 weeks, plus HRT (25 micrograms transdermal 17 beta E2 daily and 5 mg medroxyprogesterone acetate orally daily) for 20 weeks commencing with the second goserelin injection. RESULTS: There was a significant reduction in the extent of pelvic endometriosis in both groups, with no difference between the groups. Both groups experienced an improvement in symptoms and signs, again with no difference between groups. Hypoestrogenic side effects of hot flushes and loss of libido were significantly less in the group that received HRT. The amount of bone mineral density loss was significantly less in the HRT group at the lumbar spine, although it was not prevented completely. CONCLUSION: The addition of HRT to GnRH-a for the treatment of endometriosis did not reduce the efficacy of treatment, and adverse hypoestrogenic effects were decreased, although not abolished.

A randomized comparative study of the metabolic effects of two regimens of gestrinone in the treatment of endometriosis.

OBJECTIVE: To study some of the metabolic effects of oral gestrinone on plasma lipoprotein risk markers for cardiovascular disease and on bone density, a risk marker for osteoporosis. DESIGN: Randomized double-blind study. SETTING: All patients were referred to Gynaecology Clinic of Royal Free Hospital Medical School. PATIENTS: Twenty premenopausal women with laparoscopically confirmed endometriosis. INTERVENTIONS: Subjects were randomized in a double-blind fashion to receive either 1.25 mg or 2.5 mg gestrinone two times per week for 6 months. MAIN OUTCOME MEASURE: Laparoscopy was performed before treatment, and clinical responses were determined by second laparoscopy after 6 months. Plasma lipid and bone density measurements during and after therapy were compared with baseline. RESULT: Median total endometriosis scores decreased from 7.5 to 1.0 in the 1.25-mg group and from 7.0 to 0 in the 2.5-mg group. There were no significant between-group differences in endometriosis scores. At both doses, bone density in the spine and the proximal femur was conserved, but plasma concentrations of low-density lipoproteins rose by 13% and those of high-density lipoproteins fell by 40%. CONCLUSIONS: Reducing the dose of gestrinone to 1.25 mg appeared to maintain the therapeutic effectiveness of this treatment but was still associated with potentially unfavorable effects on lipids and lipoproteins.

17beta-estradiol (1 mg/day) continuously combined with dydrogesterone (5, 10 or 20 mg/day) increases bone mineral density in postmenopausal women.

Although the minimal dose of 17beta-estradiol in hormone replacement regimens was originally considered to be 2 mg/day, it is now increasingly accepted that a lower dose of 1 mg/day is effective in protecting women from the detrimental effects of the menopause. A 1-year, multicentre, double-blind, randomised study was conducted in 214 healthy postmenopausal women in order to assess the effect of 17beta-estradiol (1 mg/day) continuously combined with dydrogesterone (5, 10 or 20 mg/day) in preventing bone loss. Bone mineral density (BMD) was evaluable in 177 women who completed the study. In all women, a statistically significant increase from baseline in lumbar vertebrae (L2-L4) BMD was seen after 6 months ( + 2.4%; p < 0.01); this increase was somewhat greater after 12 months ( + 3.6%; p < 0.01). Similar effects were seen in the hip. After 6 months, BMD in the femoral neck, Ward's triangle and trochanter had increased by 0.20% (not significant [n.s.]), 0.32% (n.s.) and 1.08% (p < 0.01), respectively, compared with baseline. Greater increases were again seen after 12 months ( + 1.16%, + 1.62% and + 2.83%, respectively), all of which were statistically significant (p < 0.01) compared with baseline. The change in BMD from baseline did not differ significantly between the three dydrogesterone dosages for either L2-L4 or hip. All dosages were well-tolerated and amenorrhoea was achieved in over 70%. In conclusion, 17beta-estradiol (1 mg/day) continuously combined with dydrogesterone (5, 10 or 20 mg/day) results in a significant increase in lumbar vertebrae and hip BMD in postmenopausal women. The lower dose of oestrogen and the avoidance of cyclical bleeding make this a particularly suitable regimen for the prevention and treatment of osteoporosis in older women.

Determinants of bone density in normal women: risk factors for future osteoporosis?

Postmenopausal osteoporosis is an important public health problem in developed countries. Preventive treatment might effect a large reduction in the incidence, but this needs to be applied selectively to those women at increased risk. Loss of bone density results in an increased risk of fractures in the classical sites of vertebrae and proximal femur. A cross sectional study of bone density measurements was carried out in these sites in British women with a modern, precise densitometric technique. Possible predictors and risk factors for bone density were assessed in these women. Bone density was measured by dual photon absorptiometry in 284 apparently healthy women volunteers aged 21 to 68. The values obtained were similar to those obtained from equivalent studies performed in women in the United States. Peak adult bone density had been attained soon after the end of linear skeletal growth. Thereafter there was some decline with age in the proximal femur, but the major fall in bone density in all sites was related to the menopause. Other factors decreasing bone density, and hence increasing risk for osteoporosis, such as low body weight, alcohol and cigarette consumption, nulliparity, lack of previous use of oral contraceptives, and lack of regular exercise, seemed to be important. None, however, could predict satisfactorily women at future risk for osteoporosis. Direct measurements of bone density in the clinically relevant sites are necessary to determine which women should received preventive treatment for postmenopausal osteoporosis. This would help make such treatment more cost effective.

Preoperative 6-minute walk test adds prognostic information to Euroscore in patients undergoing aortic valve replacement.

AIMS: The authors investigated the additive prognostic value of the 6-minute walk test (6MWT) to Euroscore in patients with severe aortic stenosis undergoing aortic valve replacement (AVR) METHODS AND RESULTS: 208 patients with severe AS underwent the 6MWT before AVR, as part of a randomised trial (ASSERT) comparing stented and stentless aortic valves. Clinical follow-up was available for 200 patients up to 12 months. The rate of death, myocardial infarction (MI) or stroke (time to first event) was 13% (n = 14) in patients walking <300 metres compared to 4% (n = 4) in those who walked > or =300 metres (p = 0.017). When rate of death, MI or stroke by Euroscore risk was stratified by 6-minute walking distance, the 6MWT added prognostic information. In a Cox regression analysis 6MWT distance was the only variable retained as an independent predictor of the composite outcome of death, MI or stroke at 12 months (HR 0.28 95% CI 0.09 to 0.85, p = 0.025). CONCLUSIONS: The 6MWT is safe and feasible to carry out in patients with severe aortic stenosis before AVR, and provides potentially important functional and prognostic information to clinical assessment and the Euroscore risk score.

Pulmonary metastasectomy in colorectal cancer: time for a trial.

Pulmonary metastasectomy is undertaken for a range of cancers. The questions we raise here are specifically related to colorectal cancer, the commonest tumour for which pulmonary metastasectomy is undertaken. The primary objective of metastasectomy is to increase survival. There are no randomised trials in support of this practice nor are there any other forms of controlled studies. We present a critical look at the assumption of efficacy for this surgery and propose that a trial is needed and suggest a trial design.