Cost-Effectiveness of perioperative Vaginally Administered estrogen in postmenopausal women undergoing prolapse surgery (EVA trial): study protocol for a multicenter double-blind randomized placebo-controlled trial.

BACKGROUND: Surgery for pelvic organ prolapse (POP) is associated with high recurrence rates. The costs associated with the treatment of recurrent POP are huge, and the burden from women who encounter recurrent POP, negatively impacts their quality of life. Estrogen therapy might improve surgical outcome for POP due to its potential beneficial effects. It is thought that vaginal estrogen therapy improves healing and long-term maintenance of connective tissue integrity. Hence, this study aims to evaluate the cost-effectiveness of perioperative vaginal estrogen therapy in postmenopausal women undergoing POP surgery. METHODS: The EVA trial is a multi-center double-blind randomized placebo-controlled trial conducted in the Netherlands comparing the effectiveness and costs-effectiveness of vaginal estrogen therapy. This will be studied in 300 postmenopausal women undergoing primary POP surgery, with a POP-Q stage of ≥ 2. After randomization, participants administer vaginal estrogen cream or placebo cream from 4 to 6 weeks preoperative until 12 months postoperative. The primary outcome is subjective improvement of POP symptoms at 1 year follow-up, measured with the Patient Global Impression of Improvement (PGI-I) scale. Secondary outcomes are POP-Q anatomy in all compartments, re-interventions, surgery related complications, general and disease specific quality of life, sexual function, signs and complaints of vaginal atrophy, vaginal pH, adverse events, costs, and adherence to treatment. Follow up is scheduled at 6 weeks, 6 months and 12 months postoperative. Data will be collected using validated questionnaires and out-patient visits including gynecological examination performed by an independent gynecologist. DISCUSSION: This study investigates whether perioperative vaginal estrogen will be cost-effective in the surgical treatment of POP in postmenopausal women. It is hypothesized that estrogen therapy will show a reduction in recurrent POP symptoms and a reduction in reoperations for POP, with subsequent improved quality of life among women and cost savings. Trial registrationNetherlands Trial Registry: NL6853; registered 19-02-2018, https://www.trialregister.nl/trial/6853 . EudraCT: 2017-003144-21; registered: 24-07-2017.

Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction.

AIMS: The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI. METHODS AND RESULTS: TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7-/-) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7-/- mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7-/- heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI. CONCLUSIONS: In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium.

Lowering Low-Density Lipoprotein Particles in Plasma Using Dextran Sulphate Co-Precipitates Procoagulant Extracellular Vesicles.

Plasma extracellular vesicles (EVs) are lipid membrane vesicles involved in several biological processes including coagulation. Both coagulation and lipid metabolism are strongly associated with cardiovascular events. Lowering very-low- and low-density lipoprotein ((V)LDL) particles via dextran sulphate LDL apheresis also removes coagulation proteins. It remains unknown, however, how coagulation proteins are removed in apheresis. We hypothesize that plasma EVs that contain high levels of coagulation proteins are concomitantly removed with (V)LDL particles by dextran sulphate apheresis. For this, we precipitated (V)LDL particles from human plasma with dextran sulphate and analyzed the abundance of coagulation proteins and EVs in the precipitate. Coagulation pathway proteins, as demonstrated by proteomics and a bead-based immunoassay, were over-represented in the (V)LDL precipitate. In this precipitate, both bilayer EVs and monolayer (V)LDL particles were observed by electron microscopy. Separation of EVs from (V)LDL particles using density gradient centrifugation revealed that almost all coagulation proteins were present in the EVs and not in the (V)LDL particles. These EVs also showed a strong procoagulant activity. Our study suggests that dextran sulphate used in LDL apheresis may remove procoagulant EVs concomitantly with (V)LDL particles, leading to a loss of coagulation proteins from the blood.

Extracellular Vesicle Proteins Associated with Systemic Vascular Events Correlate with Heart Failure: An Observational Study in a Dyspnoea Cohort.

BACKGROUND: SerpinF2, SerpinG1, CystatinC and CD14 are involved in inflammatory processes and plasma extracellular vesicle (EV) -levels of these proteins have been reported to be associated with systemic vascular events. Evidence is accumulating that inflammatory processes may play a pivotal role both in systemic vascular events and in heart failure. Therefore, we studied the association between plasma extracellular vesicle SerpinF2-, SerpinG1-, CystatinC and CD14-levels and the occurrence of acute heart failure in patients. METHODS AND RESULT: Extracellular vesicle protein levels of SerpinG1, SerpinF2, CystatinC and CD14 were measured in an observational study of 404 subjects presenting with dysponea at the emergency department (4B-cohort). Plasma extracellular vesicles were precipitated in a total extracellular vesicles (TEX)-fraction and in separate LDL- and HDL-subfractions. Extracellular vesicle protein levels were measured with a quantitative immune assay in all 3 precipitates. Out of 404 subjects, 141 (35%) were diagnosed with acutely decompensated heart failure. After correction for confounders (including comorbidities and medications), levels of CD14 in the HDL-fraction (OR 1.53, p = 0.01), SerpinF2 in the TEX-and LDL-fraction (ORs respectively 0.71 and 0.65, p<0.05) and SerpinG1 in the TEX-fraction (OR 1.55, p = 0.004) were statistically significantly related to heart failure. Furthermore, extracellular vesicle CD14- and SerpinF2-levels were significantly higher in heart failure patients with preserved ejection fraction than in those with reduced ejection fraction. CONCLUSION: Extracellular vesicle levels of CD14, SerpinG1 and SerpinF2 are associated with the occurrence of heart failure in subjects suspected for acute heart failure, suggesting common underlying pathophysiological mechanisms for heart failure and vascular events.

The impact of hospital type on the efficacy of chemotherapy treatment in ovarian cancer patients.

OBJECTIVE: The hospital type affects the surgical outcomes of ovarian cancer patients. In the present study, we wanted to investigate the effect of hospital type on chemotherapy efficacy. METHODS: Data were collected from 1077 ovarian cancer patients treated from 1996 to 2003 in a random sample of 18 Dutch hospitals. Hospitals were categorized by the number of medical oncologists working in a hospital and additionally by chemotherapy volume (< or =100, 101-200, or >200 patients yearly) and ovarian cancer patient-volume (< or =6, 7-12, >12 yearly). The outcomes were the proportions of patients achieving complete remission, recurrence rates, and disease-free and overall survival. Data were analyzed using multivariable logistic regression (complete remission and recurrence) and Cox regression (survival). RESULTS: Data of 761 of the 777 patients who received chemotherapy could be analyzed. Hospital type did not affect the complete remission rates, recurrence rates, or the disease-free survival. Overall survival was better in hospitals with 2 or more medical oncologists and in hospitals with a high ovarian cancer patient-volume (hazard ratios both 0.8 (95% confidence interval=0.7-1.0)). CONCLUSIONS: Thus, hospital type did not influence the outcomes of first-line chemotherapy in ovarian cancer patients. However, overall survival was better in hospitals with 2 or more medical oncologists and in hospitals with a high ovarian cancer patient-volume, suggesting differences in second-line chemotherapy.

Specialized and high-volume care leads to better outcomes of ovarian cancer treatment in the Netherlands.

OBJECTIVE: We investigated the influence of hospital and gynecologist level of specialization and volume on surgical results and on survival of ovarian cancer patients. METHODS: Data were collected from 1077 ovarian cancer patients treated from 1996 to 2003 in a random sample of 18 Dutch hospitals. Hospitals and gynecologists were classified according to specialization (general, semi-specialized or specialized) and by volume (12 cases/year). Outcomes were percentage of adequately staged and optimally debulked patients and length of overall survival. Data were analyzed using multivariable logistic regression (surgical results) and Cox regression (survival). RESULTS: The level of specialization and the volume of hospitals and of gynecologists were strongly related to the proportion of adequately staged patients (adjusted odds ratio (OR) specialized hospitals 3.9 (95% confidence interval (CI) 2.0-7.6); specialized gynecologists 9.5 (95% CI 4.7-19)). Patients with stage III disease had a higher chance of optimal debulking when treated in specialized hospitals (adjusted OR 1.7 (95% CI 1.1-2.7)) or by high volume gynecologists (adjusted OR 2.8 (95% CI 1.4-5.7)). Overall survival was best in patients treated in specialized hospitals and by high-volume gynecologists. CONCLUSION: The specialization level of hospitals and the surgical volume of gynecologists positively influence outcomes of surgery and survival. Concentration of ovarian cancer care thus seems warranted.

Is centralization of ovarian cancer care warranted? A cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of tertiary referral care for ovarian cancer patients in the Netherlands. METHODS: We collected clinical and registry data on 1077 newly diagnosed ovarian cancer patients treated from 1996-2003 in a random sample of Dutch hospitals. Decision modelling was used to compare the cost-effectiveness of treatment in general hospitals, semi-specialized hospitals, and tertiary care centers. The actual direct medical costs of ovarian cancer treatment were evaluated. Long-term outcomes in terms of costs, quality-adjusted life-years (QALYs), and incremental costs per QALY gained were estimated. To assess uncertainty, multivariable sensitivity analyses and scenario analyses were performed. RESULTS: Treatment of ovarian cancer patients in semi-specialized hospitals costs on average euro882 more than in general hospitals (95% confidence interval -720 to 2462) and yields 0.12 additional QALYs (95% CI 0.02 to 0.22), resulting in an incremental cost-effectiveness ratio (ICER) of euro7135. Patients treated in tertiary care centers incurred again higher costs (euro10,591, 95% CI 8757 to 12,480) and also higher QALYs (0.10, 95% CI 0 to 0.21), resulting in an ICER of euro102,642 compared to semi-specialized hospitals. If the optimal debulking rate in tertiary care centers would increase to 70%, costs could drop below euro30,000 per QALY. CONCLUSION: Current treatment of ovarian cancer patients in semi-specialized hospital settings is a cost-effective strategy, while treatment in tertiary care centers becomes only cost-effective when better surgical results would be achieved.

Specialized care and survival of ovarian cancer patients in The Netherlands: nationwide cohort study.

BACKGROUND: There is much debate on the necessity of regionalization of ovarian cancer care. We investigated the association between hospital type and survival of patients with ovarian cancer in The Netherlands. METHODS: A retrospective, population-based cohort study was performed on all Dutch patients diagnosed with ovarian cancer from January 1, 1996, through December 31, 2003. We used data from the Netherlands Cancer Registry that were linked to mortality data from the Statistics Netherlands database to obtain the date and cause of death. Five-year relative survival ratios, defined as the ratio of the observed survival in the patient population to the expected survival of women in the general population with the same age, were determined for the total population and for groups stratified by tumor stage and/or hospital type. The association between hospital type and disease-specific survival was analyzed by use of multivariable Cox regression analyses. RESULTS: We analyzed data from 8621 women with epithelial ovarian cancer, of whom 3482 (40%) were treated in general hospitals, 3510 (41%) were treated in semispecialized hospitals, and 1557 (18%) were treated in specialized hospitals. Five-year relative overall survival ratios of patients treated in general, semispecialized, and specialized hospitals were 38.0% (95% confidence interval [CI] = 36.0% to 39.9%), 39.4% (95% CI = 37.5% to 41.4%), and 40.3% (95% CI = 37.4% to 43.1%), respectively; median survival of patients aged 50-75 years was 36 months (interquartile range [IQR] = 13 to >54 months), 37 months (IQR = 14 to >54 months), and 38 months (IQR = 15 to >55 months), respectively. Age and cancer stage were associated with the relationship between hospital type and ovarian cancer-specific survival but histologic tumor type, grade, year of diagnosis, and socioeconomic status were not. Among patients with early-stage ovarian cancer, treatment in semispecialized and specialized hospitals was associated with lower risks of ovarian cancer-specific mortality than treatment in general hospitals. Among patients with stage I-IIA disease who were aged 50-75 years, risk of ovarian cancer-specific mortality was 30% and 42% lower after treatment in semispecialized and specialized hospitals, respectively, than in general hospitals (for semispecialized hospitals, hazard ratio [HR] = 0.70, 95% CI = 0.53 to 0.93; for specialized hospitals, HR = 0.58, 95% CI = 0.38 to 0.87). Among patients with advanced ovarian cancer, hospital type was not associated with survival. CONCLUSION: Hospital type was statistically significantly associated with survival among Dutch ovarian cancer patients with early-stage ovarian cancer: Patients who were treated in specialized and semispecialized hospitals survived longer than patients treated in general hospitals.

The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review.

OBJECTIVE: There is much debate on the effect of specialized care for ovarian cancer patients. In this review we present an overview and summary of the recent literature on this subject. METHODS: The Pubmed database was searched for studies on the relationship between care setting (type of gynecologist or hospital) and care outcomes which were published between January 1991 and November 2006. Studies were included if they were of sufficient quality and included patients treated from 1990 onwards. RESULTS: Nineteen articles were retrieved. There were no randomized controlled trials on this subject. Staging and debulking were consistently found to be performed more adequately by gynecologic oncologists (pooled relative risk of optimal debulking by a gynecologic oncologist to <2 cm residual disease 1.4 (95%CI 1.2-1.5) and to no macroscopic disease 2.3 (95%CI 1.5-3.5)) and in specialized hospitals (odds ratios for optimal debulking varied between 1.9 and 6.0). There were no differences in postoperative complication rates between different providers. Chemotherapy was given 1-15% more often in specialized settings. Differences in chemotherapy did not lead to differences in survival of patients treated by gynecologic oncologists, but did influence the effect of hospital on survival. Long-term survival was better after treatment in a specialized hospital. Surgery by a gynecologic oncologist resulted in longer survival in subgroups of patients, leading to a 5- to 8-month median survival benefit for patients with advanced stage disease. CONCLUSIONS: The outcome of ovarian cancer is better when treatment is provided by a gynecologic oncologist or in a specialized hospital.