Analysis of risk factors for recurrence in cervical cancer patients after fertility-sparing treatment: The FERTIlity Sparing Surgery retrospective multicenter study.

BACKGROUND: Fertility-sparing treatment in patients with cervical cancer should, in principle, follow identical algorithms to that in patients without future reproductive plans. In recent years, a trend toward nonradical procedures, such as conization or simple trachelectomy, has become apparent in medical literature, because of their associations with better pregnancy outcomes. However, the published reports included small numbers of patients and heterogenous treatment strategies to ascertain the safety of such approaches. OBJECTIVE: This study aimed to collect multi-institutional data regarding the oncological outcomes after fertility-sparing treatment in patients with cervical cancer and to identify prognostic risk factors, including the influence of the radicality of individual cervical procedures. STUDY DESIGN: Patients aged 18 to 40 years with International Federation of Gynecology and Obstetrics 2018 stage IA1 with positive lymphovascular space invasion or ≥IA2 cervical cancer who underwent any type of fertility-sparing procedure were eligible for this retrospective observational study, regardless of their histotype, tumor grade, and history of neoadjuvant chemotherapy. Associations between disease- and treatment-related characteristics with the risk of recurrence were analyzed. RESULTS: A total of 733 patients from 44 institutions across 13 countries were included in this study. Almost half of the patients had stage IB1 cervical cancer (49%), and two-thirds of patients were nulliparous (66%). After a median follow-up of 72 months, 51 patients (7%) experienced recurrence, of whom 19 (2.6%) died because of the disease. The most common sites of recurrence were the cervix (53%) and pelvic nodes (22%). The risk of recurrence was 3 times higher in patients with tumors >2 cm in size than in patients with smaller tumors, irrespective of the treatment radicality (19.4% vs 5.7%; hazard ratio, 2.982; 95% confidence interval, 1.383-6.431; P=.005). The recurrence risk in patients with tumors ≤2 cm in size did not differ between patients who underwent radical trachelectomy and patients who underwent nonradical (conization and simple trachelectomy) cervical procedures (P=.957), regardless of tumor size subcategory (<1 or 1-2 cm) or lymphovascular space invasion. CONCLUSION: Nonradical fertility-sparing cervical procedures were not associated with an increased risk of recurrence compared with radical procedures in patients with tumors ≤2 cm in size in this large, multicenter retrospective study. The risk of recurrence after any type of fertility-sparing procedure was significantly greater in patients with tumors >2 cm in size.

Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer.

BACKGROUND: An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes. METHODS: One hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique. RESULTS: Significantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium (p = 0.002). The expression of miR-34a was found lower in type II than in type I cancers (p = 0.037), in p53 mutated as compared to p53 wild type cancers (p = 0.003) and in high grade compared to in low grade cancers (p = 0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS (p = 0.039) and OS (p = 0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis (p = 0.022). miR-34a promoter methylation was found higher in type II cancers than in type I (p = 0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples (p = 0.05). CONCLUSION: We demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.

Prospective evaluation of the use of the thrombolysis in myocardial infarction score as a risk stratification tool for chest pain patients admitted to an ED observation unit.

BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) score has shown use in predicting 30-day and 1-year outcomes in emergency department (ED) patients with potential acute coronary syndrome. Few studies have evaluated the TIMI score in risk stratifying patients selected for the ED observation Unit (EDOU). Risk stratification of patients in this group could identify those at risk for significant cardiac events. Our goal was to evaluate TIMI use for risk stratification in this population and compare outcomes among differing scores. METHODS: A prospective observational study with 30-day telephone follow-up for a 12 month period. Baseline data, outcomes related to EDOU stay, admission, and 30-day outcomes were recorded. TIMI scores were calculated for each patient placed in EDOU. TIMI score was not utilized in the decision to place patients in observation. RESULTS: N = 552. Composite outcomes recorded were myocardial infarction, revascularization, or death either during the EDOU stay, inpatient admission, or the 30-day follow-up. Eighteen composite outcomes were recorded: stent (12 patients), coronary artery bypass graft (3 patients), myocardial infarction and stent (2 patients), and myocardial infarction, and coronary artery bypass graft (1 patient). Distribution by TIMI score was: 0 (102 patients), 1 (196), 2 (142), 3 (72), 4 (27), and 5 (5). Risk of composite outcome increased by score: 0 (1%), 1 (2.6%), 2 (2.1%), 3 (6.9%), 4 (11.1%), and 5 (20%). Those with an intermediate risk score (3-5) were also more likely to require admission (15.4% vs 9.8%, P = .048). CONCLUSION: The TIMI risk score may serve as an effective risk stratification tool among chest pain patients selected for EDOU placement. Patients with intermediate-risk by TIMI may be considered for inpatient admission and/or more aggressive evaluation and therapy.

Prospective evaluation of an ED observation unit protocol for trauma activation patients.

BACKGROUND: The University of Utah emergency department (ED) observation unit (EDOU) cares for over 2500 patients each year, with a significant portion of these patients being trauma activation patients. We evaluated the safety and efficacy of our EDOU trauma protocol and described patient characteristics and outcomes of trauma patients managed in an EDOU. METHODS: We performed a prospective observational study of all trauma patients admitted to the EDOU over a 1-year period. Patient disposition, interventions, and adverse events during observation were recorded. Thirty-day follow-up was performed by telephone and chart review to evaluate for missed injuries, repeat hospitalizations, or repeat traumatic events. RESULTS: A total of 259 trauma patients were admitted to the EDOU during the study period and were contacted at least 30 days after discharge. There were no deaths, intubations, or other adverse events. At 30-day follow-up, there was 1 missed injury, which did not result in an adverse outcome. Ten patients were reevaluated in the ED or required hospitalization for events occurring after their initial EDOU stay but related to their initial trauma evaluation. The inpatient admission rate from the EDOU was 10.4%, and 3.1% of patients reported another traumatic event during the 30-day follow-up period. CONCLUSIONS: There were no adverse outcomes in trauma patients admitted to the EDOU, and our inpatient admission rate was within the generally accepted admission rate for patients in observation status. The EDOU appears to be a safe alternative to inpatient admission for the evaluation of minimally injured trauma activation patients.

Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness.

OBJECTIVE: To study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). METHODS: Double-blind, randomized, placebo-controlled trial. RESULTS: Two hundred ninety-four healthy Western trekkers were recruited on the Everest approach at 4280 m or 4358 m and randomly assigned to receive either 600 mg of ibuprofen or placebo 3 times daily before and during ascent to 4928 m. One hundred eighty-three of 294 participants completed the trial. Of the participants who did not complete the trial, 62 were lost to follow-up and another 49 broke trial protocol. In an intent-to-treat analysis (232 participants), ibuprofen was found to be more effective than placebo in reducing the incidence of AMS (24.4% vs 40.4%; P = .01) and the incidence of HAH (42.3% vs 60.5%; P < .01). Ibuprofen was also superior to placebo in reducing the severity of HAH (4.9% vs 14.7%; P = .01). The end point of oxygen saturation was also higher in the ibuprofen group (80.8 % vs 82.4%; P = .035). For the 183 participants who completed the trial and conformed to the protocol, the incidence of AMS between placebo and treatment groups was not significant (32.9% vs 22.7%; P = .129 for AMS incidence, 9.6% vs 8.2%; P = .74 for AMS severity, 54.8% vs 42.7%; P = .11 for HAH incidence, and 8.2% vs 3.6%; P = .18 for HAH severity). CONCLUSIONS: Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial. This loss of significance in the subjects who completed the trial may be explained by persons in the placebo group having a higher burden of illness and associated decreased compliance with the protocol. An important limitation of this study may be the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS.

γ-Glutamyltransferase and Breast Cancer Risk Beyond Alcohol Consumption and Other Life Style Factors - A Pooled Cohort Analysis.

OBJECTIVE: Elevated γ-Glutamyltransferase serum levels are associated with increased risk of overall cancer incidence and several site-specific malignancies. In the present prospective study we report on the associations of serum γ-Glutamyltransferase with the risk of breast cancer in a pooled population-based cohort considering established life style risk factors. METHODS: Two cohorts were included in the present study, i.e. the Vorarlberg (n = 97,268) and the Malmoe cohort (n = 9,790). Cox proportional hazards regression models were fitted to estimate HRs for risk of breast cancer. RESULTS: In multivariate analysis adjusted for age, body mass index and smoking status, women with γ-Glutamyltransferase levels in the top quartile were at significantly higher risk for breast cancer compared to women in the lowest quartile (HR 1.21, 95% CI 1.09 to 1.35; p = 0.005). In the subgroup analysis of the Malmoe cohort, γ-Glutamyltransferase remained an independent risk factor for breast cancer when additionally considering alcohol intake. A statistically significant increase in risk was seen in women with γ-Glutamyltransferase-levels in the top versus lowest quartile in a multivariate model adjusted for age, body mass index, smoking status, physical activity, parity, oral contraceptive-use and alcohol consumption (HR 1.37, 95% CI 1.11-1.69, p = 0.006). CONCLUSION: Our findings identified γ-Glutamyltransferase as an independent risk factor for breast cancer beyond the consumption of alcohol and other life style risk factors.

Prospective evaluation of a simplified risk stratification tool for patients with chest pain in an emergency department observation unit.

BACKGROUND: The Thrombolysis in Myocardial Infarction score has been validated as a risk stratification tool in the emergency department (ED) setting, but certain aspects of the scoring system may not be applicable when applied to patients with chest pain selected for ED observation unit (EDOU) stay. We evaluated a simplified, 3-point risk stratification tool for patients in EDOU, which we termed the CARdiac score: Coronary disease [previous myocardial infarction (MI), stent, or coronary artery bypass graft (CABG)], Age (65 years or older), and Risk factors (at least 3 of 5 cardiac risk factors). METHODS: We performed a prospective, observational study with 30-day phone follow-up for all patients with chest pain admitted to our EDOU over a 36-month period. Baseline data, outcomes related to EDOU stay, inpatient admission, and 30-day outcomes were recorded. CARdiac scores were calculated based on patient history and were used to evaluate the risk of the composite outcome of MI, stent/CABG, or death during the EDOU stay. CARdiac scores were also used to evaluate the risk of inpatient admission. The CARdiac score was not used during the EDOU stay and was calculated blinding to patient outcomes. RESULTS: One thousand two hundred seventy-six patients were evaluated. Average age was 54.1 years (18-92 years) and 46% were male. Forty patients experienced composite outcomes: stent (32), CABG (4), MI and stent (2), MI and CABG (1), and MI (1). Risk of the composite outcome generally increased by CARdiac score: 0 (1.5%), 1 (3.6%), 2 (9%), and 3 (5.4%). Patients with a CARdiac score of 2 or 3 (moderate risk) were significantly more likely to experience MI, stent, or CABG than those with a score of 0 or 1 (low risk): 16/193 moderate-risk patients (8.3%) had the composite outcome versus 24/1083 low-risk patients (2.2%, P < 0.001, relative risk = 3.8). Those at moderate risk by the CARdiac score were also more likely to require inpatient admission from the EDOU (17.6% vs. 9.8%, P < 0.001). CONCLUSION: The CARdiac score may prove to be a simple tool for risk stratification of patients with chest pain in an EDOU. Patients at moderate risk by CARdiac score may be appropriate for more intensive evaluation in the EDOU or consideration for inpatient admission rather than EDOU placement.

Prospective evaluation of the treatment of intermediate-risk chest pain patients in an emergency department observation unit.

BACKGROUND: Emergency department observation units (EDOUs) serve an important role in the evaluation and risk stratification of low-risk chest pain patients. OBJECTIVES: Our goal was to evaluate our EDOU protocol for intermediate-risk chest pain patients and compare outcomes and inpatient admission rates for low-risk and intermediate-risk patients. METHODS: Prospective observational study with 30-day telephone follow-up for all chest pain patients admitted to our EDOU from June 1, 2009 to May 31, 2010. Our protocol for intermediate-risk chest pain patients includes patients with a self-reported history of coronary artery disease and negative initial cardiac testing in the emergency department. The EDOU protocol involves telemetry, serial cardiac biomarker testing, and mandatory cardiology consultation. RESULTS: A total of 552 chest pain patients were evaluated, including 100 (18.1%) intermediate-risk and 452 (81.9%) low-risk patients. Intermediate-risk chest pain patients were significantly more likely to have a myocardial infarction or undergo revascularization (stent or coronary artery bypass graft) (8.0% vs. 2.2%, P = 0.008). Intermediate-risk patients had a higher inpatient admission rate (16.0% vs. 8.8%, P = 0.032). There were no significant unanticipated adverse events at 30-day follow-up in either group. CONCLUSIONS: In conclusion, intermediate-risk chest pain patients in an EDOU had higher rates of significant cardiac events and inpatient admission. Intermediate-risk patients may be appropriate for EDOU placement, given the acceptable inpatient admission rate and the lack of significant adverse events in the 30-day follow-up period. However, given the higher rate of significant cardiac events, the results of our study emphasize the need for increased vigilance and close cardiology consultation in the intermediate-risk group.

Treatment of low-risk pulmonary embolism patients in a chest pain unit.

BACKGROUND: Several studies have proposed the Pulmonary Embolism Severity Index (PESI) as a risk stratification tool for discharge of low-risk pulmonary embolism (PE) patients from the emergency department (ED) and treatment as outpatients, but this has not become accepted standard of care in the United States. Chest pain units (CPUs) may serve as ideal locations for the treatment and risk-stratification of low-risk PE patients, thus avoiding lengthy inpatient stays while assuring patients are appropriate for outpatient therapy for PE. We sought to characterize the number of patients at our institution who may be eligible for a short stay in our CPU and then established a protocol for the treatment of low-risk patients in the CPU. METHODS: We identified all patients admitted to the University of Utah Medical Center from the ED with a diagnosis of PE over the 6-year period between 2002 and 2007. We retrospectively reviewed the electronic medical records to identify clinical variables to calculate a PESI score for each patient. Patients who were considered to be low-risk, on the basis of PESI score (class I and II), were considered eligible for treatment in the CPU, and, on the basis of this, we estimated numbers of patients to be treated in the CPU and patient demographics. We determined results of transthoracic echocardiography (TTE) and bilateral lower extremity (BLE) venous duplex ultrasound for PE patients to estimate potential inpatient admission rates from the CPU. We reviewed the electronic medical records during the 30-day period after hospital admission for patient mortality. We then created a protocol for the treatment of these low-risk patients in the CPU. RESULTS: A total of 545 patients were admitted with PE during the 6-year period. Of these patients, 282 were considered low risk and potentially appropriate for treatment of PE in the CPU. Of those, 43.3% were male, and the average age was 43.9 years (range: 14-92 years). Mortality was 0% for the low-risk group over the 30 days after hospital admission. A total of 108 patients had TTE performed and, of these, 30 had evidence of right heart strain. Ninety patients had BLE venous duplex and, of these, 15 had a deep venous thrombosis proximal to the popliteal veins. On the basis of our findings, we created a protocol for treatment of low-risk PE patients in the CPU. Patients who are low risk according to PESI score are admitted to the CPU with administration of low-molecular-weight heparin in the ED and initiation of oral anticoagulation therapy. Patients are monitored on telemetry for at least 12 hours, with performance of BLE duplex and TTE while in the CPU. Patients are admitted to an inpatient unit from the CPU if during their stay they exhibit unstable vital signs, a new arrhythmia, deep venous thrombosis proximal to the popliteal veins on BLE duplex, or signs of right heart strain on TTE. Patients who do not meet these criteria are considered appropriate for outpatient treatment and discharged with low-molecular-weight heparin and oral anticoagulation with thrombosis clinic follow-up. Given our findings from the retrospective chart review, we estimated that, at our institution, 4 patients per month would be eligible for treatment of PE in the CPU. With the findings on TTE and BLE duplex, we estimated that 25.3% of eligible patients would eventually require inpatient admission from the CPU. CONCLUSIONS: We identified a number of low-risk patients who may be eligible for treatment of PE in our CPU. Given the resources of the CPU, this may serve as an ideal location for the treatment of low-risk PE patients and allow further risk stratification and consultation beyond that typically readily available in the ED. We described the creation of a protocol for the treatment of low-risk patients with PE in a CPU.

Quantitative myocardial perfusion analysis with a dual-bolus contrast-enhanced first-pass MRI technique in humans.

PURPOSE: To compare fully quantitative and semiquantitative analysis of rest and stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) using a dual-bolus first-pass perfusion MRI method in humans. MATERIALS AND METHODS: Rest and dipyridamole stress perfusion imaging was performed on 10 healthy humans by administering gadolinium contrast using a dual-bolus protocol. Ventricular and myocardial time-signal intensity curves were generated from a series of T1-weighted images and adjusted for surface-coil intensity variations. Corrected signal intensity curves were then fitted using fully quantitative model constrained deconvolution (MCD) to quantify MBF (mL/min/g) and MPR. The results were compared with semiquantitative contrast enhancement ratio (CER) and upslope index (SLP) measurements. RESULTS: MBF (mL/min/g) estimated with MCD averaged 1.02 +/- 0.22 at rest and 3.39 +/- 0.59 for stress with no overlap in measures. MPR was 3.43 +/- 0.71, 1.91 +/- 0.65, and 1.16 +/- 0.19 using MCD, SLP, and CER. Both semiquantitative parameters (SLP and CER) significantly underestimated MPR (P < 0.001) and failed to completely discriminate rest and stress perfusion. CONCLUSION: Rest and stress MBF (mL/min/g) and MPR estimated by dual-bolus perfusion MRI fit within published ranges. Semiquantitative methods (SLP and CER) significantly underestimated MPR.