Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer.

Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

Societal costs of ovarian cancer in a population-based cohort - a cost of illness analysis.

BACKGROUND: The societal cost associated with ovarian cancer (OC) is not well known. Increasing costs for new treatments and/or the impact of organizational changes motivates these costs to be described and communicated. This study aims to evaluate the cost of illness of OC in a population-based cohort. MATERIAL AND METHODS: All patients diagnosed with ovarian, fallopian tube, primary peritoneal cancer, and serous cancer of undesignated primary site (UPS) in 2011-2012 were followed for six years. Direct costs, i.e., costs for health care expenditures, were gathered from the regional healthcare database. Information on indirect costs, i.e., costs of loss of production due to sick leave, was retrieved from Statistics Sweden. Sub-group analyses were conducted regarding stage, income levels, residential area, and diagnosis. RESULTS: The cost of illness for all stages during the six years of follow-up was €201,086 per patient, where indirect costs constituted 43.7%. The mean cost of illness per year per patient for all stages was €33,514. Direct costs were higher in advanced stages compared to early stages for every year from diagnosis. During the first two years, there were no differences in indirect costs between early and advanced stages. However, during the third year there was a difference with higher indirect costs in advanced stages. There was no difference in direct costs depending on income levels. Regarding residential area, there was a difference in the outpatient cost during the index and second year with higher costs when chemotherapy and follow-up were provided at county hospitals, compared to at the tertiary hospital. CONCLUSIONS: Indirect costs constituted a large part of the cost of illness over 6 years from diagnosis. This could indicate that even though treatment costs can be expected to rise with the introduction of new therapies, the societal cost may decrease when survival increase.

Complications after advanced ovarian cancer surgery-A population-based cohort study.

INTRODUCTION: Surgical complications after primary or interval debulking surgery in advanced ovarian cancer were investigated and associations with patient characteristics and surgical outcomes were explored. MATERIAL AND METHODS: A population-based cohort study including all women with ovarian cancer, FIGO III-IV, treated with primary or interval debulking surgery, 2013-2017. Patient characteristics, surgical outcomes and complications according to the Clavien-Dindo (CD) classification system ≤30 days postoperatively, were registered. Uni- and multivariable regression analyses were performed with severe complications (CD ≥ III) as endpoint. PFS in relation was analyzed using the Kaplan-Meier method. RESULTS: The cohort included 384 women, where 304 (79%) were treated with primary and 80 (21%) with interval debulking surgery. Complications CD I-V were registered in 112 (29%) patients and CD ≥ III in 42 (11%). Preoperative albumin was significantly lower in the CD ≥ III cohort compared with CD 0-II (P = 0.018). For every increase per unit in albumin, the risk of complications decreased by a factor of 0.93. There was no significant difference in completed chemotherapy between the cohorts CD 0-II 90.1% and CD ≥ III 83.3% (P = 0.236). In the univariable analysis; albumin <30 g/L, primary debulking surgery, complete cytoreduction and intermediate/high surgical complexity score (SCS) were associated with CD ≥ III. In the following multivariable analysis, only intermediate/high SCS was found to be an independent significant prognostic factor. Low (n = 180) vs intermediate/high SCS (n = 204) showed a median PFS of 17.2 months (95% confidence interval [CI] 15.2-20.7) vs 21.5 months (95% CI 18.2-25.7), respectively, with a significant log-rank; P = 0.038. CONCLUSIONS: Advanced ovarian cancer surgery is associated with complications but no significant difference was seen in completion of adjuvant chemotherapy when severe complications occur. Importantly, our study shows that intermediate/high SCS is an independent prognostic risk factor for complications. Low albumin, residual disease and primary debulking surgery were found to be associated with severe complications. These results may facilitate forming algorithms in the decision-making procedure of surgical treatment protocols.

Increased disease-free and relative survival in advanced ovarian cancer after centralized primary treatment.

OBJECTIVE: To analyze 5-year disease-free survival (DFS) and relative survival (RS) before and after the 2011 implementation of centralized primary treatment of patients with advanced ovarian cancer. METHODS: A population-based cohort study using the Swedish Quality Registry for Gynecological Cancer (SQRGC). Women with FIGO stage III and IV epithelial ovarian and Fallopian tube cancers were divided into two cohorts: before and after centralization. We estimated RS using the Ederer II method, analyzed the difference in the excess mortality rate ratio (EMRR) and estimated 5-year DFS in a Cox proportional hazard regression model with centralization, age, primary treatment and complete cytoreduction as variables. RESULTS: A total of 495 women were identified with 244 women before (2008-2010) and 251 after (2011-2013) centralization. An increased 5-year RS from 24% (95%CI:19-31) to 37% (95%CI:31-44) and an increased median RS from 27 months (95%CI:23-34) to 44 months (95%CI:40-52), p < 0.001 (log-rank), were observed in the total cohort regardless of primary treatment. EMRR was found to be 0.62 (95%CI:0.51-0.76) in 2011-2013 compared to 2008-2010 for all patients. After centralization, 5-year DFS was significantly longer, hazard ratio of 0.77 (95%CI:0.64-0.93) and centralization was found to be an independent significant factor for both survival and DFS. Complete cytoreduction was found to be a significant independent factor associated with increased RS and DFS. CONCLUSION: Centralization of primary treatment of advanced ovarian cancer was associated with significantly increased complete cytoreduction, 5-year RS and DFS, and was found to be a significant independent factor for both RS and DFS.

Percutaneous coronary intervention in the very elderly with NSTE-ACS: the randomized 80+ study.

Objective: The treatment strategy in the very elderly with NSTE-ACS is debated, as they are often under-represented in clinical trials. The aim of this multicenter randomized controlled trial was to compare invasive and conservative strategies in the very elderly with NSTE-ACS.Methods: We randomly assigned patients ≥ 80 years of age with NSTE-ACS to an invasive strategy with coronary angiography and optimal medical treatment or a conservative strategy with only optimal medical treatment. The primary outcome was the combined endpoint of major adverse cardiac and cerebrovascular events (MACCE). Sample size was powered for a 50% reduction of event rate in MACCE with an invasive strategy. We used intention-to-treat analysis.Results: Altogether, 186 patients were included between 2009 and 2017. The study was terminated prematurely due to slow enrollment. At 12-month follow-up, the primary outcome occurred in 31 (33.3%) of the invasive treatment group and 34 (36.6%) of the conservative treatment group, with a hazard ratio (HR) of 0.90 (95% CI 0.55‒1.46; p = 0.66) for the invasive group relative to the conservative group. The corresponding HR value for urgent revascularization was 0.29 (95% CI 0.10‒0.85; p = 0.02), 0.56 (95% CI 0.27‒1.18; p = 0.13) for myocardial infarction, 0.70 (95% CI 0.31‒1.58; p = 0.40) for all-cause mortality, 1.35 (95% CI 0.23‒7.98; p = 0.74) for stroke, and 1.62 (95% CI 0.67‒3.90; p = 0.28) for recurrent hospitalization for cardiac reasons.Conclusion: In the very elderly with NSTE-ACS, we did not find any significant difference in MACCE between invasive and conservative treatment groups at 12-month follow-up, possibly due to small sample size. ClinicalTrials.gov: NCT02126202.

Pretreatment with P2Y12 receptor antagonists in ST-elevation myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry.

AIMS: Pretreatment of patients with ST-elevation myocardial infarction (STEMI) with P2Y12 receptor antagonists is supported by guidelines and is a common practice despite the lack of definite evidence for its benefit. METHODS AND RESULTS: Using data from the Swedish Coronary Angiography and Angioplasty Registry on procedures between 2005 and 2016, we stratified all patients who underwent primary percutaneous coronary intervention due to STEMI in Sweden by whether or not they were pretreated with P2Y12 receptor antagonists. We investigated associations between pretreatment with P2Y12 receptor antagonists and the risk of adverse outcomes using propensity score-adjusted mixed-effects logistic regression, which accounted for clustering of patients within hospitals. The primary endpoint was all-cause death within 30 days. Secondary endpoints were infarct-related artery (IRA) occlusion, 30-day stent thrombosis, in-hospital bleeding, neurological complications, and cardiogenic shock. In total, 44 804 patients were included. They were treated with clopidogrel (N = 26 136, 58.3%), ticagrelor (N = 15 792, 35.3%), or prasugrel (N = 2352, 5.3%); 37 840 (84.5%) were pretreated, and 30 387 (67.8%) had IRA occlusion. At 30 days, there were 2488 (5.6%) deaths and 267 (0.6%) stent thrombosis. Pretreatment was not associated with better survival at 30 days [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.95-1.24; P = 0.313], reduced IRA occlusion (OR 0.98, 95% CI 0.92-1.05; P = 0.608), decreased stent thrombosis (OR 0.99, 95% CI 0.69-1.43; P = 0.932), higher risk of in-hospital bleeding (OR 1.05, 95% CI 0.89-1.26; P = 0.526), or neurological complications (OR 0.72, 95% CI 0.43-1.21; P = 0.210). CONCLUSION: Pretreatment of STEMI patients with P2Y12 receptor antagonists was not associated with improved clinical outcomes.

Labeling of Anti-HER2 Nanobodies with Astatine-211: Optimization and the Effect of Different Coupling Reagents on Their in Vivo Behavior.

The use of nanobodies (Nbs) as vehicles in targeted alpha therapy (TAT) has gained great interest because of their excellent properties. They combine high in vivo affinity and specificity of binding with fast kinetics. This research investigates a novel targeted therapy that combines the α-particle emitter astatine-211 (211At) and the anti-HER2 Nb 2Rs15d to selectively target HER2+ cancer cells. Two distinctive radiochemical methodologies are investigated using three different coupling reagents. The first method uses the coupling reagents, N-succinimidyl 4-(1,2-bis-tert-butoxycarbonyl)guanidinomethyl-3-(trimethylstannyl)benzoate (Boc2-SGMTB) and N-succinimidyl-3-(trimethylstannyl)benzoate (m-MeATE), which are both directed to amino groups on the Nb, resulting in random conjugation. The second method aims at obtaining a homogeneous tracer population, via a site-specific conjugation of the N-[2-(maleimido)ethyl]-3-(trimethylstannyl)benzamide (MSB) reagent onto the carboxyl-terminal cysteine of the Nb. The resulting radioconjugates are evaluated in vitro and in vivo. 2Rs15d is labeled with 211At using Boc2-SGMTB, m-MeATE, and MSB. After astatination and purification, the binding specificity of the radioconjugates is validated on HER2+ cells, followed by an in vivo biodistribution assessment in SKOV-3 xenografted mice. α-camera imaging is performed to determine uptake and activity distribution in kidneys/tumors. 2Rs15d astatination resulted in a high radiochemical purity >95% for all radioconjugates. The biodistribution studies of all radioconjugates revealed comparable tumor uptake (higher than 8% ID/g at 1 h). [211At]SAGMB-2Rs15d showed minor uptake in normal tissues. Only in the kidneys, a higher uptake was measured after 1 h, but decreased rapidly after 3 h. Astatinated Nbs consisting of m-MeATE or MSB reagents revealed elevated uptake in lungs and stomach, indicating the presence of released 211At. α-Camera imaging of tumors revealed a homogeneous activity distribution. The radioactivity in the kidneys was initially concentrated in the renal cortex, while after 3 h most radioactivity was measured in the medulla, confirming the fast washout into urine. Changing the reagents for Nb astatination resulted in different in vivo biodistribution profiles, while keeping the targeting moiety identical. Boc2-SGMTB is the preferred reagent for Nb astatination because of its high tumor uptake, its low background signals, and its fast renal excretion. We envision [211At]SAGMB-2Rs15d to be a promising therapeutic agent for TAT and aim toward efficacy evaluation.

Breast cancer survival trends in different stages and age groups - a population-based study 1989-2013.

BACKGROUND: During the recent decades, breast cancer survival has gradually improved but there is limited knowledge on the improvement in population-based studies of patients diagnosed with different stages of the disease and in different age groups. PATIENTS AND METHODS: In two Swedish health care regions a total of 42,220 female breast cancer patients below 90 years of age were diagnosed between 1989 and 2013. They were treated and followed according to national and regional guidelines and formed a population-based cohort. RESULTS: Using patients diagnosed in 1989-1993 as a reference to the relative risk, 5-year mortality decreased with 49% for patients diagnosed at the end of the observation period (CI 95% 45-58). The mortality tended to decrease for patients with all stages of breast cancer and test for trend resulted in a statistically significant improvement over time in 5-year relative survival in stage III and IV and in 10-year survival in stage I and III. For each operable stage of disease, patients aged below 40 years or more than 70 years when diagnosed tended to have less favorable survival than patients diagnosed between 40-69 years of age. Test for trend resulted in statistically significant improvements over time for patients diagnosed at ages below 40, 40-54 and 54-69, but less marked improvements for patients older than 70 when diagnosed. CONCLUSIONS: During the period 1989-2013 the relative risk of 5-year mortality decreased with 49%. Improvements were seen in all age groups but were unevenly distributed between stages and age groups pointing to the need for further improvements for younger and elderly patients.

Sustained risk of stent thrombosis and restenosis in first generation drug-eluting Stents after One Decade of Follow-up: A Report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).

AIMS: Long-term comparisons between Drug-eluting stent and bare metal stent are not well-studied. The aim of this study was to compare two stents that were previously frequently used in regard to long-term risk of restenosis and stent thrombosis (ST). METHODS AND RESULTS: We used data from the SCAAR registry. Consecutive procedures performed between 2004 and 2014 for stable angina, UA/NSTEMI and STEMI were included. We compared two different stents: Cordis Cypher Select (C-CS), and Boston Scientific Liberte (BS-L), modeling data with multilevel Cox proportional-hazards regression. The primary endpoint was time to first occurrence of either ST or restenosis. During the study period 2210 C-CS and 6941 B-SL were implanted in 5,314 patients. Mean follow-up time was 2,288 days for C-CS and 2,297 days for BS-L. Treatment with C-CS was associated with lower risk for restenosis or ST up to one year from index procedure (HR 0.41; 95% CI 0.32-0.52; P < .001). However, after one year of follow-up, risk was substantially higher in C-CS (HR 2.81; 95% CI 2.25-3.50; P < .001). CONCLUSION: Treatment with C-CS was not associated with better outcome than BS-L. Continuation of restenosis and ST long after the index procedure with C-CS present a major concern for patient safety.

Prognosis is similar for patients who undergo primary PCI during regular-hours and off-hours: A report from SCAAR.

BACKGROUND: Timely percutaneous coronary intervention (PCI) improves prognosis in ST-elevation myocardial infarction (STEMI). However, recent reports indicate that patients with STEMI who present during non-regular working hours (off-hours) have a worse prognosis. The aim of this study was to compare outcome between patients with STEMI who underwent primary PCI during off-hours and regular hours. METHODS: We retrieved data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) for all patients who underwent primary PCI in Region Västra Götaland due to STEMI between January 2004 and May 2013. We modeled unadjusted and adjusted Cox proportional-hazards regression and logistic regression models for the outcomes death, cardiogenic shock, stent thrombosis and in-stent restenosis. A propensity score-adjusted Cox proportional-hazards model, which adjusted for traditional cardiovascular risk factors was predefined as the primary statistical model. Death at any time during the study period was pre-specified as primary end-point. RESULTS: During the study period 4.611 (65%) patients underwent primary PCI due to STEMI during off-hours and 2,525 (35%) during regular hours. The risk of dying was similar among the groups for the primary endpoint death at any time during the study period (HR 1.00, 95% CI 0.89-1.12, P = 0.991) and for secondary end-point death within 30 days (HR 1.03; 95% CI 0.85-1.25, P = 0.735). The risks of developing cardiogenic shock, stent thrombosis, or in-stent restenosis were similar between the groups. CONCLUSIONS: In our region, short- and long-term prognosis for patients with STEMI who undergo primary PCI is similar for patients presenting during off-hours and regular hours.

Immunohistochemical evaluation of epithelial ovarian carcinomas identifies three different expression patterns of the MX35 antigen, NaPi2b.

BACKGROUND: To characterize the expression of the membrane transporter NaPi2b and antigen targeted by the MX35 antibody in ovarian tumor samples. The current interest to develop monoclonal antibody based therapy of ovarian cancer by targeting NaPi2b emphasizes the need for detailed knowledge and characterization of the expression pattern of this protein. For the majority of patients with ovarian carcinoma the risk of being diagnosed in late stages with extensive loco-regional spread disease is substantial, which stresses the need to develop improved therapeutic agents. METHODS: The gene and protein expression of SLC34A2/NaPi2b were analyzed in ovarian carcinoma tissues by QPCR (n = 73) and immunohistochemistry (n = 136). The expression levels and antigen localization were established and compared to the tumor characteristics and clinical data. RESULTS: Positive staining for the target protein, NaPi2b was detected for 93% of the malignant samples, and we identified three separate distribution patterns of the antigen within the tumors, based on the localization of NaPi2b. There were differences in the staining intensity as well as the distribution pattern when comparing the tumor grade and histology, the mucinous tumors presented a significantly lower expression of both the targeted protein and its related gene. CONCLUSION: Our study identified differences regarding the level of the antigen expression between tumor grade and histology. We have identified differences in the antigen localization between borderline tumors, type 1 and type 2 tumors, and suggest that a pathological evaluation of NaPi2b in the tumors would be helpful in order to know which patients that would benefit from this targeted therapy.

Effects of interactive patient smartphone support app on drug adherence and lifestyle changes in myocardial infarction patients: A randomized study.

BACKGROUND: Patients with myocardial infarction (MI) seldom reach recommended targets for secondary prevention. This study evaluated a smartphone application ("app") aimed at improving treatment adherence and cardiovascular lifestyle in MI patients. DESIGN: Multicenter, randomized trial. METHODS: A total of 174 ticagrelor-treated MI patients were randomized to either an interactive patient support tool (active group) or a simplified tool (control group) in addition to usual post-MI care. Primary end point was a composite nonadherence score measuring patient-registered ticagrelor adherence, defined as a combination of adherence failure events (2 missed doses registered in 7-day cycles) and treatment gaps (4 consecutive missed doses). Secondary end points included change in cardiovascular risk factors, quality of life (European Quality of Life-5 Dimensions), and patient device satisfaction (System Usability Scale). RESULTS: Patient mean age was 58 years, 81% were men, and 21% were current smokers. At 6 months, greater patient-registered drug adherence was achieved in the active vs the control group (nonadherence score: 16.6 vs 22.8 [P = .025]). Numerically, the active group was associated with higher degree of smoking cessation, increased physical activity, and change in quality of life; however, this did not reach statistical significance. Patient satisfaction was significantly higher in the active vs the control group (system usability score: 87.3 vs 78.1 [P = .001]). CONCLUSIONS: In MI patients, use of an interactive patient support tool improved patient self-reported drug adherence and may be associated with a trend toward improved cardiovascular lifestyle changes and quality of life. Use of a disease-specific interactive patient support tool may be an appreciated, simple, and promising complement to standard secondary prevention.

Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates.

Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 µm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies.

Acute coronary angiography after coronary artery bypass grafting.

OBJECTIVES: Coronary angiography is the golden standard when myocardial ischemia after CABG occurs. We summarize our experience of acute coronary angiography after CABG. DESIGN: All 4446 patients (mean age 68 ± 9 years, 22% women) who underwent CABG 2007 to 2012 were included in this retrospective observational study. Incidence, indications, findings, measures of acute angiography after CABG was assessed. Outcome variables were compared between patients who underwent angiography and those who did not. RESULTS: Eighty-seven patients (2%) underwent acute coronary angiography. Patients undergoing angiography had ECG changes (92%), echocardiographic alterations (48%), hemodynamic instability (28%), angina (15%), and/or arrhythmia (13%). Positive findings were detected in 69% of the cases. Only ECG changes as indication for angiography had a moderate association with positive findings, but the precision increased if other sign(s) of ischemia were present. Thirty-day mortality (7% versus 2%, p = 0.002) was higher and long-term-cumulative survival lower (77% versus 87% at five years, p = 0.043) in angiography patients. CONCLUSIONS: Acute angiography is a rare event after CABG. Postoperative myocardial ischemia leading to acute coronary angiography is associated with increased short-term and long-term mortality.

Deferral vs. performance of percutaneous coronary intervention of functionally non-significant coronary stenosis: 15-year follow-up of the DEFER trial.

AIMS: Stenting an angiographically intermediate but functionally non-significant stenosis is controversial. Nevertheless, it has been questioned if deferral of a functionally non-significant lesion on the basis of fractional flow reserve (FFR) measurement, is safe, especially on the long term. Five-year follow-up of the DEFER trial showed that outcome after deferral of percutaneous coronary intervention (PCI) of an intermediate coronary stenosis based on FFR ≥ 0.75 is excellent and was not improved by stenting. The aim of this study was to investigate the validity of this position on the very long term. METHODS AND RESULTS: In 325 patients scheduled for PCI of an intermediate stenosis, FFR was measured just before the planned intervention. If FFR was ≥0.75, patients were randomly assigned to deferral (Defer group; n = 91) or performance (Perform group; n = 90) of PCI. If FFR was <0.75, PCI was performed as planned (Reference group; n = 144). Clinical follow-up was 15 years. There were no differences in baseline clinical characteristics between the randomized groups. Complete 15-year follow-up was obtained in 92% of patients. After 15 years of follow-up, the rate of death was not different between the three groups: 33.0% in the Defer group, 31.1% in the Perform group, and 36.1% in the Reference group (Defer vs. Perform, RR 1.06, 95% CI: 0.69-1.62, P = 0.79). The rate of myocardial infarction was significantly lower in the Defer group (2.2%) compared with the Perform group (10.0%), RR 0.22, 95% CI: 0.05-0.99, P = 0.03. CONCLUSION: Deferral of PCI of a functionally non-significant stenosis is associated with a favourable very long-term follow-up without signs of late 'catch-up' phenomenon.

Ultrarapid Induction of Hypothermia Using Continuous Automated Peritoneal Lavage With Ice-Cold Fluids: Final Results of the Cooling for Cardiac Arrest or Acute ST-Elevation Myocardial Infarction Trial.

OBJECTIVES: Hypothermia (32-34 °C) can mitigate ischemic brain injury, and some evidence suggests that it can reduce infarct size in acute myocardial infarction and acute ischemic stroke. For some indications, speed of cooling may be crucial in determining efficacy. We performed a multicenter prospective intervention study to test an ultrarapid cooling technology, the Velomedix Automated Peritoneal Lavage System using ice-cold fluids continuously circulating through the peritoneal cavity to rapidly induce and maintain hypothermia in comatose patients after cardiac arrest and a small number of awake patients with acute myocardial infarction. DESIGN: Multicenter prospective intervention study. SETTING: Intensive care- and coronary care units of multiple tertiary referral centers. MEASUREMENTS AND MAIN RESULTS: Access to the peritoneal cavity was gained using a modified blunt dilating instrument, followed by catheter placement. Patients were cooled to a temperature of 32.5 °C, maintained for 24 hours (cardiac arrest) or 3 hours (acute myocardial infarction) followed by controlled rewarming. Forty-nine patients were enrolled, and 46 patients completed treatment. One placement was unsuccessful (abdominal wall not breached), two patients were ultimately not cooled, and only safety data are reported. Average catheter insertion time was 2.3 minutes. Mean time to temperature less than 33 °C was 10.4 minutes (average cooling rate, 14 °C/hr). Median infarct size in patients who had coronary interventions was 16% of LV. No cases of stent thrombosis occurred. Survival in cardiac arrest patients with initial rhythm of ventricular tachycardia/ventricular fibrillation was 56%, of whom 82 had a complete neurologic recovery. This compares favorably to outcomes from previous studies. CONCLUSION: Automated peritoneal lavage system is a safe and ultrarapid method to induce and maintain hypothermia, which appears feasible in cardiac arrest patients and awake patients with acute myocardial infarction. The shivering response appeared to be delayed and much reduced with this technology, diminishing metabolic disorders associated with cooling and minimizing sedation requirement. Our data suggest that ultrarapid cooling could prevent subtle neurologic damage compared with slower cooling. This will need to be confirmed in direct comparative studies.

Radical prostatectomy versus high-dose irradiation in localized/locally advanced prostate cancer: A Swedish multicenter randomized trial with patient-reported outcomes.

BACKGROUND: Treatment of localized prostate cancer (PC) is controversial. This is the first randomized study comparing an open surgery procedure (radical prostatectomy) with a combination of high-dose rate brachytherapy (2×10 Gy) and external beam radiotherapy (25×2 Gy) in PC patients in Sweden 1996-2001. The two randomization arms were compared regarding differences in patients-reported outcomes, such as complications and health-related quality of life (HRQoL). MATERIAL AND METHODS: The patients had localized/locally advanced PC, clinical category T1b-T3a, N0, M0 and PSA≤50 ng/ml. All underwent total androgen blockade (six months). Self-reported HRQoL and symptoms including urinary, bowel, and sexual side effects were investigated prospectively before randomization and 12 and 24 months after randomization. A total of 89 patients were randomized and completed the EORTC QLQ C-33 and EORTC PR-25 questionnaires. RESULTS: Over the study period, there were no discernible differences in HRQoL, or complications between the two groups. Emotional functioning, however, improved statistically significantly over time, whereas Social functioning decreased, and financial difficulties increased. No statistically significant differences in group-by-time interactions were found. The survival rate was 76%. Only eight patients (9%) died of PC. CONCLUSION: Open radical prostatectomy and the combined high-dose rate brachytherapy with external beam radiation appeared to be comparable in the measured outcomes. It was not possible to draw any conclusion on the efficacy of the two treatments due to insufficient power of the study.

The Use of Green Leaf Membranes to Promote Appetite Control, Suppress Hedonic Hunger and Loose Body Weight.

On-going research aims at answering the question, which satiety signal is the most potent or which combination of satiety signals is the most potent to stop eating. There is also an aim at finding certain food items or food additives that could be used to specifically reduce food intake therapeutically. Therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery illustrates the rationale of using several hormones to treat obesity and type-2-diabetes. We have found that certain components from green leaves, the thylakoids, when given orally have a similar rationale in inducing the release of several gut hormones at the same time. In this way satiety is promoted and hunger suppressed, leading to loss of body weight and body fat. The mechanism is a reduced rate of intestinal lipid hydrolysis, allowing the lipolytic products to reach the distal intestine and release satiety hormones. The thylakoids also regulate glucose uptake in the intestine and influences microbiota composition in the intestine in a prebiotic direction. Using thylakoids is a novel strategy for treatment and prevention of obesity.

Prognosis of elderly patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention in 2001 to 2011: A report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) registry.

BACKGROUND: Elderly patients constitute a growing part of the population presenting with ST-elevation myocardial infarction (STEMI). The use of primary percutaneous coronary intervention (PCI) in this high-risk population remains poorly investigated. METHODS: Using the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), we identified consecutive patients with STEMI 80 years or older undergoing primary PCI during a 10-year period. Temporal trends in care and 1-year prognosis were investigated, and long-term outcome was compared with a reference group of patients with STEMI aged 70 to 79 years. Relative survival was calculated by dividing the observed survival rate with the expected survival rate of the general population. Adjusted end points were calculated using Cox regression. RESULTS: In total, 4,876 elderly patients with STEMI were included. During the study period, average age and presence of comorbidity increased, as well as the use of antithrombotic therapy. Procedural success remained constant. One-year mortality was exclusively reduced between the most recent vs the earliest cohort, whereas the risk of reinfarction, heart failure, stroke, and bleeding remained similar. The risk of death was higher for elderly patients early after PCI, after which the prognosis was slightly better compared with the general population. Long-term risk of adverse events increased markedly with age. CONCLUSIONS: The prognosis of patients older than 80 years treated with primary PCI for STEMI was relatively unchanged during the 10-year inclusion period, despite changes in patient characteristics and treatment. Advanced age increased the risk of adverse events, but survivors of the early phase after PCI had a slightly improved prognosis compared with the general population.

Evidence for obesity paradox in patients with acute coronary syndromes: a report from the Swedish Coronary Angiography and Angioplasty Registry.

AIMS: The obesity paradox refers to the epidemiological evidence that obesity compared with normal weight is associated with counter-intuitive improved health in a variety of disease conditions. The aim of this study was to investigate the relationship between body mass index (BMI) and mortality in patients with acute coronary syndromes (ACSs). METHODS AND RESULTS: We extracted data from the Swedish Coronary Angiography and Angioplasty Registry and identified 64 436 patients who underwent coronary angiography due to ACSs. In 54 419 (84.4%) patients, a significant coronary stenosis was identified, whereas 10 017 (15.6%) patients had no significant stenosis. Patients were divided into nine different BMI categories. The patients with significant stenosis were further subdivided according to treatment received such as medical therapy, percutaneous coronary intervention (PCI), or coronary artery by-pass grafting. Mortality for the different subgroups during a maximum of 3 years was compared using Cox proportional hazards regression with the lean BMI category (21.0 to <23.5 kg/m(2)) as the reference group. Regardless of angiographic findings [significant or no significant coronary artery disease (CAD)] and treatment decision, the underweight group (BMI <18.5 kg/m(2)) had the greatest risk for mortality. Medical therapy and PCI-treated patients with modest overweight (BMI category 26.5-<28 kg/m(2)) had the lowest risk of mortality [hazard ratio (HR) 0.52; 95% CI 0.34-0.80 and HR 0.64; 95% CI 0.50-0.81, respectively]. When studying BMI as a continuous variable in patients with significant CAD, the adjusted risk for mortality decreased with increasing BMI up to ~35 kg/m(2) and then increased. In patients with significant CAD undergoing coronary artery by-pass grafting and in patients with no significant CAD, there was no difference in mortality risk in the overweight groups compared with the normal weight group. CONCLUSION: In this large and unselected group of patients with ACSs, the relation between BMI and mortality was U-shaped, with the nadir among overweight or obese patients and underweight and normal-weight patients having the highest risk. These data strengthen the concept of the obesity paradox substantially.