A Novel Method for Real-Time Quantification of Radioligand Binding to Living Tumor Cells In Vitro.

Background: Real-time quantification of radioligand binding to cells under in vivo-like conditions improves evaluation of clinical potential. Materials and Methods: SKOV-3 tumor cells were grown in a monolayer on a thin glass plate placed in a sealable shallow chamber with a continuous flow of 125I-trastuzumab solution. The time-dependent cell binding was measured using a NaI detector, and the binding parameters were derived by computational analysis. Results: The detection efficiency of 125I was 65 cps/kBq for radioligand bound to the cells. Experiments were analyzed to find the values of kon and koff. The resulting kon was 3.2-7.9 × 104 M-1 s-1 and koff was 0.11-4.2 × 10-5 s-1. Conclusions: Radioligands can be rapidly evaluated by binding to living cells for selection and optimization of radioconjugates for diagnostic and therapeutic purposes.

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.

Estimating the Risk for Secondary Cancer After Targeted α-Therapy with 211At Intraperitoneal Radioimmunotherapy.

Intraperitoneal 211At-based targeted α-therapy (TAT) may hold great promise as an adjuvant therapy after surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies that it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought to determine whether the treatment is justified. Methods: Baseline data for risk estimates of α-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either 224Ra treatments or Thorotrast contrast agent (25% ThO2 colloid, containing 232Th). Organ dosimetry for 224Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied to our previously reported dosimetry for intraperitoneal 211At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per gray (ERR/Gy) could be sorted into 2 groups. The lower-ERR/Gy group, ranging up to a value of approximately 5, included trachea, bronchus, and lung, at 0.52 (95% CI, 0.21-0.82); stomach, at 1.4 (95% CI, -5.0-7.9); lymphoid and hematopoietic system, at 2.17 (95% CI, 1.7-2.7); bone and articular cartilage, at 2.6 (95% CI, 2.0-3.3); breast, at 3.45 (95% CI, -10-17); and colon, at 4.5 (95% CI, -3.5-13). The higher-ERR/Gy group, ranging from approximately 10 to 15, included urinary bladder, at 10.1 (95% CI, 1.4-23); liver, at 14.2 (95% CI, 13-16); kidney, at 14.9 (95% CI, 3.9-26); and lip, oral cavity, and pharynx, at 15.20 (95% CI, 2.73-27.63). Applying a typical candidate patient (female, age 65 y) and correcting for the reference population mortality rate, the total estimated excess mortality for an intraperitoneal 211At-monoclonal antibody treatment amounted to 1.13 per 100 treated. More than half this excess originated from urinary bladder and kidney, 0.29 and 0.34, respectively. Depending on various adjustments in calculation and assumptions on competing risks, excess mortality could range from 0.11 to 1.84 per 100 treated. Conclusion: Published epidemiologic data on lifelong detriment after α-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer after 211At-based intraperitoneal TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211At-monoclonal antibody-based intraperitoneal TAT.

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.

Effects of Cardiac Rehabilitation on Physical Fitness, Physical Function, and Self-reported Outcomes in Patients ≥80 yr: A RANDOMIZED CONTROLLED TRIAL.

PURPOSE: The beneficial effects of exercise-based cardiac rehabilitation (CR) after an acute coronary syndrome (ACS) are well known, but patients ≥80 yr have been less studied. The aim was to evaluate the effects of CR on patients with ACS ≥80 yr on peak cardiorespiratory fitness (CRF), physical function, and patient-reported outcome measures (PROMs) compared with a control group. METHODS: A total of 26 patients with ACS, median age 82 (81, 84) yr, were randomized to hospital-based CR combined with a home-based exercise program (CR group) or to a control group (C) for 4 mo. Outcomes were assessed at baseline and 4 mo and included the peak CRF (primary outcome), 6-min walk test (6MWT), muscle endurance, Timed Up and Go (TUG), Short Physical Performance Battery (SPPB), one-leg stand test, and PROMs. RESULTS: There were no significant differences between the groups in peak CRF. The CR group improved significantly in terms of the 6MWT ( P = .04), isotonic muscle endurance ( P < .001), one-leg stand test ( P = .001), SPPB total score ( P =.03), Activities-specific Balance Confidence ( P =.01), and anxiety ( P =.03), as compared with C. There were no significant intergroup differences in the TUG, the self-reported health question or depression. CONCLUSIONS: Patients with ACS ≥80 yr improved in walking distance, muscle endurance, physical function, and PROMs, but not in peak CRF, by participating in a CR program. These results suggest an increased referral to CR for this growing group of patients to enable preserved mobility and independence in daily living, but this needs to be confirmed in larger studies.

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.

Astatine-211 based radionuclide therapy: Current clinical trial landscape.

Astatine-211 (211At) has physical properties that make it one of the top candidates for use as a radiation source for alpha particle-based radionuclide therapy, also referred to as targeted alpha therapy (TAT). Here, we summarize the main results of the completed clinical trials, further describe ongoing trials, and discuss future prospects.

Evaluation of therapeutic efficacy of 211At-labeled farletuzumab in an intraperitoneal mouse model of disseminated ovarian cancer.

INTRODUCTION: Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L). METHODS: For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211At-farletuzumab (n = 16); or with a combination of 125I-farletuzumab and 211At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2 × 106 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211At-labeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8). RESULTS: The biodistribution of 211At-farletuzumab was similar to that with 125I as radiolabel, and also to that of 211At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211At-rituximab 14%). TFF following treatment with 211At-farletuzumab was 91%. CONCLUSION: The current investigation of intraperitoneal therapy with 211At-farletuzumab, delivered at clinically relevant 211At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing.

Association of Pretreatment With P2Y12 Receptor Antagonists Preceding Percutaneous Coronary Intervention in Non-ST-Segment Elevation Acute Coronary Syndromes With Outcomes.

Importance: Pretreatment of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) with P2Y12 receptor antagonists is a common practice despite the lack of definite evidence for its benefit. Objective: To investigate the association of P2Y12 receptor antagonist pretreatment vs no pretreatment with mortality, stent thrombosis, and in-hospital bleeding in patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI). Design, Setting, and Participants: This cohort study used prospective data from the Swedish Coronary Angiography and Angioplasty Registry of 64 857 patients who underwent procedures between 2010 and 2018. All patients who underwent PCI owing to NSTE-ACS in Sweden were stratified by whether they were pretreated with P2Y12 receptor antagonists. Associations of pretreatment with P2Y12 receptor antagonists with the risks of adverse outcomes were investigated using instrumental variable analysis and propensity score matching. Data were analyzed from March to June 2019. Exposures: Pretreatment with P2Y12 receptor antagonists. Main Outcomes and Measures: The primary end point was all-cause mortality within 30 days. Secondary end points were 1-year mortality, stent thrombosis within 30 days, and in-hospital bleeding. Results: In total, 64 857 patients (mean [SD] age, 64.7 [10.9] years; 46 809 [72.2%] men) were included. A total of 59 894 patients (92.4%) were pretreated with a P2Y12 receptor antagonist, including 27 867 (43.7%) pretreated with clopidogrel, 34 785 (54.5%) pretreated with ticagrelor, and 1148 (1.8%) pretreated with prasugrel. At 30 days, there were 971 deaths (1.5%) and 101 definite stent thromboses (0.2%) in the full cohort. Pretreatment was not associated with better survival at 30 days (odds ratio [OR], 1.17; 95% CI, 0.66-2.11; P = .58), survival at 1 year (OR, 1.34; 95% CI, 0.77-2.34; P = .30), or decreased stent thrombosis (OR, 0.81; 95% CI, 0.42-1.55; P = .52). However, pretreatment was associated with increased risk of in-hospital bleeding (OR, 1.49; 95% CI, 1.06-2.12; P = .02). Conclusions and Relevance: This cohort study found that pretreatment of patients with NSTE-ACS with P2Y12 receptor antagonists was not associated with improved clinical outcomes but was associated with increased risk of bleeding. These findings support the argument that pretreatment with P2Y12 receptor antagonists should not be routinely used in patients with NSTE-ACS.

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.

Ticagrelor is Not Superior to Clopidogrel in Patients With Acute Coronary Syndromes Undergoing PCI: A Report from Swedish Coronary Angiography and Angioplasty Registry.

Background Ticagrelor reduces ischaemic end points in acute coronary syndromes. However, outcomes of ticagrelor versus clopidogrel in real-world patients with acute coronary syndromes treated with percutaneous coronary intervention (PCI) remain unclear. We sought to examine whether treatment with ticagrelor is superior to clopidogrel in unselected patients with acute coronary syndromes treated with PCI. Methods and Results We used data from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for PCI performed in Västra Götaland County, Sweden. The database contains information about all PCI performed at 5 hospitals (∼20% of all data in SCAAR). All procedures between January 2005 and January 2015 for unstable angina/non‒ST-segment‒elevation myocardial infarction and ST-segment‒elevation myocardial infarction were included. We used instrumental variable 2-stage least squares regression to adjust for confounders. The primary combined end point was mortality or stent thrombosis at 30 days, secondary end points were mortality at 30 days and 1-year, stent thrombosis at 30 days, in-hospital bleeding, in-hospital neurologic complications and long-term mortality. A total of 15 097 patients were included in the study of which 2929 (19.4%) were treated with ticagrelor. Treatment with ticagrelor was not associated with a lower risk for the primary end point (adjusted odds ratio [aOR], 1.20; 95% CI, 0.87-1.61; P=0.250). Estimated risk of death at 30 days (aOR, 1.18; 95% CI, 0.88-1.64; P=0.287) and at 1-year (aOR, 1.28; 95% CI, 0.86-1.64; P=0.556) was not different between the groups. The risk of in-hospital bleeding was higher with ticagrelor (aOR, 2.88; 95% CI, 1.53-5.44; P=0.001). Conclusions In this observational study, treatment with ticagrelor was not superior to clopidogrel in patients with acute coronary syndromes treated with PCI.

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.

Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure.

Despite the consensus around the clinical potential of the α-emitting radionuclide astatine-211 (211At), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing 211At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of 211At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with 211At depend on custom systems for recovering 211At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of 211At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between 211At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing 211At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with 211At.

Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors.

PURPOSE: Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic α-radioimmunotherapy (α-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the α-particle emitter 211At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. METHODS: PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of α-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (~100-200 µm; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. RESULTS: Tumor targeting of 211At-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003 mm3 versus 3.79 ± 1.24 mm3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). CONCLUSION: Evaluating fractionated α-RIT with 211At-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of 211At-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of α-RIT or by altering the size of the targeting vector.

Octogenarian preferences and expectations for acute coronary syndrome treatment.

BACKGROUND: The number of elderly persons with cardiovascular disease is increasing. In Sweden, the incidence of acute myocardial infarction is the highest among individuals aged 85 years and over. However, there is still little evidence about whether this population benefits from established treatments. Furthermore, the values and preferences of octogenarians (age ⩾80 years), as well as how they could be involved in treatment decisions, have been largely overlooked in research. Overall, increased knowledge about the preferences and expectations of octogenarians is needed to incorporate their treatment expectations into the decision-making process. AIMS: This study aimed to describe the treatment choice preferences and post-treatment life expectations of octogenarians with acute coronary syndrome. METHODS: A total of 19 patients (eight women, 11 men) aged 80 years and older and diagnosed with non-ST-elevation myocardial infarction or unstable angina were enrolled in this qualitative study. Data were collected between May 2011 and June 2013 through semistructured interviews. The data were analysed using qualitative content analysis. RESULTS: We identified two main categories: Wanting the best and Hope for increased wellbeing. Participant preferences were influenced by their own and others' previous experiences and their confidence in healthcare professionals. With respect to treatment outcomes, the participants hoped to get well, stay active, experience fewer symptoms and regain vitality. CONCLUSION: The studied octogenarians desired the best treatment option and trusted that their healthcare providers will make appropriate recommendations. These patients expected their treatment to result in increased wellbeing and fewer symptoms.

Comorbidity and bystander cardiopulmonary resuscitation in out-of-hospital cardiac arrest.

​OBJECTIVE: Cardiopulmonary resuscitation (CPR) performed before the arrival of emergency medical services (EMS) is associated with increased survival after out-of-hospital cardiac arrest (OHCA). The aim of this study was to determine whether patients who receive bystander CPR have a different comorbidity compared with patients who do not, and to determine the association between bystander CPR and 30-day survival when adjusting for such a possible difference. ​METHODS: Patients with witnessed OHCA in the Swedish Registry for Cardiopulmonary Resuscitation between 2011 and 2015 were included, and merged with the National Patient Registry. The Charlson Comorbidity Index (CCI) was used to measure comorbidity. Multiple logistic regression was used to examine the effect of CCI on the association between bystander CPR and outcome. ​RESULTS: In total, 11 955 patients with OHCA were included, 71% of whom received bystander CPR. Patients who received bystander CPR had somewhat lower comorbidity (CCI) than those who did not (mean±SD: 2.2±2.3 vs 2.5±2.4; p<0.0001). However, this difference in comorbidity had no influence on the association between bystander CPR and 30-day survival in a multivariable model including other possible confounders (OR 2.34 (95% CI 2.01 to 2.74) without adjustment for CCI and OR 2.32 (95% CI 1.98 to 2.71) with adjustment for CCI). ​CONCLUSION: Patients who undergo CPR before the arrival of EMS have a somewhat lower degree of comorbidity than those who do not. Taking this difference into account, bystander CPR is still associated with a marked increase in 30-day survival after OHCA.

Prognostic impact of percutaneous coronary intervention in octogenarians with non-ST elevation myocardial infarction: A report from SWEDEHEART.

AIMS: Percutaneous coronary intervention (PCI) improves outcomes in non-ST elevation acute coronary syndromes (NSTE-ACSs). Octogenarians, however, were underrepresented in the pivotal trials. This study aimed to assess the effect of PCI in patients ≥80 years old. METHODS AND RESULTS: We used data from the SWEDEHEART registry for all hospital admissions at eight cardiac care centres within Västra Götaland County. Consecutive patients ≥80 years old admitted for NSTE-ACS between January 2000 and December 2011 were included. We performed instrumental variable analysis with propensity score. The primary endpoint was all-cause mortality at 30 days and one year after index hospitalization. During the study period 5200 patients fulfilled the inclusion criteria. In total, 586 (11.2%) patients underwent PCI, the remaining 4613 patients were treated conservatively. Total mortality at 30 days was 19.4% (1007 events) and 39.4% (1876 events) at one year. Thirty-day mortality was 20.7% in conservatively treated patients and 8.5% in the PCI group (adjusted odds ratio 0.34; 95% confidence interval 0.12-0.97, p = 0.044). One-year mortality was 42.1% in the conservatively treated group and 16.3% in the PCI group (adjusted odds ratio 0.97; 95% confidence interval 0.36-2.51, p = 0.847). CONCLUSIONS: PCI in octogenarians with NSTE-ACS was associated with a lower risk of mortality at 30 days. However, this survival benefit was not sustained during the entire study-period of one-year.

PROspective evaluation of coronary FLOW reserve and molecular biomarkers in patients with established coronary artery disease the PROFLOW-trial: cross-sectional evaluation of coronary flow reserve.

BACKGROUND: Survivors of myocardial infarction (MI) are at high risk of new major adverse cardiovascular events (MACE). Coronary flow reserve (CFR) is a strong and independent predictor of MACE. Understanding the prevalence of impaired CFR in this patient group and identifying risk markers for impaired CFR are important steps in the development of personalized and targeted treatment for high-risk individuals with prior MI. METHODS: PROFLOW is a prospective, exploratory, cross-sectional open study. We used information from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) to identify high-risk patients with a history of type-1 MI. We measured CFR non-invasively in a left anterior descending artery (LAD) using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperemia by intravenous infusion of adenosine (140 µg/kg/min). Independent predictors of CFR were assessed with multiple linear regression. RESULTS: We included 619 patients. The median age was 69 (IQR 65-73), and 114 (18.4%) were women. Almost one-half of the patients, 285 (46.0%) had the multi-vessel disease, and 147 (23.7%) were incompletely revascularized. The majority were on optimal standard treatment eg ASA (93.1%), statins (90.0%), ACEI/ARB (82.6%) and beta-blockers (80.8%). The majority, 547 (88.4%) had no angina pectoris, and 572 (92.2%) were in NYHA class I. Evaluation of CFR was possible in 611 (98.7%) patients. Mean CFR was 2.74 (±0.79 (mean ± SD)). A substantial number of patients (39.7%) had CFR ≤2.5. In a multiple linear regression model age, dyslipidemia, smoking, hypertension, body mass index, incomplete revascularization, and treatment with angiotensin receptor blockers were independent predictors of CFR. CONCLUSION: In this high-risk group of patients with prior MI, the prevalence of impaired CFR was high. Further risk stratification with CFR in addition to traditional cardiovascular risk factors may improve predictive accuracy for future MACE in this patient population.

Towards elucidating the radiochemistry of astatine - Behavior in chloroform.

Targeted alpha therapy of disseminated cancer is an emerging technique where astatine-211 is one of the most promising candidate nuclides. Although astatine has been known for over 70 years, its chemistry is still largely unexplored, mainly due to the lack of stable or long-lived isotopes. However, substantial amounts of astatine-211 can be produced in cyclotrons by the bombardment of natural bismuth. The astatine can be recovered from the resulting irradiated target material through either wet extraction or dry-distillation. Chloroform has become an important intermediate solvent for the recovery of astatine after production, especially following dry distillation. In this work, the radiochemistry of astatine in chloroform was investigated using evaporation, solvent extraction, chromatographic methods and molecular modeling. The extraction of astatine in chloroform led to the formation of multiple astatine species, allowing for evaporation of the solvent to dryness without any loss of activity. Radiolysis products of chloroform were shown to play an important role in the speciation of astatine forming both reactive and kinetically stable compounds. It was hypothesized that reactions with chlorine, as well as trichloromethyl hydroperoxide, forming polar astatine compounds are important reactions under the current experimental conditions.

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.