Application of 89Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody.

PURPOSE: The recent conditional FDA approval of Aducanumab (Adu) for treating Alzheimer's disease (AD) and the continued discussions around that decision have increased interest in immunotherapy for AD and other brain diseases. Reliable techniques for brain imaging of antibodies may guide decision-making in the future but needs further development. In this study, we used 89Zr-immuno-PET to evaluate the targeting and distribution of a bispecific brain-shuttle IgG based on Adu with transferrin receptor protein-1 (TfR1) shuttling mechanism, mAbAdu-scFab8D3, designated Adu-8D3, as a candidate theranostic for AD. We also validated the 89Zr-immuno-PET platform as an enabling technology for developing new antibody-based theranostics for brain disorders. METHODS: Adu, Adu-8D3, and the non-binding control construct B12-8D3 were modified with DFO*-NCS and radiolabeled with 89Zr. APP/PS1 mice were injected with 89Zr-labeled mAbs and imaged on days 3 and 7 by positron emission tomography (PET). Ex vivo biodistribution was performed on day 7, and ex vivo autoradiography and immunofluorescence staining were done on brain tissue to validate the PET imaging results and target engagement with amyloid-ß plaques. Additionally, [89Zr]Zr-DFO*-Adu-8D3 was evaluated in 3, 7, and 10-month-old APP/PS1 mice to test its potential in early stage disease. RESULTS: A 7-fold higher brain uptake was observed for [89Zr]Zr-DFO*-Adu-8D3 compared to [89Zr]Zr-DFO*-Adu and a 2.7-fold higher uptake compared to [89Zr]Zr-DFO*-B12-8D3 on day 7. Autoradiography and immunofluorescence of [89Zr]Zr-DFO*-Adu-8D3 showed co-localization with amyloid plaques, which was not the case with the Adu and B12-8D3 conjugates. [89Zr]Zr-DFO*-Adu-8D3 was able to detect low plaque load in 3-month-old APP/PS1 mice. CONCLUSION: 89Zr-DFO*-immuno-PET revealed high and specific uptake of the bispecific Adu-8D3 in the brain and can be used for the early detection of Aß plaque pathology. Here, we demonstrate that 89Zr-DFO*-immuno-PET can be used to visualize and quantify brain uptake of mAbs and contribute to the evaluation of biological therapeutics for brain diseases.

Healthcare cost variation in patients with heart failure: a nationwide study.

OBJECTIVE: Heart failure (HF) imposes a major economic burden; however, the individual management for patients varies, potentially leading to large cost heterogeneity. The aim of this study was to investigate the spectrum of health cost by patients with HF and factors associated with high direct health cost. STUDY DESIGN: This was a nationwide, retrospective longitudinal study. METHODS: Using Danish nationwide registries from 2012 to 2015, we identified all patients aged >18 years with a first-time diagnosis of HF. Total health costs were investigated using two perspectives-at index and during 3 years of follow-up. Patients were investigated by decile cost groups. A multivariable logistic regression was used to identify variables associated with being in the highest cost decile compared with the rest (90%). RESULTS: A total of 11,170 patients with HF were included, and those in the highest cost decile (n = 1117, 10%) were younger (69 vs. 75 years), fewer were females (34% vs. 43%), and more were inpatients (83% vs. 70%) compared with the rest of the patients with HF (n = 10,053, 90%). Patients in the highest cost decile (10%) incurred a 30 times higher cost with a mean total health cost in index year of €86,607 compared with €2893 for patients in lowest cost decile (10%). The results were similar for 3 years aggregated (€139,473 vs. €4086), corresponding to a 34 times higher cost. CONCLUSION: In patients with HF, a large total health cost heterogeneity exists with younger age, inpatient admittance, male sex, and comorbidities being associated with a higher likelihood of belonging to the highest cost group.

Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.

Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.

Soft X-Ray Second Harmonic Generation as an Interfacial Probe.

Nonlinear optical processes at soft x-ray wavelengths have remained largely unexplored due to the lack of available light sources with the requisite intensity and coherence. Here we report the observation of soft x-ray second harmonic generation near the carbon K edge (∼284 eV) in graphite thin films generated by high intensity, coherent soft x-ray pulses at the FERMI free electron laser. Our experimental results and accompanying first-principles theoretical analysis highlight the effect of resonant enhancement above the carbon K edge and show the technique to be interfacially sensitive in a centrosymmetric sample with second harmonic intensity arising primarily from the first atomic layer at the open surface. This technique and the associated theoretical framework demonstrate the ability to selectively probe interfaces, including those that are buried, with elemental specificity, providing a new tool for a range of scientific problems.

Cilostazol induces C-fos expression in the trigeminal nucleus caudalis and behavioural changes suggestive of headache with the migraine-like feature photophobia in female rats.

Introduction Research in development of new migraine therapeutics is hindered by the lack of suitable, predictive animal models. Cilostazol provokes headache in healthy humans and migraineurs by increasing intracellular cAMP levels. We aimed to investigate whether cilostazol could provoke headache-like behaviours and c-fos expression in rats. In order to evaluate the predictive validity of the model, we examined the response to the migraine specific drug sumatriptan. Methods The effect of cilostazol (125 mg/kg p.o.) in female Sprague Dawley rats was evaluated on a range of spontaneous behavioural parameters, light sensitivity and mechanical sensitivity thresholds. We also measured c-fos expression in the trigeminal nucleus caudalis. Results Cilostazol increased light sensitivity and grooming behaviour. These manifestations were not inhibited by sumatriptan. Cilostazol also induced c-fos expression in the trigeminal nucleus caudalis. Furthermore, trigeminal - but not hind paw hyperalgesia was observed. Conclusion The altered behaviours are suggestive of cilostazol induced headache with migraine-like features, but not specific. The presence of head specific hyperalgesia and the c-fos response in the trigeminal nucleus caudalis imply that the model involves trigeminal nociception. The model will be useful for studying mechanisms related to the cAMP pathway in headache, but its predictive properties appear to be more limited due to the lack of response to sumatriptan.

Out-of-hours intensive care unit admission and 90-day mortality: a Danish nationwide cohort study.

BACKGROUND: Mortality rates in critically ill adult patients admitted to the intensive care unit (ICU) remains high, and numerous patient- and disease-related adverse prognostic factors have been identified. In recent years, studies in a variety of emergency conditions suggested that outcome is dependent on the time of hospital admission. The importance of out-of-hours admission to the ICU has been sparsely evaluated and with ambiguous findings. We assessed the association between out-of-hours (16:00 to 07:00) and weekend admission to the ICU, respectively, and 90-day mortality in a nationwide cohort. METHODS: We included all Danish adult patients admitted to the ICU between 1 January 2011 and 30 June 2014, with an ICU stay > 24 h. The crude and adjusted association between out-of-hours and weekend admission and 90-day mortality was assessed (odds ratio (ORs) with 95% confidence intervals (CI)). RESULTS: A total of 44,797 patients were included, 53.3% were admitted out-of-hours, and 22.6% during weekends. Median age was 67 years (interquartile range (IQR) 55-76), and median SAPS II was 42 (IQR 30-54). Patients admitted in-hours vs. out-of-hours displayed a 90-day mortality rate of 41.0% vs. 44.2%. The adjusted association (OR with 95% CI) between out-of-hours admission and 90-day mortality was 1.07 (1.02-1.11), and the adjusted association (OR with 95% CI) between weekend admission and 90-day mortality was 1.10 (1.05-1.15). CONCLUSION: This nationwide study suggests that critically ill adult patients admitted to the ICU during weekends and out-of-hours, and with an ICU stay > 24 h are at slightly increased risk of mortality.

Attitudes of physicians towards the care of critically ill elderly patients - a European survey.

BACKGROUND: Very elderly patients are one of the fastest growing population in ICUs worldwide. There are lots of controversies regarding admission, discharge of critically ill elderly patients, and also on treatment intensity during the ICU stay. As a consequence, practices vary considerably from one ICU to another. In that perspective, we collected opinions of experienced ICU physicians across Europe on statements focusing on patients older than 80. METHODS: We sent an online questionnaire to the coordinator ICU physician of all participating ICUs of an recent European, observational study of Very old critically Ill Patients (VIP1 study). This questionnaire contained 12 statements about admission, triage, treatment and discharge of patients older than 80. RESULTS: We received answers from 162 ICUs (52% of VIP1-study) spanning 20 different European countries. There were major disagreements between ICUs. Responders disagree that: there is clear evidence that ICU admission is beneficial (37%); seeking relatives' opinion is mandatory (17%); written triage guidelines must be available either at the hospital or ICU level (20%); level of care should be reduced (25%); a consultation of a geriatrician should be sought (34%) and a geriatrician should be part of the post-ICU trail (11%). The percentage of disagreement varies between statements and European regions. CONCLUSION: There are major differences in the attitude of European ICU physicians on the admission, triage and treatment policies of patients older than 80 emphasizing the lack of consensus and poor level of evidence for most of the statements and outlining the need for future interventional studies.

Intensive care doctors' preferences for arterial oxygen tension levels in mechanically ventilated patients.

BACKGROUND: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors' preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors' preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. METHODS: In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. RESULTS: The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO2 ) the most important parameter; 24% a combination of PaO2 and arterial oxygen saturation (SaO2 ); and 23% preferred SaO2 . Increasing, decreasing or not changing a default fraction of inspired oxygen of 0.50 showed preferences for a PaO2 around 8 kPa in patients with chronic obstructive pulmonary disease, a PaO2 around 10 kPa in patients with healthy lungs, acute respiratory distress syndrome or sepsis, and a PaO2 around 12 kPa in patients with cardiac or cerebral ischaemia. Eighty per cent would accept a PaO2 of 8 kPa or lower and 77% would accept a PaO2 of 12 kPa or higher in a clinical trial of oxygenation targets. CONCLUSION: Intensive care unit doctors preferred PaO2 to SaO2 in monitoring oxygen treatment when peripheral oxygen saturation was not included in the question. The identification of PaO2 as the preferred target and the thorough clarification of preferences are important when ascertaining optimal oxygenation targets. In particular when designing future clinical trials of higher vs lower oxygenation targets in ICU patients.

Blood flow after contraction and cuff occlusion is reduced in subjects with muscle soreness after eccentric exercise.

Delayed onset muscle soreness (DOMS) occurs within 1-2 days after eccentric exercise, but the mechanism mediating hypersensitivity is unclear. This study hypothesized that eccentric exercise reduces the blood flow response following muscle contractions and cuff occlusion, which may result in accumulated algesic substances being a part of the sensitization in DOMS. Twelve healthy subjects (five women) performed dorsiflexion exercise (five sets of 10 repeated eccentric contractions) in one leg, while the contralateral leg was the control. The maximal voluntary contraction (MVC) of the tibialis anterior muscle was recorded. Blood flow was assessed by ultrasound Doppler on the anterior tibialis artery (ATA) and within the anterior tibialis muscle tissue before and immediately after 1-second MVC, 5-seconds MVC, and 5-minutes thigh cuff occlusion. Pressure pain thresholds (PPTs) were recorded on the tibialis anterior muscle. All measures were done bilaterally at day 0 (pre-exercise), day 2, and day 6 (post-exercise). Subjects scored the muscle soreness on a Likert scale for 6 days. Eccentric exercise increased Likert scores at day 1 and day 2 compared with day 0 (P<.001). Compared with pre-exercise (day 0), reduced PPT (~25%, P<.002), MVC (~22%, P<.002), ATA diameter (~8%, P<.002), ATA post-contraction/occlusion blood flow (~16%, P<.04), and intramuscular peak blood flow (~23%, P<.03) were found in the DOMS leg on day 2 but not in the control leg. These results showed that eccentric contractions decreased vessel diameter, impaired the blood flow response, and promoted hyperalgesia. Thus, the results suggest that the blood flow reduction may be involved in the increased pain response after eccentric exercise.

Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.

Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.

Motor Cortex Reorganization and Impaired Function in the Transition to Sustained Muscle Pain.

Primary motor cortical (M1) adaptation has not been investigated in the transition to sustained muscle pain. Daily injection of nerve growth factor (NGF) induces hyperalgesia reminiscent of musculoskeletal pain and provides a novel model to study M1 in response to progressively developing muscle soreness. Twelve healthy individuals were injected with NGF into right extensor carpi radialis brevis (ECRB) on Days 0 and 2 and with hypertonic saline on Day 4. Quantitative sensory and motor testing and assessment of M1 organization and function using transcranial magnetic stimulation were performed prior to injection on Days 0, 2, and 4 and again on Day 14. Pain and disability increased at Day 2 and increased further at Day 4. Reorganization of M1 was evident at Day 4 and was characterized by increased map excitability. These changes were accompanied by reduced intracortical inhibition and increased intracortical facilitation. Interhemispheric inhibition was reduced from the "affected" to the "unaffected" hemisphere on Day 4, and this was associated with increased pressure sensitivity in left ECRB. These data provide the first evidence of M1 adaptation in the transition to sustained muscle pain and have relevance for the development of therapies that seek to target M1 in musculoskeletal pain.

Extracorporeal cardiopulmonary resuscitation after out-of-hospital cardiac arrest in a Danish health region.

BACKGROUND: Extracorporeal Cardiopulmonary Resuscitation (ECPR) has emerged as a feasible rescue therapy for refractory, normothermic out-of-hospital cardiac arrest (OHCA). Reported survival rates vary and comparison between studies is hampered by heterogeneous study populations, differences in bystander intervention and in pre-hospital emergency service organisation. We aimed to describe the first experiences, treatment details, complications and outcome with ECPR for OHCA in a Danish health region. METHODS: Retrospective study of adult patients admitted at Aarhus University Hospital, Denmark between 1 January 2011 and 1 July 2015 with witnessed, refractory, normothermic OHCA treated with ECPR. OHCA was managed with pre-hospital advanced airway management and mechanical chest compression during transport. Relevant pre-hospital and in-hospital data were collected with special focus on low-flow time and ECPR duration. Survival to hospital discharge with Cerebral Performance Category (CPC) of 1 and 2 at hospital discharge was the primary endpoint. RESULTS: Twenty-one patients were included. Median pre-hospital low-flow time was 54 min [range 5-100] and median total low-flow time was 121 min [range 55-192]. Seven patients survived (33%). Survivors had a CPC score of 1 or 2 at hospital discharge. Five survivors had a shockable initial rhythm. In all survivors coronary occlusion was the presumed cause of cardiac arrest. CONCLUSION: Extracorporeal cardiopulmonary resuscitation is feasible as a rescue therapy in normothermic refractory OHCA in highly selected patients. Low-flow time was longer than previously reported. Survival with favourable neurological outcome is possible despite prolonged low-flow duration.

Impact of diabetes duration on achieved reductions in glycated haemoglobin, fasting plasma glucose and body weight with liraglutide treatment for up to 28 weeks: a meta-analysis of seven phase III trials.

This meta-analysis of seven randomized, placebo-controlled studies (total 3222 patients) evaluated whether type 2 diabetes (T2D) duration affects the changes in blood glucose control and body weight that can be achieved with liraglutide and placebo. With liraglutide 1.2 mg, shorter diabetes duration was associated with a significantly greater, but clinically non-relevant, difference in glycated haemoglobin (HbA1c) reduction (p < 0.05), i.e. a 0.18% (1.96 mmol/mol) reduction in HbA1c per 10 years shorter diabetes duration. With liraglutide 1.8 mg, shorter diabetes duration was associated with a small but statistically significant trend for greater fasting plasma glucose (FPG) reduction (p < 0.05), i.e. a 0.38 mmol/l reduction in FPG per 10 years shorter diabetes duration. Neither the liraglutide 1.8 mg nor placebo results showed a significant association between HbA1c and diabetes duration and neither the liraglutide 1.2 mg nor placebo results showed a significant association between FPG and diabetes duration. Likewise, neither liraglutide nor placebo showed a significant association between change in weight and diabetes duration. These results suggest diabetes duration has a clinically negligible effect on achievable blood glucose control and weight outcomes with liraglutide and placebo in patients with T2D.

Multi-primer qPCR assay capable of highly efficient and specific detection of the vast majority of all known Mycoplasma.

Mycoplasma bacteria are able to pass through sterilizing grade filters due to their small size and lack of a cell wall, making them a common contaminant of biopharmaceutical productions. The classical method for detecting Mycoplasma is described in the European Pharmacopeia (Ph.Eur) 2.6.7. The method takes 28 days to perform, due to the slow growing nature of some Mycoplasma species. The Ph.Eur has described Nucleic Acid Testing (NAT) as a rapid alternative to the classical method. Here we present the development of a quantitative polymerase chain reaction (qPCR) assay capable of unambiguous detection of Mycoplasma with high sensitivity and specificity. The broadness of detection and the specificity towards Mycoplasma has been investigated by in silico analysis of the primer sequences followed by testing on purified Mycoplasma DNA as well as DNA from closely related genera. The assay will in all probability detect at least 356 species and strains of Mycoplasma, Spiroplasma and Acholeplasma with high sensitivity. To our knowledge this assay has the most uniform amplification efficiency over the broadest range of species and it is extremely specific towards Mycoplasma. With appropriate validation, the assay can be applied as a powerful tool for rapid Mycoplasma detection in the biopharmaceutical industry.

Chronic hepatitis C patients prior to broad access to interferon-free treatments in Germany.

In 2014, the first interferon-free treatment options for chronic Hepatitis C (CHC) became available in Europe introducing a new era of highly effective and well tolerated oral treatment options for CHC. The data from the cross-sectional study CURRENT-C highlights the epidemiological characteristics of patients with CHC in Germany. During the period that the study was conducted, the approval of the combination drugs for the treatment of CHC was imminent.Between June and November 2014, 1471 CHC-patients not receiving anti-HCV treatment were included nationwide in 40 German centers specializing in viral hepatitis. The mean age was 52.4 years with 41.2 % of the patients being female. Presumed route of infection in male patients was most frequently drug use (46.2 %) and blood products in females (22.8 %). The route of infection was unknown in 28.2 % of male and 43.1 % of female patients. Compared to male patients, female patients were older (55.6 vs. 50.1 years) and longer diagnosed with HCV (18 vs. 15 years). First language of the patients was most frequently German (72.2 %), followed by Russian (14.2 %), and Polish (2.9 %). HCV genotype (GT) 1 was found in 73.8 % (1a 29.0 %, 1b 38.4 %), GT2 in 3.5 %, GT3 in 18.3 %, GT4 in 4.2 %, GT5 in 0.2 %, and GT6 in 0.3 %. Liver cirrhosis was diagnosed in 15.7 % of the patients (17.1 % male, 13.7 % female). 43.2 % of the patients had already received HCV treatment, most frequently dual therapy with pegIFN + RBV (75.8 %) or triple therapy with telaprevir or boceprevir (20.3 %). Compared to treatment-naïve patients, pretreated HCV patients were older (55.1 vs. 50.3 years) and more frequently had liver cirrhosis as clinical diagnosis (22.2 % vs. 10.8 %). Patients scheduled for HCV treatment within the next 3 months had higher rates of pre-treatment (49.4 % vs. 37.0 %), and liver cirrhosis (21.4 % vs. 10.0 %).Compared to epidemiological data of Hüppe et al. 1 from 2003 to 2006, Klass et al. 2 stated in 2012 in a comparable setting that the German CHC population were older and had more advanced liver disease. The current data seem to support this ongoing trend towards more difficult to treat patients with an urgent need for new treatment options.

Ipsilateral fibular transfer as a salvage procedure for large traumatic tibial defects in children in an austere environment.

Large tibial defects present a challenging scenario for the orthopaedic surgeon, particularly in the paediatric patient. Most management options, such as the vascularised fibular graft or Ilizarov technique, require microsurgical techniques or specialist equipment. In an austere environment, acute shortening or limb amputation may be most appropriate. However, limb salvage may be achieved by ipsilateral fibular transfer. In a one-stage operation, the fibular graft is harvested and either placed in the tibial defect in an intramedullary position or secured to the tibia with screws. We present two paediatric cases where this approach was used to preserve the lower limb despite extensive explosive trauma. In the first case, an 11 cm tibial defect was managed with an ipsilateral fibular graft. The graft was placed in an intercalary position proximally, with medial displacement of the ankle and fixation of the fibula as a strut graft. In the second case, a 10 cm tibial defect was managed with an ipsilateral fibular graft, using intercalary placement proximally and distally. Both children returned to weight bearing with crutches within several months of surgery. For large tibial defects, ipsilateral fibular transfer is an effective one-stage operation that represents a viable alternative to amputation in austere environments.

Background risk of breast cancer influences the association between alcohol consumption and mammographic density.

BACKGROUND: Alcohol consumption has been suggested to increase risk of breast cancer through a mechanism that also increases mammographic density. Whether the association between alcohol consumption and mammographic density is modified by background breast cancer risk has, however, not been studied. METHODS: We conducted a population-based cross-sectional study of 53 060 Swedish women aged 40-74 years. Alcohol consumption was assessed using a web-based self-administered questionnaire. Mammographic density was measured using the fully-automated volumetric Volpara method. The Tyrer-Cuzick prediction model was used to estimate risk of developing breast cancer in the next 10 years. Linear regression models were used to evaluate the association between alcohol consumption and volumetric mammographic density and the potential influence of Tyrer-Cuzick breast cancer risk. RESULTS: Overall, increasing alcohol consumption was associated with higher absolute dense volume (cm(3)) and per cent dense volume (%). The association between alcohol consumption and absolute dense volume was most pronounced among women with the highest (⩾5%) Tyrer-Cuzick 10-year risk. Among high-risk women, women consuming 5.0-9.9, 10.0-19.9, 20.0-29.9, and 30.0-40.0 g of alcohol per day had 2.6 cm(3) (95% confidence interval (CI), 0.2-4.9), 2.9 cm(3) (95% CI, -0.6 to 6.3), 4.6 cm(3) (95% CI, 1.5-7.7), and 10.8 cm(3) (95% CI, 4.8-17.0) higher absolute dense volume, respectively, as compared with women abstaining from alcohol. A trend of increasing alcohol consumption and higher absolute dense volume was seen in women at low (⩽3%) risk, but not in women at moderate (3.0-4.9%) risk. CONCLUSION: Alcohol consumption may increase breast cancer risk through increasing mammographic density, particularly in women at high background risk of breast cancer.

Long-term subjective cognitive functioning following adjuvant systemic treatment: 7-9 years follow-up of a nationwide cohort of women treated for primary breast cancer.

BACKGROUND: There is growing concern among breast cancer (BC) patients and survivors about cognitive impairment following systemic treatments. The aim of the present study was to investigate the long-term effects of standard systemic adjuvant therapies on subjective cognitive impairment (SCI) in a large nationwide cohort of BC survivors 7-9 years after primary surgery. METHODS: Participants were recruited from the nationwide Psychosocial Factors and Breast Cancer inception cohort of Danish women treated for primary BC. SCI was assessed with the Cognitive Failures Questionnaire and women allocated to systemic treatment according to nationwide standard protocols were compared with women who had not received any systemic treatments. RESULTS: A total of 1889 recurrence-free survivors were eligible for analysis. No difference in SCI was found between survivors across standardized systemic treatment protocols when analyses were stratified by menopausal status and adjusted for possible sociodemographic and treatment-related confounders. The frequency of significant SCI in a subgroup of survivors in the age range 65-74 years was ∼7%. CONCLUSIONS: No differences in long-term SCI at 7-9 years post surgery were found between women who had received systemic therapies and those who had not. Furthermore, the observed proportion of survivors with significant SCI was comparable to normative data. These results are important to communicate to patients, survivors, and clinicians alike, especially in the light of increasing concern about cognitive impairment following systemic therapies.

A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas.

BACKGROUND: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. METHODS: Seventy-one adults with advanced STS who received ⩽ 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS). RESULTS: There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N = 11) over single agent (N = 10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P = 0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each). CONCLUSIONS: While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.