A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage

A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury

Background Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects.<p></p> Results Here we identified p38MAPKα as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKα signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death.<p></p> Conclusions These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.<p></p&gt

Predictive value of clinical and 18F-FDG-PET/CT derived imaging parameters in patients undergoing neoadjuvant chemoradiation for esophageal squamous cell carcinoma.

Aim of this study was to validate the prognostic impact of clinical parameters and baseline 18F-FDG-PET/CT derived textural features to predict histopathologic response and survival in patients with esophageal squamous cell carcinoma undergoing neoadjuvant chemoradiation (nCRT) and surgery. Between 2005 and 2014, 38 ESCC were treated with nCRT and surgery. For all patients, the 18F-FDG-PET-derived parameters metabolic tumor volume (MTV), SUVmax, contrast and busyness were calculated for the primary tumor using a SUV-threshold of 3. The parameter uniformity was calculated using contrast-enhanced computed tomography. Based on histopathological response to nCRT, patients were classified as good responders (< 10% residual tumor) (R) or non-responders (≥ 10% residual tumor) (NR). Regression analyses were used to analyse the association of clinical parameters and imaging parameters with treatment response and overall survival (OS). Good response to nCRT was seen in 27 patients (71.1%) and non-response was seen in 11 patients (28.9%). Grading was the only parameter predicting response to nCRT (Odds Ratio (OR) = 0.188, 95% CI: 0.040-0.883; p = 0.034). No association with histopathologic treatment response was seen for any of the evaluated imaging parameters including SUVmax, MTV, busyness, contrast and uniformity. Using multivariate Cox-regression analysis, the heterogeneity parameters busyness (Hazard Ratio (HR) = 1.424, 95% CI: 1.044-1.943; p = 0.026) and contrast (HR = 6.678, 95% CI: 1.969-22.643; p = 0.002) were independently associated with OS, while no independent association with OS was seen for SUVmax and MTV. In patients with ESCC undergoing nCRT and surgery, baseline 18F-FDG-PET/CT derived parameters could not predict histopathologic response to nCRT. However, the PET/CT derived features busyness and contrast were independently associated with OS and should be further investigated

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Purpose: The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods: The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results: In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs

Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate

Purpose: The radiolanthanide 161Tb (T 1/2 = 6.90days, Eβ− av = 154keV) was recently proposed as a potential alternative to 177Lu (T 1/2 = 6.71days, Eβ− av = 134keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare 161Tb and 177Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). Methods: 161Tb-cm09 and 177Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo 161Tb-cm09 and 177Lu-cm09 (10MBq, 0.5nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6months by determination of plasma parameters and examination of kidney function with quantitative SPECT using 99mTc-dimercaptosuccinic acid (DMSA). Results: To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for 161Tb-cm09 (IC50 ~0.014MBq/ml and ~2.53MBq/ml) compared to 177Lu-cm09 (IC50 ~0.063MBq/ml and ~4.52MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies 161Tb-cm09 reduced tumour growth more efficiently than 177Lu-cm09. These findings were in line with the higher absorbed tumour dose for 161Tb-cm09 (3.3Gy/MBq) compared to 177Lu-cm09 (2.4Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Conclusion: Compared to 177Lu-cm09 we demonstrated equal imaging features for 161Tb-cm09 but an increased therapeutic efficacy for 161Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of 161Tb

Experience of primary care services among early adolescents in England and association with health outcomes

This document is the Accepted Manuscript version of the following article: Arrash A. Yassaee, Dougal S. Hargreaves, Kayleigh Chester, Stephanie Lamb, Ann Hagell, and Fiona Brooks, Experience of Primary Care Services Among Early Adolescents in England and Associated with Health Outcomes, Journal of Adolescent Health, Vol. 60 (4): 388-394, first published 1 December 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ The version of record is available online at doi: http://dx.doi.org/10.1016/j.jadohealth.2016.09.22 © 2016 Society for Adolescent Health and Medicine. All rights reserved.Purpose The aim of this study was to investigate adolescents' (11–15 years) experience of their general practitioner (GP), whether poor reported GP experience was associated with worse physical and mental health measures and whether poor previous GP experience was linked to lower utilization of these services. Methods We used logistic regression to analyze data from the 2014 Health Behaviour in School-aged Children study. Four aspects of recent care experience were studied: feeling at ease, feeling treated with respect, satisfaction with doctor's explanation, and feeling able to discuss personal matters. Five dichotomized measures of health status were used: ever self-harmed; fair or poor self-reported health; frequent (at least weekly) low mood; sleeping problems; or headaches. Results Of 5,335 students, 4,149 reported having visiting their GP within the past year. Of these, 91.8% felt treated with respect, 78.7% felt at ease, 85.7% were satisfied with explanation, and 53.9% felt able to discuss personal matters. After adjusting for ethnicity, age, gender, and family affluence score, poor experience on any indicator was strongly associated with increased risk of self-harm (adjusted odds ratio range, 2.01–2.70; all p < .001); feeling low (AOR range, 1.53–2.11; all p < .001); and sleeping problems (AOR range, 1.49–1.91; all p ≤ .001). Poor experience on all indicators, except discussing personal matters, was associated with worse self-reported health. Conclusions Nearly half of this large, national study of adolescents did not feel able to discuss personal matters with their doctor. There was a consistent, strong association between reported lack of good GP experience and poor health measures.Peer reviewedFinal Accepted Versio

Management of patients with persistent medically unexplained symptoms: a descriptive study

Background: In 2013 the Dutch guideline for management of medically unexplained symptoms (MUS) was published. The aim of this study is to assess medical care for patients with persistent MUS as recorded in their electronic medical records, to investigate if this is in line with the national guideline for persistent MUS and whether there are changes in care over time. Methods: We conducted an observational study of adult primary care patients with MUS. Routinely recorded health care data were extracted from electronic medical records of patients participating in an ongoing randomised controlled trial in 30 general practices in the Netherlands. Data on general practitioners’ (GPs’) management strategies during MUS consultations were collected in a 5-year period for each patient prior. Management strategies were categorised according to the options offered in the Dutch guideline. Changes in management over time were analysed. Results: Data were collected from 1035 MUS consultations (77 patients). Beside history-taking, the most frequently used diagnostic strategies were physical examination (24.5%) and additional investigations by the GP (11.1%). Frequently used therapeutic strategies were prescribing medication (24.6%) and providing explanations (11.2%). As MUS symptoms persisted, GPs adjusted medication, discussed progress and scheduled follow-up appointments more frequently. The least frequently used strategies were exploration of all complaint dimensions (i.e. somatic, cognitive, emotional, behavioural and social) (3.5%) and referral to a psychologist (0.5%) or psychiatrist (0.1%). Conclusions: Management of Dutch GPs is partly in line with the Dutch guideline. Medication was possibly prescribed more frequently than recommended, whereas exploration of all complaint dimensions, shared problem definition and referral to mental health care were used less

Blood pressure control in chronic kidney disease: A cross-sectional analysis from the German Chronic Kidney Disease (GCKD) study

We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30 +/- 60 mL/min/1.73 m 2 or overt proteinuria in the presence of an eGFR> 60 mL/min/1.73 m 2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use

The CIPRUS study, a nurse-led psychological treatment for patients with undifferentiated somatoform disorder in primary care: study protocol for a randomised controlled trial

Background: Up to a third of patients presenting medically unexplained physical symptoms in primary care may have a somatoform disorder, of which undifferentiated somatoform disorder (USD) is the most common type. Psychological interventions can reduce symptoms associated with USD and improve functioning. Previous research has either been conducted in secondary care or interventions have been provided by general practitioners (GPs) or psychologists in primary care. As efficiency and cost-effectiveness are imperative in primary care, it is important to investigate whether nurse-led interventions are effective as well. The aim of this study is to examine the effectiveness and cost-effectiveness of a short cognitive behavioural therapy (CBT)-based treatment for patients with USD provided by mental health nurse practitioners (MHNPs), compared to usual care. Methods: In a cluster randomised controlled trial, 212 adult patients with USD will be assigned to the intervention or care as usual. The intervention group will be offered a short, individual CBT-based treatment by the MHNP in addition to usual GP care. The main goal of the intervention is that patients become less impaired by their physical symptoms and cope with symptoms in a more effective way. In six sessions patients will receive problem-solving treatment. The primary outcome is improvement in physical functioning, measured by the physical component summary score of the RAND-36. Secondary outcomes include health-related quality of life measured by the separate subscales of the RAND-36, somatization (PHQ-15) and symptoms of depression and anxiety (HADS). Problem-solving skills, health anxiety, illness perceptions, coping, mastery and working alliance will be assessed as potential mediators. Assessments will be done at 0, 2, 4, 8 and 12 months. An economic evaluation will be conducted from a societal perspective with quality of life as the primary outcome measure assessed by the EQ-5D-5L. Health care, patient and lost productivity costs will be assessed with the Tic-P. Discussion: We expect that the intervention will improve physical functioning and is cost-effective compared to usual care. If so, more patients might successfully be treated in general practice, decreasing the number of referrals to specialist care. Trial registration: Dutch Trial Registry, identifier: NTR4686, Registered on 14 July 2014. © 2017 The Author(s)