Dalotuzumab in chemorefractory KRAS exon 2 mutant colorectal cancer: Results from a randomised phase II/III trial

Limited data are available on the efficacy of anti‐IGF‐1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double‐blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression‐free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment‐related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF‐1R, IGF‐1, IGF‐2 and EREG by quantitative real‐time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild‐type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF‐1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti‐IGF‐1R agents in KRAS exon 2 mutant CRC. Data on IGF‐1R, IGF‐1 and IGF‐2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.     

New quality regulations versus established nursing home practice: a qualitative study

Background

Western governments have initiated reforms to improve the quality of care for nursing home residents. Most of these reforms encompass the use of regulations and national quality indicators. In the Norwegian context, these regulations comprise two pages of text that are easy to read and understand. They focus particularly on residents?? rights to plan their day-to-day life in nursing homes. However, the research literature indicates that the implementation of the new regulations, particularly if they aim to change nursing practice, is extremely challenging. The aim of this study was to further explore and describe nursing practice to gain a deeper understanding of why it is so hard to implement the new regulations.

Methods

For this qualitative study, an ethnographic design was chosen to explore and describe nursing practice. Fieldwork was conducted in two nursing homes. In total, 45 nurses and nursing aides were included in participant observation, and 10 were interviewed at the end of the field study.

Results

Findings indicate that the staff knew little about the new quality regulations, and that the quality of their work was guided by other factors rooted in their nursing practice. Further analyses revealed that the staff appeared to be committed to daily routines and also that they always seemed to know what to do. Having routines and always knowing what to do mutually strengthen and enhance each other, and together they form a powerful force that makes daily nursing care a taken-for-granted activity.

Conclusion

New regulations are challenging to implement because nursing practices are so strongly embedded. Improving practice requires systematic and deeply rooted practical change in everyday action and thinking.     

Intra-articular vs. systemic administration of etanercept in antigen-induced arthritis in the temporomandibular point. Part I: histological effects

Background  

Temporomandibular joint (TMJ) arthritis in children causes alterations in craniomandibular growth. This abnormal growth may be prevented by an early anti-inflammatory intervention. We have previously shown that intra-articular (IA) corticosteroid reduces TMJ inflammation, but causes concurrent mandibular growth inhibition in young rabbits. Blockage of TNF-α has already proven its efficacy in children with juvenile idiopathic arthritis not responding to standard therapy. In this paper we evaluate the effect of IA etanercept compared to subcutaneous etanercept in antigen-induced TMJ-arthritis in rabbits on histological changes using histomorphometry and stereology. This article presents the data and discussion on the anti-inflammatory effects of systemic and IA etanercept. In Part II the data on the effects of systemic and IA etanercept on facial growth are presented.     

CSF biomarker pathology correlates with a medial temporo-parietal network affected by very mild to moderate Alzheimer's disease but not a fronto-striatal network affected by healthy aging

It is suggested that reductions in a medial temporo-parietal episodic memory network characterize Alzheimer's disease (AD), while changes in a fronto-striatal executive network characterize healthy aging. In the present study, magnetic resonance imaging (MRI) was used to test this directly. MRI scans of 372 participants from two samples were analyzed: Sample 1 consisted of 96 very mild to moderate AD patients, 93 healthy elderly (HE), and 137 young (HY), all with available MR scans, while Sample 2 consisted of 46 MCI patients, with available MR scans and measures of CSF biomarkers Aβ42 and tau protein. Substantial morphometric reductions of the medial temporo-parietal network were found in AD, while the fronto-striatal network was less affected. Both networks were affected by healthy aging, but the fronto-striatal to a greater degree than the medial temporo-parietal. Further exploratory analyses of 49 cortical and subcortical structures indicated no overlap between predictors of AD vs. HE and predictors of HE vs. HY. CSF biomarker pathology correlated with the medial temporo-parietal but not fronto-striatal network. Likewise, the AD-prone structures from the exploratory analyses were related to CSF biomarkers, while the aging-prone structures were not. It is concluded that the pattern of macrostructural brain changes in very mild to moderate AD can be clearly delineated from that of healthy aging.     

Mitochondrial tRNA genes and flanking regions in sudden infant death syndrome

AIM: Mitochondrial DNA (mtDNA) mutations have been proposed as a genetic risk factor for sudden infant death syndrome (SIDS). The aim of this study was to further investigate this issue, by sequencing the mitochondrial tRNA genes with flanking regions in SIDS cases and controls. METHOD: The selected genes were investigated in 24 cases of SIDS and 10 controls, the method used were direct sequencing. In addition, the A10398G mutation in the ND3 gene was investigated in 220 SIDS cases, 26 cases of infectious death and 93 controls, using allele-specific PCR. RESULTS: Mutations, recorded as differences from the revised Cambridge sequence, were found in 32 different sites in the coding regions investigated. There was no difference in mutation frequency between SIDS cases and controls, and no single mutation was found associated with SIDS. CONCLUSION: The present study does not indicate an association between a specific mitochondrial tRNA gene mutation and SIDS, nor a higher mtDNA tRNA mutation frequency in SIDS cases than in controls.     

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer’s disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/−) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ− controls. In MCI-Aβ+ compared with Aβ− controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.     

HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus

Summary Three groups of patients with insulin-dependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n=164), and a subset (n=93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR4 was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system. Note. A list with detailed data on all patients is available from the authors on request.     

Executive dysfunction in mild cognitive impairment is associated with changes in frontal and cingulate white matter tracts

Mild cognitive impairment (MCI) may affect multiple neuropsychological domains. While amnestic MCI is associated with Alzheimer's disease, patterns of brain pathology in non-amnestic subtypes have been less studied. Twenty-three patients with attention/executive MCI (a/e MCI), seen at a university-based memory clinic, and 23 normal controls, matched according to age, gender, and education, were included in this study. All subjects were assessed with a neuropsychological test battery, including tests of memory, attention and executive function, and underwent magnetic resonance imaging. Diffusion tensor imaging derived white matter (WM) tract radial and mean diffusivity (DR and MD) were assessed using Tract-Based Spatial Statistics, and cortical thickness (CTH) was assessed using FreeSurfer. This study investigated changes of WM DR/MD and CTH in subjects with a/e MCI, and associations between these changes and different a/e subfunctions. WM DR/MD underlying rostral middle frontal, medial orbitofrontal, caudal anterior cingulate, posterior cingulate, retrosplenial and entorhinal cortices was higher for the a/e MCI than the control group, but CTH was not different from controls in any of the regions. WM DR/MD underlying superior frontal, rostral middle frontal, lateral/medial orbitofrontal and retrosplenial cortices were significantly associated with inhibition/switching performance, while caudal middle frontal CTH was significantly associated with attention and divided attention in the patient group. We conclude that increased WM DR/MD in frontal and cingulate regions and cortical thinning in caudal middle frontal region are both associated with executive dysfunction in MCI.     

Neurological outcome after surgery for thoracic and lumbar spine injuries

Summary New techniques for internal fixation, employed by neurosurgeons and orthopaedic surgeons, provide reduction and stabilization with early mobilization of patients after injuries of the thoracolumbar spine. It has, however, appeared difficult to prove that the neurological outcome after surgery may be superior to conservative treatment.In this study the neurological results after surgery are evaluated in 30 patients with injuries of the spinal cord and/or cauda equina. Canal encroachment was found on tomograms or CT in all patients. The unstable fractures, dislocations or fracture-dislocations were all reduced and stabilized by the Harrington distraction device. However, peroperative inspection revealed that the Harrington instrumentation alone may be inadequate in achieving intraspinal decompression. Additional anterior decompression by posterolateral approach was necessary in 13 of the 30 patients (43%). In this series there was an unexpectedly high rate of dural tears. These were found in 8 patients (27%) and nerve roots (cauda equina) appeared to have herniated through the tear in 6 of the 8 patients. Significant improvement of the neurological deficit was obtained in 22 of the 30 patients (73%), and the improvement rate in patients with incomplete lesions of the spinal cord was 83% (25 of 30 patients). In this series there was a definite trend toward greater neurological recovery when compared to the results obtained in patients treated conservatively.The importance of a neurosurgical approach in diagnosis and treatment of these patients is stressed.