Fourteen gene GBM prognostic signature identifies association of immune response pathway and mesenchymal subtype with high risk group

Background: Recent research on glioblastoma (GBM) has focused on deducing gene signatures predicting prognosis. The present study evaluated the mRNA expression of selected genes and correlated with outcome to arrive at a prognostic gene signature. Methods: Patients with GBM (n = 123) were prospectively recruited, treated with a uniform protocol and followed up. Expression of 175 genes in GBM tissue was determined using qRT-PCR. A supervised principal component analysis followed by derivation of gene signature was performed. Independent validation of the signature was done using TCGA data. Gene Ontology and KEGG pathway analysis was carried out among patients from TCGA cohort. Results: A 14 gene signature was identified that predicted outcome in GBM. A weighted gene (WG) score was found to be an independent predictor of survival in multivariate analysis in the present cohort (HR = 2.507; B = 0.919; p < 0.001) and in TCGA cohort. Risk stratification by standardized WG score classified patients into low and high risk predicting survival both in our cohort (p = <0.001) and TCGA cohort (p = 0.001). Pathway analysis using the most differentially regulated genes (n = 76) between the low and high risk groups revealed association of activated inflammatory/immune response pathways and mesenchymal subtype in the high risk group. Conclusion: We have identified a 14 gene expression signature that can predict survival in GBM patients. A network analysis revealed activation of inflammatory response pathway specifically in high risk group. These findings may have implications in understanding of gliomagenesis, development of targeted therapies and selection of high risk cancer patients for alternate adjuvant therapies.

Variation in precursor lesions of pancreatic cancer among high-risk groups

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. EXPERIMENTAL DESIGN Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0-127 months) or 36 months (0-110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. RESULTS Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. CONCLUSION In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group.

First-trimester glycosylated hemoglobin in women at high risk for gestational diabetes.

INTRODUCTION Our aim was to investigate the prognostic value of first-trimester glycosylated hemoglobin (HbA1c) in pregnant women with risk factors for developing gestational diabetes mellitus (GDM). MATERIAL AND METHODS This is an observational retrospective cohort study conducted at the Department of Obstetrics and Gynecology, University Hospital Bern, Switzerland. We included pregnant women at high risk for GDM (n = 208), who had an HbA1c measurement in the first trimester. We compared HbA1c values of women who later developed GDM with those who did not develop GDM. Diagnosis of GDM was made on the basis of a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation. We further examined the prevalence of GDM in relation to the first-trimester HbA1c value. RESULTS The prevalence of GDM in our high-risk group was 14.7%. Women who developed GDM had significantly higher first-trimester HbA1c values [5.43 ± 0.31% (36 ± 3 mmol/mol) vs. 5.23 ± 0.28% (34 ± 3 mmol/mol); p = 0.0026]. Moreover, all pregnant women with HbA1c ≥6.0% (42 mmol/mol) developed GDM, whereas those with <4.5% (26 mmol/mol) did not. CONCLUSIONS Women at risk for GDM have higher first-trimester HbA1c levels and values ≥6.0% (42 mmol/mol) are predictive of GDM. This information may be useful for counseling these women and providing appropriate advice on diet and lifestyle modification early in pregnancy.

First steps: study protocol for a randomized controlled trial of the effectiveness of the Group Family Nurse Partnership (gFNP) program compared to routine care in improving outcomes for high-risk mothers and their children and preventing abuse

Background: Evidence from the USA suggests that the home-based Family Nurse Partnership program (FNP), extending from early pregnancy until infants are 24 months, can reduce the risk of child abuse and neglect throughout childhood. FNP is now widely available in the UK. A new variant, Group Family Nurse Partnership (gFNP) offers similar content but in a group context and for a shorter time, until infants are 12 months old. Each group comprises 8 to 12 women with similar expected delivery dates and their partners. Its implementation has been established but there is no evidence of its effectiveness.

Methods/Design: The study comprises a multi-site randomized controlled trial designed to identify the benefits of gFNP compared to standard care. Participants (not eligible for FNP) must be either aged <20 years at their last menstrual period (LMP) with one or more previous live births, or aged 20 to 24 at LMP with low educational qualifications and no previous live births. 'Low educational qualifications' is defined as not having both Maths and English Language GCSE at grade C or higher or, if they have both, no more than four in total at grade C or higher. Exclusions are: under 20 years and previously received home-based FNP and, in either age group, severe psychotic mental illness or not able to communicate in English. Consenting women are randomly allocated (minimized by site and maternal age group) when between 10 and 16 weeks pregnant to either to the 44 session gFNP program or to standard care after the collection of baseline information. Researchers are blind to group assignment. The primary outcomes at 12 months are child abuse potential based on the revised Adult-Adolescent Parenting Inventory and parent/infant interaction coded using the CARE Index based on a video-taped interaction. Secondary outcomes are maternal depression, parenting stress, health related quality of life, social support, and use of services.

Discussion: This is the first study of the effectiveness of gFNP in the UK. Results should inform decision-making about its delivery alongside universal services, potentially enabling a wider range of families to benefit from the FNP curriculum and approach to supporting parenting.

SLCO1B1 rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group

Background Recent studies reported the association between SLCO1B1 polymorphisms and the development of statin-induced myopathy. In the scenario of the Brazilian population, being one of the most heterogeneous in the world, the main aim here was to evaluate SLCO1B1 polymorphisms according to ethnic groups as an initial step for future pharmacogenetic studies. Methods One hundred and eighty-two Amerindians plus 1,032 subjects from the general urban population were included. Genotypes for the SLCO1B1 rs4149056 (c.T521C, p.V174A, exon 5) and SLCO1B1 rs4363657 (g.T89595C, intron 11) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis with the Rotor Gene 6000® instrument. Results The frequencies of the SLCO1B1 rs4149056 and rs4363657 C variant allele were higher in Amerindians (28.3% and 26.1%) and were lower in African descent subjects (5.7% and 10.8%) compared with Mulatto (14.9% and 18.2%) and Caucasian descent (14.8% and 15.4%) ethnic groups (p < 0.001 and p < 0.001, respectively). Linkage disequilibrium analysis show that these variant alleles are in different linkage disequilibrium patterns depending on the ethnic origin. Conclusion Our findings indicate interethnic differences for the SLCO1B1 rs4149056 C risk allele frequency among Brazilians. These data will be useful in the development of effective programs for stratifying individuals regarding adherence, efficacy and choice of statin-type.

Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95

PURPOSE: To compare adjuvant dose-intensive epirubicin and cyclophosphamide chemotherapy administered with filgrastim and progenitor cell support (DI-EC) with standard-dose anthracycline-based chemotherapy (SD-CT) for patients with early-stage breast cancer and a high risk of relapse, defined as stage II disease with 10 or more positive axillary nodes; or an estrogen receptor-negative or stage III tumor with five or more positive axillary nodes. PATIENTS AND METHODS: Three hundred forty-four patients were randomized after surgery to receive seven cycles of SD-CT over 22 weeks, or three cycles of DI-EC (epirubicin 200 mg/m2 plus cyclophosphamide 4 gm/m2 with filgrastim and progenitor cell support) over 6 weeks. All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). RESULTS: After a median follow-up of 5.8 years (range, 3 to 8.4 years), 188 DFS events had occurred (DI-EC, 86 events; SD-CT, 102 events). The 5-year DFS was 52% for DI-EC and 43% for SD-CT, with hazard ratio of DI-EC compared with SD-CT of 0.77 (95% CI, 0.58 to 1.02; P = .07). The 5-year overall survival was 70% for DI-EC and 61% for SD-CT, with a hazard ratio of 0.79 (95% CI, 0.56 to 1.11; P = .17). There were eight cases (5%) of anthracycline-induced cardiomyopathy (two fatal) among those who received DI-EC. Women with hormone receptor-positive tumors benefited significantly from DI-EC. CONCLUSION: There was a trend in favor of DI-EC with respect to disease-free survival. A larger trial or meta-analysis will be required to reveal the true effect of dose-intensive therapy.

The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up

BACKGROUND: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. PATIENTS AND METHODS: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m(2) plus cyclophosphamide 4 mg/m(2) with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. RESULTS: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58-1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). CONCLUSIONS: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged.

High-Risk Merkel Cell Carcinoma of the Skin Treated With Synchronous Carboplatin/Etoposide and Radiation: A Trans-Tasman Radiation Oncology Group Study-TROG 96:07

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy was prospectively assessed in a group of patients with high-risk Merkel cell carcinoma (MCC) of the skin. Patients and Methods: Patients were eligible if they had disease localized to the primary site and nodes, and were required to have at least one of the following high risk features: recurrence after initial therapy, involved nodes, primary tumor size greater than 1 cm, gross residual disease after surgery, or occult primary with nodes. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks and synchronous carboplatin (area under the curve, 4.5) and intravenous etoposide 80 mg/m(2) days 1 to 3 was given in weeks 1, 4, 7, and 10. The median age of the group was 67 (range, 43-86) years, and there were 39 males and 14 females. Involved nodes (stage II) were present in 33 cases (62%). The sites involved were head and neck (22 patients), occult primary (13 patients), upper limb (eight patients), lower limb (eight patients), and trunk (two patients). Results: Fifty-three patients were entered between 1996 and 2001. The median potential follow-up was 48 months. There were no treatment related deaths. The 3-year overall survival, locoregional control, and distant control were 76%, 75%, and 76%, respectively. Tumor site and the presence of nodes were factors that were predictive for local control and survival. Multivariate analysis indicated that the major factor influencing survival was the presence of nodes; however, this was not a significant factor in locoregional control. Conclusion: High levels of locoregional control and survival have been achieved with the addition of chemotherapy to radiation treatment for high-risk MCC of the skin. The role of chemoradiotherapy for high-risk MCC warrants further investigation. (C) 2003 by American Society of Clinical Oncology.

Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for renal disease and hypertension

Aborigines in remote areas of Australia have much higher rates of renal disease, as well as hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney findings in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19 Aborigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected death in the Top End of the Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines-202000 fewer glomeruli per kidney, or an estimated 404000 fewer per person (P=0.036). Their mean glomerular volume was 27% larger (P=0.016). Glomerular number was significantly correlated with adult height, inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than non-Aboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than those without-250000 fewer per kidney (P=0.03), or 500000 fewer per person, and their mean glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is compatible with their susceptibility to renal failure. The additional nephron deficit associated with hypertension is compatible with other reports. Lower nephron numbers are probably due in part to reduced nephron endowment, which is related to a suboptimal intrauterine environment. Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total filtering surface area, might be exacerbating nephron loss. Optimization of fetal growth should ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease.

Improved functional ability and independence in activities of daily living for older adults at high risk of hospital readmission : a randomised controlled trial

Objective: During hospitalisation older people often experience functional decline which impacts on their future independence. The objective of this study was to evaluate a multifaceted transitional care intervention including home-based exercise strategies for at-risk older people on functional status, independence in activities of daily living, and walking ability. Methods: A randomised controlled trial was undertaken in a metropolitan hospital in Australia with 128 patients (64 intervention, 64 control) aged over 65 years with an acute medical admission and at least one risk factor for hospital readmission. The intervention group received an individually tailored program for exercise and follow-up care which was commenced in hospital and included regular visits in hospital by a physiotherapist and a Registered Nurse, a home visit following discharge, and regular telephone follow-up for 24 weeks following discharge. The program was designed to improve health promoting behaviours, strength, stability, endurance and mobility. Data were collected at baseline, then 4, 12 and 24 weeks following discharge using the Index of Activities of Daily Living (ADL), Instrumental Index of Activities of Daily Living (IADL), and the Walking Impairment Questionnaire (Modified). Results: Significant improvements were found in the intervention group in IADL scores (p<.001), ADL scores (p<.001), and WIQ scale scores (p<.001) in comparison to the control group. The greatest improvements were found in the first four weeks following discharge. Conclusions: Early introduction of a transitional model of care incorporating a tailored exercise program and regular telephone follow-up for hospitalised at-risk older adults can improve independence and functional ability.

Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and 1H-MRS percentage change scores between scans were compared using one-way ANOVA and correlated with behavioural change scores. Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects were seen for any brain metabolites as measured with 1H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Validity of the malnutrition screening tool for older adults at high risk of hospital readmission

Malnutrition is a serious problem in older adults, particularly for those at risk of hospital readmission. The essential step in managing malnutrition is early identification using a valid nutrition screening tool. The purpose of this study was to validate the Malnutrition Screening Tool (MST) in older adults at high risk of hospital readmission. Two registered nurses administered the MST to identify malnutrition risk, and compared it to the comprehensive Subjective Global Assessment (SGA) to assess nutritional status for patients aged 65 years who had at least one risk factor for hospital readmission. The MST demonstrates substantial sensitivity, specificity and agreement with the SGA. These findings indicate that nursing staff can use the MST as a valid tool for routine screening and rescreening to identify patients at risk of malnutrition. Use of the MST may prevent hospital-acquired malnutrition for acute hospitalized older adults at high risk of readmission.

A randomised controlled trial to prevent hospital readmissions and loss of functional ability in high risk older adults: a study protocol

Background Older people have higher rates of hospital admission than the general population and higher rates of readmission due to complications and falls. During hospitalisation, older people experience significant functional decline which impairs their future independence and quality of life. Acute hospital services comprise the largest section of health expenditure in Australia and prevention or delay of disease is known to produce more effective use of services. Current models of discharge planning and follow-up care, however, do not address the need to prevent deconditioning or functional decline. This paper describes the protocol of a randomised controlled trial which aims to evaluate innovative transitional care strategies to reduce unplanned readmissions and improve functional status, independence, and psycho-social well-being of community-based older people at risk of readmission. Methods/Design The study is a randomised controlled trial. Within 72 hours of hospital admission, a sample of older adults fitting the inclusion/exclusion criteria (aged 65 years and over, admitted with a medical diagnosis, able to walk independently for 3 meters, and at least one risk factor for readmission) are randomised into one of four groups: 1) the usual care control group, 2) the exercise and in-home/telephone follow-up intervention group, 3) the exercise only intervention group, or 4) the in-home/telephone follow-up only intervention group. The usual care control group receive usual discharge planning provided by the health service. In addition to usual care, the exercise and in-home/telephone follow-up intervention group receive an intervention consisting of a tailored exercise program, in-home visit and 24 week telephone follow-up by a gerontic nurse. The exercise only and in-home/telephone follow-up only intervention groups, in addition to usual care receive only the exercise or gerontic nurse components of the intervention respectively. Data collection is undertaken at baseline within 72 hours of hospital admission, 4 weeks following hospital discharge, 12 weeks following hospital discharge, and 24 weeks following hospital discharge. Outcome assessors are blinded to group allocation. Primary outcomes are emergency hospital readmissions and health service use, functional status, psychosocial well-being and cost effectiveness. Discussion The acute hospital sector comprises the largest component of health care system expenditure in developed countries, and older adults are the most frequent consumers. There are few trials to demonstrate effective models of transitional care to prevent emergency readmissions, loss of functional ability and independence in this population following an acute hospital admission. This study aims to address that gap and provide information for future health service planning which meets client needs and lowers the use of acute care services.

Attitudes and expectations of technologies to manage high risk wandering and elopement in persons with dementia : an Australian perspective

Wandering is aimless and repetitive locomotion that may expose persons with dementia (PWD) to elopement, getting lost and death. This study is an Australian replication of a US study. Cross-disciplinary consensus- based analysis was applied to data from five focus groups (N =47: cognitively intact LTC residents (5), carers of PWD (11), home care workers (13) allied health professionals and health-focused engineers (7) and RNs (11). Groups received briefing about wandering monitoring and elopement management systems. Consistent with US attitudes, participants in all groups agreed on what a wandering technology should do, how it should do it, and necessary technical specifications. Within each group participants raised the need for a continuum of care for PWD and the imperative for early recognition of potentially dangerous wandering and getting lost when they occur. Global Positioning System elopement management was the preferred option. Interestingly, the prospective value of GPS to recover a lost or eloped wanderer far outweighed privacy concerns, as in the US. A pervasive theme was that technologies need to augment, but cannot replace, attentive, compassionate caregiver presence. A significant theme raised only by Australian carers of PWD was the potential for development of implantable GPS technologies and the need for public debate about attendant ethical issues. Given that 60% or more of over 200,000 Australians and 4.5 million Americans with dementia will develop wandering, there is a pressing need to develop effective locator systems that may delay institutionalization, help allay carer concern and enhance PWD safety.