Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

Zero the hero: Evidence for involvement of the ventromedial prefrontal cortex in affective bias for free items.

Recent evidence from psycho-economics shows that when the price of an item decreases to the extent that it becomes available for free, one can observe a remarkable increase of subjective utility toward this item. This phenomenon, which is not observed for any other price but zero, has been termed the zero-price effect (ZPE). The ZPE is attributed to an affective heuristic where the positive affect elicited by the free status of an item provides a mental shortcut biasing choice towards that item. Given that the ZPE relies on affective processing, a key role of the ventromedial prefrontal cortex (vmPFC) has been proposed, yet neuroscientific studies of the ZPE remain scarce. This study aimed to explore the role of the vmPFC in the ZPE using a novel, within-subject assessment in participants with either an acquired (lesion patients) or degenerative (behavioural-variant frontotemporal dementia patients) lesion of the vmPFC, and age-matched healthy controls. All participants were asked to make a series of choices between pairs of items that varied in price. One choice trial involved an equal decrease of both item prices, such that one of the items was priced zero. In contrast to controls, patients with both vmPFC-lesion and behavioural-variant frontotemporal dementia showed marked reductions in zero-related changes of preference in pairs of gift-cards, but not for pairs of food items. Our findings suggest that affective evaluations driving the ZPE are altered in patients with focal or degenerative damage to the vmPFC. This supports the notion of a key role of the vmPFC in the ZPE and, more generally, the importance of this region in value-based affective decision-making. Our findings also highlight the potential utility of affective heuristic tasks in future clinical assessments.

Promoting the get healthy information and coaching service (GHS) in Australian-Chinese communities: facilitators and barriers.

Obesity and being overweight are major public health concerns that health coaching can assist people to manage through encouraging self-management and behaviour change. The Get Healthy Information and Coaching Service (GHS) is a telephone health coaching service in Australia that has effectively improved the health of the general population but has had less participation of culturally and linguistically diverse (CALD) populations. The Chinese population is the largest migrant group in Australia with increased risk of diabetes but had reduced access to the GHS program due to communication barriers. The GHS developed a pilot program for Chinese (Mandarin and Cantonese-speaking) communities using bilingual coaches and translated material to address these barriers. Qualitative research was undertaken with Chinese stakeholders (14 interviews) and 11 program participants from the group which had completed the program (2 focus groups in Mandarin and Cantonese) to understand their experiences and the success of promotional activities. This research does not contain the experiences of the people that withdrew from the program. The bilingual program was culturally and linguistically appropriate and addressed risk factors for chronic conditions. Participants formed positive relationships with bilingual coaches who they preferred to interpreters. They felt the program promoted healthy eating, weight and physical activity. Although Chinese stakeholders had concerns about participants' ability to goal set, participants said they met their health goals and were committed to the GHS program. Strategies to enhance the program included promoting the bilingual GHS to the communities and stakeholders. Factors to consider beyond language in adapting the program to the Australian Chinese communities include meeting the heterogenous needs of the older population, ensuring community engagement and addressing cultural beliefs and practices.

Obesity and being overweight are major public health concerns that health coaching can assist people to manage. The Get Healthy Information and Coaching Service (GHS) is a government telephone health coaching service that has improved the health of the general population but has had less participation of culturally and linguistically diverse populations. The Chinese population is the largest migrant group in Australia with increased risk of diabetes but had reduced access to the GHS program due to communication barriers. The GHS developed a pilot program for Chinese (Mandarin and Cantonese-speaking) communities using bilingual coaches and translated material. Findings from 14 interviews with Chinese stakeholders and two focus groups (in Mandarin and Cantonese) with program participants sought to understand their experiences and success of promotional activities. Results demonstrated the bilingual program was culturally and linguistically appropriate. Participants formed positive relationships with coaches and felt the service promoted healthy eating and weight, and physical activity. Although Chinese stakeholders had concerns about participants' cultural familiarity with goal setting and achieving long-term change, participants said that they met their goals and were committed to the program. Strategies to enhance the program will include promoting the bilingual GHS to the communities and stakeholders.

Reduced kidney function at presentation in unselected acute emergency medical admissions: incidence, outcome and associated factors.

We sought to assess the impact of renal impairment on acute medical admissions and to identify potential contributory factors to admissions involving renal impairment at presentation. In a prospective cohort study, 29.5% of all acute medical emergency admissions had an eGFR <60ml/min/1.73m2 at presentation. Of these, 19.9% had definite chronic kidney disease and 8.4% had definite acute kidney injury. Detailed analysis of a random subset of patients with an eGFR <60ml/min/1.73m2 at presentation demonstrated that the major reasons for admission included falls, dehydration and fluid overload. 46% were on diuretics and 53% were on an ACEI or ARB or both. Gastrointestinal disturbance and recent medication changes were common and diuretic use persisted even with diarrhoea or vomiting.

Hypertension as a predictor of advanced colorectal cancer outcome and cetuximab treatment response.

Background: Adrenergic receptor stimulation is involved in the development of hypertension (htn) and has been implicated in cancer progression and dissemination of metastases in various tumours, including colon cancer. Adrenergic antagonists such as beta-blockers (bbs) demonstrate inhibition of invasion and migration in colon cancer cell lines and have been associated with decreased mortality in colorectal cancer (crc). We examined the association of baseline htn and bb use with overall (os) and progression-free survival (pfs) in patients with pretreated, chemotherapy refractory, metastatic crc (mcrc). We also examined baseline htn as a predictor of cetuximab efficacy. Methods: Using data from the Canadian Cancer Trials Group co.17 study [cetuximab vs. best supportive care (bsc)], we coded baseline htn and use of anti-htn medications, including bbs, for 572 patients. The chi-square test was used to assess the associations between those variables and baseline characteristics. Cox regression models were used for univariate and multivariate analyses of os and pfs by htn diagnosis and bb use. Results: Baseline htn, bb use, and anti-htn medication use were not found to be prognostic for improved os. Baseline htn and bb use were not significant predictors of cetuximab benefit. Conclusions: In chemorefractory mcrc, neither baseline htn nor bb use is a significant prognostic factor. Baseline htn and bb use are not predictive of cetuximab benefit. Further investigation to determine whether baseline htn or bb use have a similarly insignificant impact on prognosis in patients receiving earlier lines of treatment remains warranted.

Nurse Triage in an Irish Out-of-hours General Practice Co-Operative.

Specially trained triage nurses play a crucial role in the operation of out-of-hours GP co-operatives. This study aimed to establish the proportion of all patient contacts with the out-of-hours GP co-operative based in the Mid-West of Ireland (Shannondoc), which were managed by triage nurses. A retrospective, descriptive analysis was conducted on the database of contacts to the Shannondoc urgent, out-of-hours primary care co-operative. Of the 110,039 contacts to the service in 2013, 19,147 (17.4%) were classified as being managed by nurses and 14.2% were managed by nurse telephone triage alone. Twenty-four percent of the 19,147 calls managed by nurses involved children under six years. Triage nurses play an important role in administering safe medical advice over the phone. This has implications for the training of triage nurses and the future planning of urgent out-of-hours primary care services.

The Canine POMC Gene, Obesity in Labrador Retrievers and Susceptibility to Diabetes Mellitus.

BACKGROUND: Diabetes mellitus (DM) in dogs is a common endocrinopathy with a complex genetic architecture. Disease susceptibility in several breeds is associated with polymorphisms in immune response genes, but in the Labrador retriever breed, no genetic associations with DM have been identified. A deletion in the pro-opiomelanocortin (POMC) gene in Labrador retrievers is associated with increased appetite and risk of obesity. HYPOTHESIS/OBJECTIVES: To characterize the POMC deletion in Labrador retrievers, to develop a simple genetic test for this mutation, and to test the hypothesis that the POMC gene deletion is associated with an increased risk of DM in this breed. ANIMALS: Sixty-one non-diabetic Labrador retrievers aged >6 years and 57 Labrador retrievers with DM. METHODS: Case-control genotyping study to compare the frequency of the POMC deletion in dogs with and without DM. After polymerase chain reaction (PCR) and sequencing to characterize the mutation, a PCR-based test was developed and validated using 2 different restriction fragment length polymorphism assays. RESULTS: A 14-base-pair deletion was confirmed and localized to exon 3 of the canine POMC gene. A PCR-based test for the deletion was successfully developed. There was no association between the presence of the POMC deletion mutation and DM in this population of Labrador retriever dogs (P = .31). CONCLUSIONS AND CLINICAL IMPORTANCE: This study adds to the existing scientific literature indicating that there is little evidence for a direct link between obesity and DM in dogs.

Germline polymorphisms as biomarkers of tumor response in colorectal cancer patients treated with anti-EGFR monoclonal antibodies: a systematic review and meta-analysis.

Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.

Diurnal blood pressure and urine production in acute spinal cord injury compared with controls.

STUDY DESIGN: This is a prospective observational study. OBJECTIVES: The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI). SETTING: This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia. METHODS: Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers. RESULTS: Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension. CONCLUSION: People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.

Co-percolation to tune conductive behaviour in dynamical metallic nanowire networks.

Nanowire networks act as self-healing smart materials, whose sheet resistance can be tuned via an externally applied voltage stimulus. This memristive response occurs due to modification of junction resistances to form a connectivity path across the lowest barrier junctions in the network. While most network studies have been performed on expensive noble metal nanowires like silver, networks of inexpensive nickel nanowires with a nickel oxide coating can also demonstrate resistive switching, a common feature of metal oxides with filamentary conduction. However, networks made from solely nickel nanowires have high operation voltages which prohibit large-scale material applications. Here we show, using both experiment and simulation, that a heterogeneous network of nickel and silver nanowires allows optimization of the activation voltage, as well as tuning of the conduction behavior to be either resistive switching, memristive, or a combination of both. Small percentages of silver nanowires, below the percolation threshold, induce these changes in electrical behaviour, even for low area coverage and hence very transparent films. Silver nanowires act as current concentrators, amplifying conductivity locally as shown in our computational dynamical activation framework for networks of junctions. These results demonstrate that a heterogeneous nanowire network can act as a cost-effective adaptive material with minimal use of noble metal nanowires, without losing memristive behaviour that is essential for smart sensing and neuromorphic applications.

Significance of baseline and change in quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3.

BACKGROUND: There is insufficient information regarding the prognostic significance of baseline and change in quality of life (QoL) scores on overall survival (OS) in advanced pancreatic cancer. METHODS: QoL was assessed prospectively using the EORTC QLQ-C30 as part of the PA.3 trial of gemcitabine + erlotinib (G + E) vs. gemcitabine + placebo (G + P). Relevant variables and QoL scores at baseline and change at 8 weeks were analyzed by Cox stepwise regression to determine predictors of OS. RESULTS: 222 of 285 patients (pts) treated with G + E and 220 of 284 pts treated with G + P completed baseline QoL assessments. In a multivariable Cox analysis combining all pts, better QoL physical functioning (PF) score independently predicted longer OS (HR 0.86; CI: 0.80-0.93), as did non-white race (HR 0.64; CI: 0.44-0.95), PS 0-1 (HR 0.65; CI: 0.50-0.85), locally advanced disease (HR 0.55; CI: 0.43-0.71) and G + E (HR 0.78; CI: 0.64-0.96). Improvement in physical function at week 8 also predicted for improved survival (HR 0.89; CI: 0.81-0.97 for 10 point increase in score, p = 0.02). CONCLUSION: In addition to clinical variables, patient reported QoL scores at baseline and change from baseline to week 8 added incremental predictive information regarding survival for advanced pancreatic cancer patients.

Recent advances in anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody-associated vasculitis is an uncommon inflammatory disease of small to medium-sized vessels that frequently presents with rapidly progressive glomerulonephritis and renal failure though it can affect any organ system. If untreated, the vast majority of patients will die within a year. Current treatments improve prognosis but affected patients remain at a substantially higher risk of death and adverse outcomes. We review the classification of the disease, our understanding of the pathogenesis and epidemiology, and propose future directions for research. We also evaluate the evidence supporting established treatment regimens and the progress of clinical trials for newer treatments to inform the design of future studies.

Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada.

BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study.

In 2010, a tissue-engineered trachea was transplanted into a 10-year-old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti-HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross-sectional area analysis showed restriction of growth within an area of in-stent stenosis. This report demonstrates the long-term viability of a decellularized tissue-engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.

Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17.

BACKGROUND: Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab. METHODS: Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS). RESULTS: Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79-1.44], p = 0.67) or OS (HR 0.96 [0.70-1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18-0.45], p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42-1.27], p = 0.26), [interaction p = 0.002]. CONCLUSION: In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.

A retrospective review of the ambulatory blood pressure patterns and diurnal urine production in subgroups of spinal cord injured patients.

STUDY DESIGN: Retrospective study. OBJECTIVES: To quantify diurnal blood pressure (BP) patterns and nocturnal hypertension and to measure diurnal urine production in spinal cord injury (SCI) patients with clinically significant disorders of BP control. SETTING: A specialist state-based spinal cord service in Victoria, Australia. METHODS: Medical records of patients with traumatic SCI who were referred to a specialist service for management of a BP disorder were examined. Ambulatory BP and nocturnal urine production were compared between groups of patients classified according to level, completeness and chronicity of SCI. Patients with night:day systolic BP <90% were classified as dippers, 90-100% as non-dippers and >100% as reversed dippers. RESULTS: Patients (44 tetraplegic, 10 paraplegic) were predominantly males (92.6%) aged 41±2.5 years (mean±s.e.m.). Referral was for orthostatic intolerance (n=37), autonomic dysreflexia (n=6), nocturnal polyuria (n=4), elevated BP (n=1) and peripheral oedema (n=1). The average BP was 111.1±1.4/65.0±1.2 mm Hg. In 56% of patients (n=30), BP at night was higher than during the day and another 37% (n=20) were non-dippers. Nocturnal hypertension was present in 31% (n=17) of the patients. In the tetraplegic patients, urine flow rate was greater during the night than day (121±9.5 ml h(-1) vs 89±8.2 ml h(-1), P=0.025). CONCLUSION: Ambulatory BP monitoring in patients with SCI and clinically significant BP disorders detected a high incidence of reversed dipping and nocturnal hypertension. We postulate elevated nocturnal BP may contribute to nocturnal diuresis that might cause relative volume depletion and thereby contribute to daytime orthostatic hypotension.

Neuropsychiatric symptoms in Parkinson's disease: fronto-striatal atrophy contributions.

BACKGROUND: Neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) have been mostly attributed to neurotransmitter imbalances. However, recent findings suggest that gray matter atrophy also contributes to NPS in PD. We contrast PD patients with different levels of NPS, who are well-matched for dopaminergic medication levels and disease stage, to identify the fronto-striatal gray matter atrophy areas associated with NPS in PD. METHODS: Fifty mild, non-demented PD patients were included. We median-split the group via a neuropsychiatric screening tool (Cambridge Behavioural Inventory-Revised), which resulted in higher vs. lower NPS groups (n = 25 in each group). Using T1 brain scans acquired on a 3 Tesla MRI scanner, voxel-based morphometry analysis was applied to characterize the pattern of fronto-striatal gray matter atrophy associated with elevated NPS. RESULTS: We found that the higher NPS group was characterized by greater atrophy in the prefrontal cortex, but not striatal areas. This was further corroborated by a post-hoc analysis cross-correlating the severity of NPS with gray matter loss across the whole PD group, which revealed that atrophy in the orbitofrontal cortex and frontal pole was specifically associated with elevated NPS. CONCLUSIONS: Prefrontal cortex atrophy in PD has an additional effect to dopamine replacement therapy on the generation of NPS in these patients. These findings are an important step towards the delineation of atrophy vs. neurochemical imbalance in PD, and the results emphasize the importance of considering interactions between prefrontal atrophy and neurochemical dysfunction in the genesis of neuropsychiatric symptoms in PD.

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer.

BACKGROUND: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. METHODS: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction. RESULTS: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group. CONCLUSION: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.