A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Mediation of work-family support and affective commitment between family supportive supervisor Behaviour and workplace deviance.

Employees' Workplace Deviant Behavior (WDB) is an organizational threat to its sustainability. This study examines the impact of the supervisors' role in improving organizational behavior because of the gap in the body of knowledge indicating the inconsistency, paucity, and uncertainties of relationships between variables when relating to their underpinning theories. The conceptualized model consists of the impact of family supportive supervisor behavior (FSSB) on workers' workplace deviant behavior (WDB) while considering Affective Commitment and Work-Family Supportive Behavior Attribution between the key variables. In terms of methodology, this quantitative study analyzed 321 valid surveys through descriptive and inferential statistics to ascertain if FSSB negatively impacts employees' WDB. As findings and novelty of this study, FSSB is found to negatively affect employees' WDB, while affective commitment mediates between FSSB and employees' WDB. Work-family supportive behavior attribution and personal life attribution of employees moderated the negative relationship between affective commitment and WDB, while work productivity attribution of employees had no significant effect as a moderator. With three (out of four) hypotheses supported by empirical evidence, this research has broadened previous studies of workers' WDB and offers organizations theoretical and practical recommendations for managing employees' WDB. More studies could be conducted in the future to address limitations in this research, examine other related theories in a new context, location, and/or culture, or select other suitable research methods.

Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial.

BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.

Mediating Role of Intra-Team Conflict between Paternalistic Leadership and Decision-Making Quality among China University's CMT during COVID-19.

Universities across China have set up crisis management teams (CMTS) to deal with the crisis brought on by the COVID-19 pandemic. This study focuses on how the paternalistic leadership practices of a Chinese university CMT influence crisis strategic decisions by managing conflict. These relationships were verified using hierarchical regression analysis on 312 samples from the surveyed university during the pandemic and found the following: benevolent leadership and moral leadership have positive effects on decision quality. However, unlike most studies on paternalistic leadership, in crisis situations, the negative effects of authoritarian leadership disappear under the mediating effect of affective conflict. This means that affective conflict within CMT fully mediates the relationship between authoritarian leadership and decision quality, and partially mediates the relationship between moral leadership and decision quality, while cognitive conflict partially mediates the relationship between benevolent leadership and crisis decision quality. It indicates that a CMT must stimulate and maintain a certain level of cognitive conflict while suppressing affective conflict to achieve high-quality crisis decision-making. This state can be achieved by practicing lower levels of authoritarian leadership and maintaining high levels of moral and benevolent leadership practices.

Neurotransmitter receptor autoradiography in immunohistochemically identified neurons.

A method for the simultaneous visualization of neurotransmitter receptor binding sites and immunohistochemically characterized cells is described using in vitro sections of rat striatum. The striatum provides a rich neurochemical environment in which to examine muscarinic acetylcholine receptor relations to peptide-reactive somata, or to assess the cellular locale of the dopamine receptor linked to adenylate cyclase activation. Different modifications of the procedure are employed to determine the localization pattern of 3H-radioligands with slow or rapid receptor dissociation times. The present technique is compatible for use with any combination of immunohistochemical antibody/radioligand probe that can be studied on fresh-frozen, slide-mounted tissue sections.

Striatal muscarinic receptors are associated with substance P and somatostatin containing neurons.

The cellular localization of muscarinic acetylcholine binding sites (mAChr) in relation to immunohistochemically characterized cell populations within the rat caudate nucleus has been determined using in vitro autoradiography of the reversible antagonist ligand, quinuclidinyl benzilate [( 3H]QNB). The pattern of autoradiographic silver grain deposition in the striatum was contrasted with the localization of two peptide-containing neuronal populations in the striatum. Substance P-immunoreactive somata demonstrated prevalent association of mAChr binding sites, as did somatostatin-immunoreactive cells. Substantially more striatal muscarinic binding sites were aggregated over the somatostatin interneuron population of the caudate nucleus than were associated with the substance P somata in concurrently performed experiments. This data further substantiates the heterogeneity in organization of the caudate nucleus, and the results are discussed in relation to the processing of information within this basal ganglia region.

Neurochemical differences in the superior cervical ganglion of the spontaneously hypertensive rat stroke-prone variant.

The localization and distribution of catecholamines, selected neuropeptides, and the cyclic nucleotide second messengers has been determined in the superior cervical ganglion of the stroke-prone variant of the spontaneously hypertensive rat (SHR) and its normotensive Wistar-kyoto (WKY) control. Significant alteration in the frequency of occurrence of dopaminergic small intensely fluorescent cell clusters was seen in the stroke-prone variant of the SHR. The immunofluorescent localization of cyclic AMP (cAMP) and cyclic GMP (cGMP) were also changed in the stroke-prone variant, as was the immunofluorescent staining quantity of the neuropeptides somatostatin and substance P. The morphological pattern of staining for the various compounds in the normotensive control (WKY) was equivalent to the Sprague-Dawley rat strain. The implications of the altered neurochemistry in the superior cervical ganglion on the high blood pressure, and the predisposition for stroke in this strain are discussed.

Peptide coincidence in rat superior cervical ganglion.

The immunofluorescent localization of substance P (SP), somatostatin and methionine enkephalin has been determined in the rat superior cervical ganglion of the sympathetic nervous system. Immunoreactivity was confined to the norepinephrine-containing post-ganglionic neurons and their processes. Nearly 20% of the postganglionic somata demonstrate dual coincidence in staining for SP-somatostatin, somatostatin-enkephalin, or SP-enkephalin. Almost 10% of the positively stained neurons show a coincident staining of all 3 peptide compounds within their somata. This suggests that multiple neurotransmitter chemicals may be employed by the postganglionic cells of the superior cervical ganglion.

Eradication of Pseudomonas aeruginosa in adults with cystic fibrosis.

BACKGROUND: Eradication of new infection of Pseudomonas aeruginosa is an important intervention in managing cystic fibrosis (CF). Previous trials, studying predominantly under 18-year-olds, indicate that antibiotic eradication therapy (AET) has success rates of 62.8-93.0%. In this retrospective cohort study, we report the outcomes of AET in an adult population. METHODS: Adults with a confirmed diagnosis of CF and a first isolation of P aeruginosa were studied between 1999 and 2012. Choice of therapy, time to eradication and reinfection, and lung function (forced expiratory volume in 1 s (FEV1)) were determined. RESULTS: 20 patients (median age 27 years) isolated P aeruginosa during the study period. 10 patients were treated with oral ciprofloxacin (median duration 6 weeks) and nebulised colomycin (median duration 3 months). 7 patients were treated with intravenous antipseudomonal antibiotics (median duration 14 days). 2 patients received other combinations of oral and inhaled antipseudomonal therapy and one patient received no therapy. AET was successful in 15 cases who received antipseudomonal therapy (79%). The median time to eradication was 1 month. The median time to reinfection with P aeruginosa was 43 months. There was no significant change in FEV1 after 12 months. CONCLUSIONS: Aggressive AET of new infection of P aeruginosa in adults is successful in the majority of patients and has similar efficacy to the reported efficacy in paediatric populations.

The immunofluorescence localization of glutamate decarboxylase in the rat superior cervical ganglion.

The immunofluorescence localization of glutamate decarboxylase (GAD, EC 4.1.1.15) has been determined in the superior cervical ganglion of the rat. Immunoreactivity was confined to clusters of small cells whose size is similar to that of the dopaminergic small intensely fluorescent (SIF) cells. In serial sections tested for GAD immunofluorescence and catecholamine histofluorescence there was no evidence of co-localization. These results suggest that a separate population of gamma-aminobutyric acid (GABA) synthesizing cells is present in the rat superior cervical ganglion.