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Abstract Background Impairment in social functioning is a key component of personality disorder. Therefore psycho-education and problem solving (PEPS) therapy may benefit people with this disorder. Psycho-education aims to educate, build rapport, and motivate people for problem solving therapy. Problem solving therapy aims to help clients solve interpersonal problems positively and rationally, thereby improving social functioning and reducing distress. PEPS therapy has been evaluated with community adults with personality disorder in an exploratory trial. At the end of treatment, compared to a wait-list control group, those treated with PEPS therapy showed better social functioning, as measured by the Social Functioning Questionnaire (SFQ). A definitive evaluation is now being conducted to determine whether PEPS therapy is a clinically and cost-effective treatment for people with personality disorder Methods This is a pragmatic, two-arm, multi-centre, parallel, randomised controlled clinical trial. The target population is community-dwelling adults with one or more personality disorder, as identified by the International Personality Disorder Examination (IPDE). Inclusion criteria are: Living in the community (including residential or supported care settings); presence of one or more personality disorder; aged 18 or over; proficiency in spoken English; capacity to provide informed consent. Exclusion criteria are: Primary diagnosis of a functional psychosis; insufficient degree of literacy, comprehension or attention to be able to engage in trial therapy and assessments; currently engaged in a specific programme of psychological treatment for personality disorder or likely to start such treatment during the trial period; currently enrolled in any other trial. Suitable participants are randomly allocated to PEPS therapy plus treatment as usual (TAU) or TAU only. We aim to recruit 340 men and women. The primary outcome is social functioning as measured by the SFQ. A reduction (i.e., an improvement) of 2 points or more on the SFQ at follow-up 72 weeks post-randomisation is our pre-specified index of clinically significant change. Secondary outcomes include a reduction of unscheduled service usage and an increase in scheduled service usage; improved quality of life; and a reduction in mental distress. Discussion PEPS therapy has potential as an economical, accessible, and acceptable intervention for people with personality disorder. The results from this randomised controlled trial will tell us if PEPS therapy is effective and cost-effective. If so, then it will be a useful treatment for inclusion in a broader menu of treatment options for this group of service users. Trial Registration International Standard Randomised Controlled Trial Number - ISRCTN70660936

Aim: Continued smoking in patients diagnosed with cancer affects treatment outcomes and overall survival. With national surveys of Australian medical oncologists (MO) and radiation oncologists (RO) we sought to determine current clinical practices, preferences and barriers in providing patient smoking cessation support., Methods: Oncologist members of the Medical Oncology Group of Australia (n = 452) and Trans-Tasman Radiation Oncology Group (n = 230) were invited to participate in a multiple choice survey exploring smoking cessation practices and beliefs., Results: The survey response rate was 43%. At first consultations more than 90% of MO and RO regularly asked patients if they smoke or use tobacco products, closely followed by documentation of duration of smoking history and current level of consumption. Less common was asking the patient if they intended to quit (MO 63%, RO 53%) and advising cessation (MO 70%, RO 72%). Less than 50% of oncologists regularly asked about current smoking in follow-up consultations. Although a range of referral options for smoking cessation care were used by oncologists, only 2% of MO and 3% of RO actively managed the patients' smoking cessation themselves and this was the least preferred option. The majority believed they require more training in cessation interventions (67% MO, 57% RO) and cited multiple additional barriers to providing cessation care., Conclusions: Oncologists strongly prefer smoking cessation interventions to be managed by other health workers. A collaborative approach with other health professionals is needed to aid the provision of comprehensive smoking cessation care tailored to patients with cancer., (© 2018 John Wiley & Sons Australia, Ltd.)

Background: The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer., Patients and Methods: Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m 2 , then 250 mg/m 2 cetuximab weekly, with or without irinotecan 180 mg/m 2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life., Results: From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ., Conclusion: In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Background: Pituitary volume enlargements have been observed among individuals with first-episode psychosis. These abnormalities are suggestive of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, which may contribute to the development of psychosis. However, the extent to which these abnormalities characterize individuals at elevated risk for schizophrenia prior to illness onset is currently unclear, as volume increases, decreases and no volume differences have all been reported relative to controls. The current study aimed to determine whether antipsychotic-naive, putatively at-risk children who present multiple antecedents of schizophrenia (ASz) or a family history of illness (FHx) show pituitary volume abnormalities relative to typically developing (TD) children. An additional aim was to explore the association between pituitary volume and experiences of psychosocial stress., Method: ASz (n = 30), FHx (n = 22) and TD (n = 32) children were identified at age 9-12 years using a novel community-screening procedure or as relatives of individuals with schizophrenia. Measures of pituitary volume and psychosocial stress were obtained at age 11-14 years., Results: Neither ASz nor FHx children showed differences in pituitary volume relative to TD children. Among FHx children only, pituitary volume was negatively associated with current distress relating to negative life events and exposure to physical punishment., Conclusions: The lack of pituitary volume abnormalities among ASz and FHx children is consistent with our previous work demonstrating that these children are not characterized by elevated diurnal cortisol levels. The findings imply that these biological markers of HPA axis hyperactivity, observed in some older samples of high-risk individuals, may emerge later, more proximally to disease onset.

Background: Bullying victimisation has been suggested to contribute to paranoid ideation in general population samples and recent evidence found that individuals with an ultra high risk (UHR) for psychosis are twice as likely to have been bullied than controls., Aims: This study sought to examine whether a history of bullying would be associated with higher levels of paranoid ideation in individuals with an UHR and in healthy controls (HCs)., Method: The study included 64 UHR and 43 HC participants. Following the baseline assessment, participants entered a Virtual Reality (VR) London Underground train. Paranoid ideation was measured immediately after the end of the VR experience., Results: Compared to HCs, UHR participants described higher levels of childhood bullying (OR 5.19, 95% CI=2.21-12.19, p<.001) and experienced more paranoid ideation during VR (χ(2)(1)=21.06, p<.001). Childhood bullying was associated with paranoid ideation during VR in both groups (χ(2)(1)=5.931, p=,021) but prolonged exposure to bullying was not associated with increased paranoid ideation., Conclusion: A history of bullying in childhood is particularly common in young adults at high risk for psychosis. However bullying is associated with paranoid ideation in later life, independent of clinical status, consistent with dimensional models of psychotic phenomena., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC., Patients and Methods: Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression., Results: From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34-92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant., Conclusions: Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted.

Background: Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear. The objective of this study was to assess prospectively the influence of cannabis use on transition to psychosis in people at ultra-high risk (UHR) for the disorder., Method: Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people (104 male, 78 female) at UHR for psychosis. Individuals were then followed clinically for 2 years to determine their clinical outcomes., Results: Lifetime cannabis use was reported by 134 individuals (73.6%). However, most of these individuals had stopped using cannabis before clinical presentation (n=98, 73.1%), usually because of adverse effects. Among lifetime users, frequent use, early-onset use and continued use after presentation were all associated with an increase in transition to psychosis. Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently (frequent early-onset use: 25%; infrequent or late-onset use: 5%; χ(2)1=10.971, p=0.001). However, within the whole sample, cannabis users were no more likely to develop psychosis than those who had never used cannabis (cannabis use: 12.7%; no use: 18.8%; χ(2)1=1.061, p=0.303)., Conclusions: In people at UHR for psychosis, lifetime cannabis use was common but not related to outcome. Among cannabis users, frequent use, early-onset use and continued use after clinical presentation were associated with transition to psychosis.

Background: There is a consensus that stress plays a role in the onset of psychosis but the precise underlying mechanism remains unclear. The hypothalamic-pituitary-adrenal (HPA) axis is hypothesised to mediate the relationship between stress and psychosis and evidence indicates a potential role for the stress hormone cortisol as a biomarker of psychosis risk., Objective: We explored this hypothesis by examining the HPA axis in people at ultra-high risk (UHR) for psychosis and its relationship to symptoms., Method: UHR (n=52) and healthy control (HC; n=42) participants were compared on two measures of HPA axis function: cortisol response to awakening and daytime cortisol release., Results: UHR participants displayed a blunted cortisol awakening response compared with HC participants. No group difference in daytime cortisol levels was found, nor were any associations between cortisol measures and symptoms., Conclusions: These findings are broadly consistent with previous studies and neurobiological models which propose that stress and the HPA axis are involved in the onset of psychosis, although they raise further questions regarding the precise nature of this involvement., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal-regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial., Experimental Design: A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12-13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594)., Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status., Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS(mut)) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes.

Gastrointestinal stromal tumors lacking mutations in KIT or PDGFRα are known as wild type (WT) and are less responsive to imatinib. These WT tumors are hypothesized to be dependent on signaling through the insulin-like growth factor 1 receptor (IGF-1R). We report the case of a 29-year-old woman with neurofibromatosis type 1-associated WT GIST treated with an anti-IGF-1R monoclonal antibody. Treatment was ineffective, and the potential basis for lack of response is discussed in the context of IGF-1R expression levels measured within this patients' primary tumor. We suggest that future clinical trials of anti-IGF-1R therapies prospectively determine tumor IGF-1R expression levels for correlation with response to treatment.

Purpose: Universal screening for chronic hepatitis B virus (HBV) infection before chemotherapy has been recommended. We evaluated the cost-effectiveness of HBV screening before chemotherapy given for nonhematopoietic solid tumors (STs)., Methods: A decision-analytic model was used to compare the cost-effectiveness of universal screening conducted per professional guidelines versus no screening in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non-small-cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy., Results: Using an incremental cost-effectiveness ratio threshold of $50,000 (Australian dollars) per life-year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients ($88,224/LY, 13% probability of being cost-effective), palliative patients ($1,344,251/LY, 0%), or pooled (all) patients ($149,857/LY, 1%). Sensitivity analyses found that screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%, $59,445/LY) or HBV reactivation with chemotherapy (41%, $56,537/LY). Cost- effectiveness was also significantly influenced by HBV population prevalence. An alternative screening strategy using hepatitis B surface antigen testing only produced the most economically favorable results, with $30,126/LY (80% probability) for adjuvant patients and $51,201/LY (43%) for the pooled cohort., Conclusion: Universal HBV screening conducted per current guidelines is not cost-effective in patients with STs. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy.

Background: The aim was to investigate the correlation between (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus., Methods: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response., Results: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively)., Conclusion: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.

Aims: There is a scarcity of data regarding medical hospitalizations for breast cancer. The aim was to determine whether the burden of inpatient care for breast cancer was declining., Methods: A retrospective study was conducted of all admissions to a single medical oncology inpatient unit in 1996 and 2006 related to the treatment of breast cancer. The total number of hospitalizations, patients' length of stay in hospital, clinical indications for hospitalization and utilization of inpatient services were determined. Data analysis involved pairwise comparisons between the cohorts., Results: The total number of breast cancer hospitalizations was similar in 1996 and 2006. However, the number of hospitalizations for adjuvant treatment complications was 50% lower in 2006, attributable to a lower rate of chemotherapy-associated febrile neutropenia. Acute clinical problems necessitating inpatient care differed between 1996 and 2006. Fewer hospitalizations for symptomatic hypercalcemia, uncontrolled pain and chemotherapy toxicity were required in 2006 but a significant increase was seen in central nervous system complications. Recent practice involved greater inpatient consultation of other medical and surgical teams. There was a trend towards a shorter duration of admissions in 2006 in both adjuvant and metastatic patients., Conclusion: Although total annual breast cancer admission numbers and length of stay did not change significantly, hospitalization for treatment-related complications was less frequent in 2006. The clinical manifestations of metastatic breast cancer appear to be changing, and in our institution are being managed with broader multidisciplinary care., (© 2011 Blackwell Publishing Asia Pty Ltd.)

Purpose: Universal screening for chronic hepatitis B virus (HBV) before chemotherapy has been recommended by the Centers for Disease Control. We sought to determine the practice of Australian oncologists with regard to HBV screening in patients with solid tumors (STs) and their clinical experience of HBV reactivation (HBVR)., Methods: A survey was sent to all consultant members of the Medical Oncology Group of Australia. One hundred eighty-eight responses (63% response rate) were received. We also reviewed the incidence of HBV in patients with STs screened at the Peter MacCallum Cancer Centre (Melbourne, Australia)., Results: Fifty-three percent of medical oncologists screen for HBV, but only 19% screen all patients. The most common reasons given for performing screening were anecdotal experience of HBVR (46%) and perceived sufficient evidence for screening of some patient subgroups (42%). Sixty-five percent of those who screened did so only in subgroups, usually selecting patients on the basis of ethnicity (82%). Oncologists who did not screen most commonly cited inadequate evidence for a benefit of screening (72%). Twenty-two percent of oncologists had witnessed one or more HBVR events, representing one event per 45 years of respondents' practice. HBVR events reported (n = 54) consisted of asymptomatic liver test abnormalities only (44%), symptomatic hepatitis (28%), decompensated liver failure (19%), and death (7%). In 206 patients with STs screened for HBV, 1.0% (n = 2) were HBV surface antigen positive, and 14.9% hepatitis B core antibody positive., Conclusion: The majority of Australian medical oncologists have not adopted universal HBV screening before chemotherapy. Further evidence of the benefit and cost effectiveness of universal screening in patients with STs will be required to alter practice.

Background: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy., Methods: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15-30 mg m(-2) per week and cisplatin 15-30 mg m(-2) per week in six planned dose levels (DLs) in 3-6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy., Results: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m(-2), cisplatin 15 mg m(-2)) and grade 3 nausea in DL2 (20 mg m(-2), 15 mg m(-2)). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial)., Conclusion: Cisplatin and docetaxel each 30 mg m(-2) per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

Angiotensin II (ATII) and platelet-derived growth factor (PDGF) are two vasoconstrictors implicated in the maintenance of normal vascular homeostasis. PDGF A-chain levels increase in cultured vascular smooth muscle cells (SMCs) exposed to ATII. The molecular mechanisms underlying this induction are not known. We used transient transfection analysis to show that ATII can increase reporter gene activity driven by fragments of the PDGF-A promoter bearing recognition elements for the transcription factor, Egr-1. Nuclear run-off experiments indicate that ATII induces Egr-1 expression at the level of transcription. Gel shift and supershift studies show that Egr-1 protein accumulates in the nuclei of SMCs exposed to ATII and binds to the proximal region of the PDGF-A promoter in a specific, time-dependent manner. ATII induced extracellular-signal regulated kinase (p42/44 ERK) activity as did phorbol 12-myristate 13-acetate. The specific MEK1/2 inhibitor, PD98059, suppressed both PDGF-A and Egr-1 endogenous and promoter-dependent expression inducible by ATII. The ATII type 1 receptor (AT1) antagonist, Losartan, inhibited ATII-induction of p42/44 ERK, as well as Egr-1 and PDGF-A, whereas neither PD123319, an AT2 receptor antagonist, nor wortmannin, an inhibitor of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase, had any effect. ATII-induction of Egr-1 and PDGF-A was blocked by SIN-1, a NO donor. In addition, this pathway was blocked by overexpression of NO synthase. Collectively, these findings demonstrate that ATII activation of the PDGF-A promoter is mediated via the MEK/ERK/Egr-1 pathway and AT1 receptor and that this process is antagonized by NO.

Cell migration and proliferation that follows injury to the artery wall is preceded by signaling and transcriptional events that converge at the promoters of multiple genes whose products can influence formation of the neointima. Transcription factors, such as early growth response factor-1 (Egr-1), with nucleotide recognition elements in the promoters of many pathophysiologically relevant genes, are expressed at the endothelial wound edge within minutes of injury. The mechanisms underlying the inducible expression of Egr-1 in this setting are not clear. Understanding this process would provide important mechanistic insights into the earliest events in the response to injury. In this report, we demonstrate that fibroblast growth factor-2 (FGF-2) is released by injury and that antibodies to FGF-2 almost completely abrogate the activation and nuclear accumulation of Egr-1. FGF-2-inducible egr-1-promoter-dependent expression is blocked by PD98059, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-1/2 (MEK-1/2), as well as by dominant negative mutants of ERK-1/2. Inducible ERK phosphorylation after injury is dependent on release and stimulation by endogenous FGF-2. Antisense oligonucleotides directed at egr-1 mRNA suggest that Egr-1 plays a necessary role in endothelial repair after denudation of the monolayer. These findings demonstrate that inducible Egr-1 expression after injury is contingent on the release and paracrine action of FGF-2.