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Objective: Alcohol and other drug (AoD) use is a significant factor in the poor health status of people in prison. Our aim is to explore associations of alcohol consumption with tobacco and illicit drug use among Aboriginal and non-Aboriginal people in prison to inform health services, clinical care and support., Methods: We analysed the alcohol, tobacco and illicit drug use data of the 2015 Network Patient Health Survey of adults in custody in New South Wales (n=1,132). A comparative analysis of Aboriginal to non-Aboriginal participants including bi-variant and multivariant analysis was undertaken., Results: Significantly more Aboriginal than non-Aboriginal participants reported alcohol consumption before prison that was consistent with possible dependence. More Aboriginal than non-Aboriginal participants used cannabis on a daily or almost on daily basis before prison. There was significant association between alcohol and cannabis use among Aboriginal participants., Conclusions: There are differences in Aboriginal and non-Aboriginal AoD use patterns, which should be considered when providing treatment and support programs within and post-release from prison., Implications for Public Health: Specific programs are needed to assist Aboriginal people in this population who co-use alcohol and cannabis., Competing Interests: Conflicts of interest None of the authors have a conflict of interest towards publishing this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Objectives: This study investigated how adults in the United Kingdom perceived their arts and cultural engagement to facilitate social connectedness over two phases in the first year of the COVID-19 pandemic., Study Design: The study used the HEartS Survey, a newly designed online survey tool to capture arts engagement in the United Kingdom and its associations with social and mental well-being, over two phases in 2020: March to May (Phase 1) and October (Phase 2)., Methods: Qualitative data were provided at both phases by 581 respondents, who identified which arts and cultural activity they felt most connected them to others and how during the last month., Results: Thematic analysis revealed that, at both phases, arts and cultural engagement was perceived to facilitate social connectedness through four pathways that were also identified prepandemic: social opportunities, sharing, feelings of commonality and belonging and collective understanding. The subthemes shed light on specific ways that respondents used the arts during the pandemic to connect with others, including using the arts: as a catalyst for conversations, to maintain, reinstate or strengthen relationships during social distancing and to facilitate social interactions (Theme 1); to bring people together through shared experiences and sharing of art (Theme 2); to elicit feelings of direct and indirect proximity to others, to connect people with common interests, to feel a sense of belonging to something and to feel part of a collective 'COVID-19 experience' or to feel collectively distracted from the pandemic (Theme 3); and to learn from and about other people and to relate to others (Theme 4). The activity most frequently cited as connecting was watching a film or drama, followed by listening to recorded music., Conclusions: Engagement in arts and cultural activities supported feelings of social connection among adults in the United Kingdom over two phases in the first year of the COVID-19 pandemic, highlighting the importance of access to the arts and culture to support social connectedness., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of 'platinum-sensitive' ovarian cancer and has been shown to improve progression-free survival (PFS)., Patients and Methods: ICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here., Results: After a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch-Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: -0.09 to 9.74 months)., Conclusions: Although a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken., Competing Interests: Disclosure ACE-T, HH, MV, ED, BP, LF, and AMS declare no conflicts of interest. JAL has attended AstraZeneca, GSK, Clovis Oncology, MSD, Eisai, Pfizer advisory boards and spoken at symposia with remuneration and has institutional grants from AstraZeneca and MSD. TJP reports grants, personal fees, non-financial support from Roche; personal fees from Novartis; personal fees from AstraZeneca, other fees paid to the institution from multiple other pharmaceutical companies and research organisations in connection with the costs of running a broad research portfolio, outside the submitted work. GCJ attended AstraZeneca advisory board and has received research funding for investigator-led trials. Also research grant from Roche. GJSR has attended advisory boards for AstraZeneca, Amgen and OXiGENE, in addition to data management costs from the MRC. SBK has attended an AstraZeneca advisory board. AO is Principal Investigator for investigator-initiated trials with AstraZeneca and has institutional grants from AstraZeneca outside the submitted work, and non compensated membership of steering committees with AstraZeneca and Clovis and a noncompensated advisory role with AstraZeneca and GSK. MF has attended advisory board meetings for AstraZeneca, Takeda, Novartis, MSD and Lilly and received personal fees. Travel support from AstraZeneca, research funding to institution for investigator-initiated trials. AG-M reports personal fees for advisory boards to Amgen, AstraZeneca, Clovis, Genmab, GSK-TESARO, Novartis, MSD, Oncoinvent, PharmaMar, Pfizer-Merck, Roche, SOTIO. RSK reports grants from Cancer Research UK and AstraZeneca, as well as drug supply from AstraZeneca. MKBP reports an educational grant from AstraZeneca., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir., Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4 + T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074., Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log 10 copies HIV DNA per 10 6 CD4 + T-cells in the ART-only group versus 3·06 log 10 copies HIV DNA per 10 6 CD4 + T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log 10 copies HIV DNA per 10 6 CD4 + T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events., Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required., Funding: Medical Research Council (MR/L00528X/1)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Rates of stroke and obesity have increased in recent years. This study aimed to determine the body mass index (BMI) of fatal stroke cases amongst young adults, their clinical characteristics and the association with BMI with risk factors. All cases aged 15-44 years where death was attributed to stroke for whom BMI was available were retrieved from the National Coronial Information System (1/1/2009-31/12/2016). 179 cases were identified: haemorrhagic (165), ischaemic (5), thrombotic (6), mycotic (3), embolic (0). Proportions in each BMI category were: underweight (5.6%), normal weight (37.4%), overweight (27.4%), obese (29.6%). There was a significant linear trend in the proportion of subarachnoid haemorrhages as BMI increased (p < 0.05), and between higher BMI and hypertension (p < 0.001). There were no group differences in cardiomegaly or left ventricular hypertrophy where known causes were other than hypertension, cardiomyopathy, severe coronary artery atherosclerosis, endocarditis or cerebral arteries atherosclerosis. A history of alcoholism (p < 0.01) was less likely with higher BMI. There was no association between BMI and previous stroke, diabetes, vasculitis, gravid/post-partum, tobacco use, psychostimulant use or injecting drug use. Overweight and obese cases were prominent among young fatalities of stroke. Reducing rates of obesity, and associated hypertension, would be expected to reduce the escalating stoke rates among young adults., (Copyright © 2019 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Purpose: To compare methods for evaluating refractive outcomes after cataract surgery to detect outliers., Design: Case series database study of the evaluation of diagnostic technology., Participants: Consecutive patients who had uneventful cataract operations over a 5-year period., Methods: The intended and postoperative refractive outcome and differences between these were analyzed as a spherical equivalent, cylinder, and spherocylinder. The average keratometry and differences between steep and flat keratometric meridians were used to calculate the intended refractive error., Main Outcome Measures: Outliers were defined as patients for whom the difference between the intended and postoperative refractive errors was more than 3 standard deviations (SDs) away from the mean., Results: A total of 9000 patients were included. Twelve patients had missing data and were excluded. The mean intended refractive outcome was -0.12+0.12×2 (95% lower confidence limit [LCL], -1.94+1.06×44; 95% upper confidence limit [UCL], +0.77+1.05×140). The actual postoperative refractive error was -0.30+0.47×6 (95% LCL, -2.36+1.31×36; 95% UCL, +1.00+1.18×148) with a difference from the intended of -0.18+0.35×7 (95% LCL, -1.91+1.22×38; 95% UCL, +0.75+1.09×145). Treating the components of the refractive error independently, outliers were observed in 82 eyes (0.91%) based on the sphere, 46 eyes (0.51%) based on the spherical equivalent, 115 eyes (1.28%) based on treating the cylinder as a scalar, and 76 eyes (0.85%) based on treating the cylinder as a vector. When the differences between the intended and postoperative refractive errors were calculated as a compound spherocylinder, outliers were observed for 233 eyes (2.59%)., Conclusions: Treating the intended refractive outcome as a spherocylinder improves the precision for detecting clinically significant refractive outliers., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Choriocarcinoma associated with cornual pregnancy is extremely rare. To our knowledge, only three other cases have been reported in the literature., Case: A 38-year-old woman was found to have a left cornual ectopic pregnancy on ultrasound after presenting with abdominal pain, irregular vaginal bleeding, and a positive pregnancy test. Laparoscopy confirmed the diagnosis and she underwent total abdominal hysterectomy. Three weeks later, she presented with vaginal bleeding. A solid ulcerating lesion was found arising from the vaginal wall and biopsy revealed metastatic gestational choriocarcinoma., Conclusion: Careful histopathological examination of the surgical specimen and diligent monitoring of β-human chorionic gonadotropin to zero is crucial to prevent potentially missing this very malignant, but highly curable disease. Early systemic metastases are common and presentation can include bleeding from vaginal metastases., (Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Background: Methamphetamine dependence is a major public health problem. This study examined the nature, and extent, of cardiovascular disease amongst cases of methamphetamine-related death in Australia, 2009-2015., Methods: Analysis of 894 cases of methamphetamine-related death with full autopsy reports retrieved from the National Coronial Information System., Results: The mean age was 37.9yrs (range 15-69yrs) and 78.5% were male. A quarter (26.3%) of cases had enlarged hearts and left ventricular hypertrophy was diagnosed in 18.9%. Severe coronary artery disease was present in 19.0%, the left coronary artery being the vessel most frequently stenosed (16.6%). Replacement fibrosis (evidence of earlier ischaemic events) in the heart muscle was observed in 19.8% of cases, and cardiomyopathy was diagnosed in 5.5%. Histological evidence of hypertension was observed in 32.7% of cases. With the exception of cardiomyopathy, equally common amongst both sexes, cardiovascular disease was more common amongst males, and those aged >35yrs. Clinically significant levels of cardiovascular disease were also observed amongst cases where the cause of death was not attributed to cardiovascular disease: cardiomegaly (19.3%), left ventricular hypertrophy (14.6%), severe coronary artery disease (9.4%), replacement fibrosis (14.4%), cardiomyopathy (3.3%)., Conclusions: Cardiovascular disease was highly prevalent, despite the relatively young age of cases. With methamphetamine use increasing rapidly in major regions, cardiovascular disease and cardiovascular-related death will likely increase amongst methamphetamine users., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In vascularized organ transplants, gender mismatches have higher rates of immunological rejection. We investigated the influence of gender incompatibility, including H-Y incompatibility, on corneal transplant graft rejection and failure. Patients were included who had undergone a first corneal transplant for keratoconus (KC), Fuchs endothelial dystrophy (FED), pseudophakic bullous keratopathy (PBK), infection and other indications. A Cox regression model was fitted for each indication to determine factors affecting graft failure and rejection at 5 years. The impact of gender, including H-Y, matching was analyzed after accounting for other factors, including known risk factors. Of 18 171 patients, 4314 had undergone a transplant for FED, 4783 for KC, 3669 for PBK, 1903 for infection and 3502 for other disorders. H-Y mismatched (male [M]→female [F]) corneas were at greater risk of graft failure or rejection. For FED, F→F were 40% less likely to fail (p < 0.0001) and 30% less likely to reject (p = 0.01); M→M were 20% less likely to fail (p = 0.04) and 30% less likely to reject (p = 0.01). For KC, M→M matched corneas were 30% less likely to fail (p = 0.05) and 20% less likely to reject (p = 0.01) compared with H-Y mismatches. H-Y antigen mismatched (M→F) patients were at greater risk of rejection or graft failure., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The potential of methamphetamine, and high-potency crystal methamphetamine in particular, to precipitate psychotic symptoms and psychotic illness is the subject of much speculation internationally. Established psychotic illness is disabling for individuals and costly to society. The aim of this study was to investigate whether use of crystal methamphetamine was associated with greater prevalence of self-reported psychotic illness, compared to use of other forms of methamphetamine., Methods: The sample comprised participants interviewed as part of an annual cross-sectional survey of Australian people who inject drugs. Comparisons were made between groups according to the nature of their methamphetamine use: crystal methamphetamine or other forms of methamphetamine. Self-reported diagnoses of psychotic illness and other mental health problems were compared between groups. Predictors of self-reported psychotic illness were examined using multivariable logistic regression analyses., Results: Self-reported psychotic illness was highly prevalent among users of crystal methamphetamine (12.0%), and significantly more so than among users of other forms of methamphetamine (3.9%) (OR=3.36; CI: 1.03-10.97). Significant predictors of self-reported psychosis in the cohort were: use of crystal methamphetamine; dependent use; lack of education beyond high school; and younger age., Conclusion: Highly increased prevalence of self-reported psychotic illness is associated with use of high-potency crystal methamphetamine in people who inject drugs, particularly where there is dependent use. There is an urgent need to develop effective interventions for dependent crystal methamphetamine use; and a need to monitor for symptoms of psychotic illness in drug-using populations., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The significant activity of poly(ADP-ribose)polymerase (PARP) inhibitors in the treatment of germline BRCA mutation-associated ovarian cancer, which represents ∼15% of HGS cases, has recently led to European Medicines Agency and food and drug administration approval of olaparib. Accumulating evidence suggests that PARP inhibitors may have a wider application in the treatment of sporadic ovarian cancers. Up to 50% of HGS ovarian cancer patients may exhibit homologous recombination deficiency (HRD) through mechanisms including germline BRCA mutations, somatic BRCA mutations, and BRCA promoter methylation. In this review, we discuss the role of somatic BRCA mutations and BRCA methylation in ovarian cancer. There is accumulating evidence for routine somatic BRCA mutation testing, but the relevance of BRCA epigenetic modifications is less clear. We explore the challenges that need to be addressed if the full potential of these markers of HRD is to be utilised in clinical practice., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy., Patients and Methods: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline., Results: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively., Conclusion: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy., Clinicaltrialsgov: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

For several years, a major obstacle in the systemic treatment of ovarian cancer has been the lack of a therapeutic strategy tailored to specific biomarkers present in the individual patient's tumour. However, considerable progress has been made recently through the development of drugs targeting cells deficient in the key mechanism of double-strand DNA repair, known as homologous recombination (HRD). These drugs, inhibitors of the enzyme poly (ADP) ribose polymerase (PARP), selectively kill HRD cells through a process known as tumour-selective synthetic lethality. Olaparib is the first such agent, now approved for the treatment of ovarian cancer associated with mutations in the BRCA 1/2 genes, since these are characterised by cells with HRD. Importantly, another group of patients with tumours bearing a similar repair deficiency but without BRCA mutations may also be susceptible to PARP inhibition and efforts to develop an HRD assay are therefore a priority so that these patients can be identified as PARPi candidates. In addition, combination strategies are an area of intense research; these include combinations with antiangiogenic agents and with inhibitors of the P13K/AKT pathway and others are likely to merit assessment since resistance to PARP inhibitors will certainly emerge as the next challenge. While olaparib is the first PARP inhibitor to receive approval for ovarian cancer treatment, others including rucaparib and niraparib are clearly effective in this disease and, within the next year or two, the results of ongoing randomised trials will clarify their respective roles. PARP inhibitors are generally well tolerated; regulatory approval at present supports their use as a maintenance therapy (in Europe) and as treatment for advanced recurrent disease (in the United States), but it is likely that these indications will extend as the results of ongoing trials become available. Ten years have elapsed between the first pre-clinical publications and the regulatory approval of PARP inhibitors and the next 10 years promise to be even more productive., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In response to concern about whether mixing caffeinated energy drinks with alcohol (AED) increases alcohol consumption and related harm, and the role of industry in this debate, we conducted a comprehensive review of the research evidence on the effects of AED and documented industry involvement in this research., Method: A systematic review of 6 databases. Studies must have examined the effect of consuming alcohol with energy drinks (ED) or caffeine on alcohol-related outcomes., Results: 62 studies were identified; 29 were experiments, 9 had industry ties (8 with Red Bull GmbH). Young adults who consumed AED drank more alcohol and experienced more alcohol-related harm than other drinkers. There was insufficient evidence to conclude that AED led to increased alcohol consumption or altered the nature of alcohol-related harm. However, AED consumers reported that AED increased stimulation and alertness, offset fatigue from drinking, and facilitated drinking. Experimental research also found that combining ED or caffeine with alcohol increased stimulation and alertness, offset alcohol-related fatigue and increased the desire to keep drinking. It did not change BAC, perceived intoxication, perceived impairment and it did not reverse alcohol-induced impairment on simple psychomotor tasks. Combining ED/caffeine with alcohol reduced alcohol-induced impairment on some but not all aspects of complex tasks. Although few in number, studies with industry ties presented contrary evidence., Conclusion: A growing body of evidence suggests that AED may facilitate drinking and related harms via its effects on intoxication but a causal link needs to be confirmed. The influence of industry involvement in this area of research needs to be monitored., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Impulsivity and consequent risk-taking are features of both Attention Deficit Hyperactivity Disorder (ADHD) and substance use disorder (SUD). To date there are no data on the impact of comorbid ADHD on the likelihood and frequency of risk-taking behaviour among individuals with SUD. The current study aimed to examine drug-related, sexual and driving-related risk behaviours in people seeking treatment for SUD with co-occurring symptoms of Attention Deficit Hyperactivity Disorder (ADHD), taking into account potential confounders., Methods: 489 Australian adult SUD treatment seekers were administered a structured interview assessing demographics, drug use and SUD treatment history, psychiatric history, self-reported adult ADHD symptoms and self-reported drug-related, sexual and driving-related risk behaviours., Results: Almost a third (32%) screened positive for adult ADHD symptoms with onset prior to age 12. Those screening positive were more likely to report early onset (<15 years) nicotine and illicit drug use and to have a prior diagnosis of childhood ADHD, anxiety, depression and personality disorder. ADHD symptom status was not independently associated with injecting drug use-related or sexual risk-taking in the preceding month, but was an independent predictor of a greater overall number of driving offences, a higher frequency of driving without a seatbelt, a greater likelihood of having driven without a valid licence, more at-fault accidents and having one's licence disqualified at the time of interview., Conclusions: These findings suggest that the risk-taking behaviour that is common among people with SUD is further increased among those with comorbid ADHD symptoms, particularly with respect to dangerous driving practices., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: We investigated whether the Src inhibitor saracatinib (AZD0530) improved efficacy of weekly paclitaxel in platinum-resistant ovarian cancer., Patients and Methods: Patients with platinum-resistant ovarian, fallopian tube or primary peritoneal cancer were randomised 2 : 1 to receive 8-week cycles of weekly paclitaxel (wPxl; 80 mg/m(2)/week ×6 with 2-week break) plus saracatinib (S; 175 mg o.d.) or placebo (P) continuously, starting 1 week before wPxl, until disease progression. Patients were stratified by taxane-free interval (<6 versus ≥6 months/no prior taxane). The primary end point was progression-free survival (PFS) rate at 6 months. Secondary end points included overall survival (OS) and response rate (RR)., Results: A total of 107 patients, median age 63 years, were randomised. Forty-three (40%) had received >2 lines of prior chemotherapy. The 6-month PFS rate was 29% (wPxl + S) versus 34% (wPxl + P) (P = 0.582). Median PFS was 4.7 versus 5.3 months (hazard ratio 1.00, 95% confidence interval 0.65-1.54; P = 0.99). RR (complete + partial) was 29% (wPxl + S) versus 43% (wPxl + P), P value = 0.158. Grade 3/4 adverse events were 36% versus 31% (P = 0.624); the most frequent G3/4 toxicities were vomiting (5.8% saracatinib versus 8.6% placebo), abdominal pain (5.8% versus 0%) and diarrhoea (4.3% versus 5.7%). Febrile neutropenia was more common in the saracatinib arm (4.3%) than placebo (0%). Response, PFS and OS were all significantly (P < 0.05) better in patients with taxane interval ≥6 months/no prior taxane (n = 85) than those <6 months (n = 22), regardless of randomisation., Conclusions: Saracatinib does not improve activity of weekly paclitaxel in platinum-resistant ovarian cancer. Taxane-free interval of ≥6 months/no prior taxane was associated with better outcome in both groups., Trials Registration: Clinicaltrials.gov NCT01196741; ISRCTN 32163062., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Although sarcomas account for only 1% of all solid tumours, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials., Patients and Methods: We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007., Results: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line., Conclusion: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients., Patients and Methods: A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life., Results: The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity., Conclusions: Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

Background: Available studies vary in their estimated prevalence of attention deficit/hyperactivity disorder (ADHD) in substance use disorder (SUD) patients, ranging from 2 to 83%. A better understanding of the possible reasons for this variability and the effect of the change from DSM-IV to DSM-5 is needed., Methods: A two stage international multi-center, cross-sectional study in 10 countries, among patients form inpatient and outpatient addiction treatment centers for alcohol and/or drug use disorder patients. A total of 3558 treatment seeking SUD patients were screened for adult ADHD. A subsample of 1276 subjects, both screen positive and screen negative patients, participated in a structured diagnostic interview., Results: Prevalence of DSM-IV and DSM-5 adult ADHD varied for DSM-IV from 5.4% (CI 95%: 2.4-8.3) for Hungary to 31.3% (CI 95%:25.2-37.5) for Norway and for DSM-5 from 7.6% (CI 95%: 4.1-11.1) for Hungary to 32.6% (CI 95%: 26.4-38.8) for Norway. Using the same assessment procedures in all countries and centers resulted in substantial reduction of the variability in the prevalence of adult ADHD reported in previous studies among SUD patients (2-83%→5.4-31.3%). The remaining variability was partly explained by primary substance of abuse and by country (Nordic versus non-Nordic countries). Prevalence estimates for DSM-5 were slightly higher than for DSM-IV., Conclusions: Given the generally high prevalence of adult ADHD, all treatment seeking SUD patients should be screened and, after a confirmed diagnosis, treated for ADHD since the literature indicates poor prognoses of SUD in treatment seeking SUD patients with ADHD., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Institutional monographs/medical textbooks mention seizures as a neurological complication of cocaine, but no systematic reviews (SRs) have been published on this issue. We aimed to conduct a SR of the literature on the relationship between cocaine use and seizures and to summarize the biological plausibility of that relationship., Methods: The pathophysiological mechanisms that may underlie an association between cocaine and seizures were summarized; a SR was then performed using three databases (EMBASE, Medline, PsycINFO) and the Cochrane-library to search for published papers (1980-2012) aimed at quantifying the associations between cocaine use and seizures. The inclusion criteria for selection were: articles based on clinical trials, cohort, case-control (CC) or cross-sectional (CS) studies, participants ≥ 14 years old and not pregnant, and use of cocaine in the last 72 h. Information was extracted, evaluated and cross-checked independently by two researchers., Results: Of the 1243 potentially relevant articles initially identified; one CC and 22 CS studies were finally selected. The CC study did not find cocaine use to be a risk-factor for seizures. In addition to the limitations of the CS design, these studies had important methodological weaknesses and biases., Conclusions: Despite its biological plausibility, no rigorous scientific evidence supports a causal relationship between cocaine use and seizures. The misinterpretation of the role of cocaine may have important implications in medical services. Well-conducted studies are urgently needed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Over the past 40 years, the treatment of ovarian cancer has undoubtedly improved as a result of better multi-modality care and platinum-based chemotherapy. More recently, the introduction of anti-angiogenic therapy, PARP inhibitors and a weekly regimen for paclitaxel indicate that results are likely to improve further. However, major challenges remain and these will be reviewed in this article. We assess key issues in anti-angiogenic treatment including potential ways for addressing resistance; we review the current studies of PARP inhibitor treatment, which shows most promise in patients with germline BRCA mutations; we describe the potential for folate-receptor-directed therapy, given the high level of FR expression in ovarian cancer and we highlight the potential for molecular targeted therapy, focusing on specific subgroups of the disease with targets such as the PI3 K/AKT and RAS/RAF/MEK pathways and the ErbB family of oncogenes. We anticipate that progress will accelerate with a better understanding of the molecular pathogenesis of the various subtypes of ovarian cancer, leading to an increasingly personalized approach to treating women with this disease.

Background: We have addressed whether inter-individual methylation variation in somatic (white blood cells, WBCs) DNA of ovarian cancer patients provides potential for prognostic and/or pharmacoepigenetic stratification., Patients and Methods: WBC DNA methylation was analysed by bisulphite pyrosequencing at ataxia telangiectasia mutated (ATM), estrogen receptor 1 (ESR1), progesterone receptor (PGR), mutL homologue 1 (MLH1), breast cancer susceptibility gene (BRCA1), secreted frizzled-related protein 1 (SFRP1), stratifin (SFN), retinoic acid receptor beta (RARB) loci and the repetitive element LINE1 in 880 SCOTROC1 trial patients [paclitaxel (Taxol)-carboplatin versus docetaxel (Taxotere)-carboplatin as primary chemotherapy for stage Ic-IV epithelial ovarian cancer]., Results: We observed no significant associations (P < 0.005, after correction for multiple testing) for progression-free survival (PFS) using test and validation sets. However, we did identify mean SFN methylation associated with PFS (hazard ratio, HR = 1.01 per 1% increase in methylation, q = 0.028); particularly in the paclitaxel (HR = 1.01, q = 0.006), but not in the docetaxel arm in stratified analyses. Furthermore, higher methylation within the ESR1 gene was associated with CA125 response (odds ratio, OR = 1.06, q = 0.04) and with neuropathy (HR = 0.95, q = 0.002), but only in the paclitaxel arm of the trial., Conclusions: This is the first study linking DNA methylation variability in WBC to clinical outcomes for any tumour type; the data generated on novel prognostic and pharmacoepigenetic DNA methylation biomarkers in the circulation now need independent further evaluation.

Background: To detect attention deficit hyperactivity disorder (ADHD) in treatment seeking substance use disorders (SUD) patients, a valid screening instrument is needed., Objectives: To test the performance of the Adult ADHD Self-Report Scale V 1.1(ASRS) for adult ADHD in an international sample of treatment seeking SUD patients for DSM-IV-TR; for the proposed DSM-5 criteria; in different subpopulations, at intake and 1-2 weeks after intake; using different scoring algorithms; and different externalizing disorders as external criterion (including adult ADHD, bipolar disorder, antisocial and borderline personality disorder)., Methods: In 1138 treatment seeking SUD subjects, ASRS performance was determined using diagnoses based on Conner's Adult ADHD Diagnostic Interview for DSM-IV (CAADID) as gold standard., Results: The prevalence of adult ADHD was 13.0% (95% CI: 11.0-15.0%). The overall positive predictive value (PPV) of the ASRS was 0.26 (95% CI: 0.22-0.30), the negative predictive value (NPV) was 0.97 (95% CI: 0.96-0.98). The sensitivity (0.84, 95% CI: 0.76-0.88) and specificity (0.66, 95% CI: 0.63-0.69) measured at admission were similar to the sensitivity (0.88, 95% CI: 0.83-0.93) and specificity (0.67, 95% CI: 0.64-0.70) measured 2 weeks after admission. Sensitivity was similar, but specificity was significantly better in patients with alcohol compared to (illicit) drugs as the primary substance of abuse (0.76 vs. 0.56). ASRS was not a good screener for externalizing disorders other than ADHD., Conclusions: The ASRS is a sensitive screener for identifying possible ADHD cases with very few missed cases among those screening negative in this population., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing., Patients and Methods: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS)., Results: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value., Conclusions: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.

Background: Pertuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor (HER)-mediated signalling, has shown activity in ovarian cancer in preclinical models and in the clinic. This randomized phase II study evaluated efficacy and safety of pertuzumab in combination with carboplatin-based chemotherapy in patients with platinum-sensitive, recurrent advanced ovarian cancer., Patients and Methods: Patients were randomized to receive six cycles of chemotherapy (carboplatin and either paclitaxel (Taxol) or gemcitabine) with or without pertuzumab. The primary end point was progression-free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors and/or by CA 125 measurements. Secondary end points evaluated the response rate, safety profile, duration of response, time to progression and overall survival for both treatment arms., Results: A total of 149 patients received either chemotherapy with pertuzumab (arm A, n=74) or chemotherapy alone (arm B, n=75). There was no significant difference either in median PFS or in the secondary end points between the two arms. No differences were seen in an exploratory biomarker analysis of HER3 mRNA expression between the two arms. Pertuzumab was well tolerated, with no increase in cardiac adverse events compared with chemotherapy alone., Conclusions: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive ovarian cancer.

Background: To compare the cognitive performances of maintenance patients (MAIN), abstinent ex-users (ABST) and healthy non-heroin using controls (CON)., Methods: Case control study of 125 MAIN (94 subjects maintained on methadone, 31 on buprenorphine), 50 ABST and 50 CON. Neuropsychological tests measuring executive function, working memory, information processing speed, verbal learning and non-verbal learning were administered., Results: There were no differences between the cognitive profiles of those maintained on methadone or buprenorphine on any administered test. After controlling for confounders, the MAIN group had poorer performance than controls in six of the 13 administered tests, and were poorer than the ABST group in five. The MAIN group exhibited poorer performance in the Haylings Sentence Completion, Matrix Reasoning, Digit Symbol, Logical Memory (immediate and delayed recall), and the Complex Figure Test (immediate recall). There were no differences between the ABST and CON groups on any of the administered tests., Conclusions: Poorer cognitive performance, across a range of test and domains, was seen amongst maintenance patients, regardless of their maintenance drug. This is a group that is likely might benefit from approaches for managing individuals with cognitive and behavioural difficulties arising from brain dysfunction., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: This study defined the risk of serious toxicity in phase I trials of molecularly targeted agents (MTA)., Patients and Methods: A retrospective analysis of toxicity data from patients treated in phase I trials of MTAs was carried out to define the rate of treatment-related grade 3/4 toxic effects, deaths and risk factors associated with grade 3 or more toxicity., Results: Data from 687 patients [median age, 59.1 years (range 12.5-85.5)] treated in 36 trials were analysed. Two hundred and eleven patients were of Eastern Cooperative Oncology Group performance status (PS) zero, 432 of PS one, 38 of PS two and 6 unknown. The rate of grade 3 and 4 events was 14.1% (n=97) and 1.9% (n=13), respectively. Twenty-four percent of events were gastrointestinal, 22% constitutional and 20% metabolic. PS two was associated with a higher risk of toxicity [odds ratio (OR), 2.6; 95% confidence interval (CI) 1.1-6.1; P=0.032] as was receiving >100% of maximum tolerated dose or maximum administered dose (OR 2.5; CI 1.6-3.9; P<0.001). Mortality rate was 0.43% (n=3)., Conclusions: Therapy with novel MTAs in phase I trials is associated with a moderate risk of significant toxicity. This appears less than in phase I studies involving cytotoxic agents, particularly in relation to grade 4 toxicity. The risk of death is low.

NHS Blood and Transplant (NHSBT) was established in 2005 as a Special Health Authority when the National Blood Authority and UK Transplant merged. This helped to bring tissue banking and organ transplantation services under one umbrella organization. This merger means that ~!95% of all deceased donors (whether tissue, organ or both) are now facilitated by one organization. NHSBT Tissue Services is the largest tissue establishment in the UK, and is a multi-tissue bank that specializes in the consent, retrieval, processing, storage, and dispatch of donated tissue coordinated from a purpose built, state-of-the-art tissue bank in Liverpool. Tissue donations can come from either tissue-only donors or solid organ donors who also donate tissue. Annually there are ~450 multi-tissue donors and 2500 eye donors in the UK, resulting in many thousands of transplants, including 3564 cornea transplants in 2010-2011. The separation of tissue- and organ-specific donors is largely artificial, and while organ transplantation can be life-saving, tissue transplantation can also have a dramatic effect on a patient's quality of life. It is hoped that all donors, both organ and tissue, will be recognized for the gift they make to society after their death.

Background: Sagopilone, the first fully synthetic epothilone, has shown promising preclinical activity in tumour models. This open-label randomised phase II study investigated two infusion schedules of sagopilone in women with ovarian cancer., Patients and Methods: Women with ovarian cancer recurring within 6 months of end of last platinum-containing treatment received sagopilone 16 mg/m(2) as a 3- or 0.5-h i.v. infusion every 21 days for up to 6 weeks., Results: Sixty-three patients received sagopilone as a 3-h (n=38) or 0.5-h (n=25) infusion. There were nine confirmed tumour responses [by modified RECIST (n=8) and by Gynecologic Cancer Intergroup CA-125 criteria (n=1)] in 57 patients assessable for efficacy overall [three (13%) with 0.5-h and six (18%) with 3-h infusions]. The 0.5-h arm was closed when it failed to meet its target efficacy. Main drug-related adverse events were peripheral sensory neuropathy (73%; 16% grade 3), nausea (37%; 2% grade 3), fatigue (35%; 3% grade 3) and arthralgia (30%; 5% grade 3). Overall incidence of peripheral sensory neuropathy was similar in both treatment arms, with no grade 4 neuropathy events. No acute allergic infusion reactions were observed., Conclusion: Sagopilone is effective, with balanced tolerability, in patients with recurrent platinum-resistant ovarian cancer.

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [6-12 months platinum-free interval (PFI)] is unclear., Patients and Methods: within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup., Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) = 0.65, 95% confidence interval (CI), 0.45-0.92; P = 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR = 0.59; 95% CI, 0.43-0.82; P = 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR = 0.63; P = 0.0357; median 13.3 versus 9.8 months)., Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 6-12 months).

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6-12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy., Patients and Methods: a detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted., Results: similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357)., Conclusion: the superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.

Approximately two million fractions of radiotherapy are administered in the UK every year, as part of adjuvant, radical or palliative cancer treatment. For many tumour types, radiotherapy is routinely combined with concomitant chemotherapy as part of adjuvant or radical treatment. In addition, new agents have been developed in recent years and tested in phase 1, 2 and 3 trials concomitantly with radiotherapy or chemoradiotherapy. One such class of drugs, the poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in conjunction with radiotherapy in several cancer cell lines. Pre-clinical data suggest that PARP inhibitors may potentiate the effects of radiotherapy in several tumour types, namely lung, colorectal, head and neck, glioma, cervix and prostate cancers. In vitro, PARP inhibitors are radiosensitisers in various cell lines with enhancement ratios of up to 1.7. In vivo, non-toxic doses of PARP inhibitors have been shown to increase radiation-induced growth delay of xenograft tumours in mice. Clinical trials to assess the toxicity and potential benefit of combining radiotherapy with PARP inhibition are now needed., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Platinum compounds, taxanes and anthracyclines provide the major effective drug classes in the treatment of advanced and recurrent endometrial cancer and carcinosarcoma., Patients and Methods: A total of 52 women with advanced or recurrent endometrial cancer and carcinosarcoma were treated with four cycles of carboplatin area under the curve (AUC) 5 and doxorubicin (50 mg/m(2)) for four cycles before or after four cycles of carboplatin AUC5 and paclitaxel (175 mg/m(2)) with each cycle administered at 21-day intervals., Results: Thirty-seven patients (71.2%) completed all planned treatment. Excluding six patients who did not complete treatment for non-drug-related causes, 80.4% completed all planned treatment. Three hundred and seventy-one treatment cycles were administered and 303 (81.7%) occurred on time. Common Toxicity Criteria grade 3/4 haematological toxic effects, particularly neutropenia and thrombocytopenia, were the predominant cause of treatment delays and dose reductions. A low incidence of grade 3 neurotoxicity and no cardiac toxicity were observed. The overall response rates for patients with evaluable disease were 82.1% and 66.7% for endometrial and carcinosarcoma, respectively. At a median follow-up of 21 months, the median progression-free survival for the endometrial adenocarcinoma and carcinosarcoma cohorts were 15.3 and 12.0 months, respectively., Conclusion: This regimen is generally well tolerated with encouraging efficacy.

Aim: To examine the demographic characteristics, circumstances, toxicology and major organ pathology of MDMA-related deaths in Australia., Methods: Retrospective review of cases in which MDMA was a cause of death, as identified from the National Coronial Information System., Results: 82 cases over a 5-year period were identified. The majority of decedents were male (83%), with a median age of 26 years. Deaths were predominantly due to drug toxicity (82%), with MDMA the sole drug causing death in 23% of cases, and combined drug toxicity in 59% of cases. The remaining deaths (18%) were primarily due to pathological events/disease or injury, with MDMA a significant contributing condition. Cardiovascular pathology, typically atherosclerosis, was detected in 58% of decedents, with moderate-severe atherosclerosis in 23% of cases. The prevalence of such pathology is higher than that expected among similarly aged members of the general population. Cerebrovascular pathology, primarily cerebral haemorrhage and hypoxic damage, was present in 12% of cases., Conclusions: MDMA has contributed to a clinically significant number of deaths in Australia. The prevalence of cardiovascular pathology was similar to that among methamphetamine and cocaine fatalities. Whilst cardiovascular pathology may reflect the use of other stimulants, the cardiotoxic properties of MDMA have been well-documented. Future studies examining MDMA-related morbidity and mortality in the context of other risk factors are recommended. Overall, the current study highlights the need to educate users about the potential harms of MDMA use, particularly that in conjunction with other stimulants, opioids and alcohol, which are known to increase overall toxicity.

Background: Previous studies have indicated an association between obesity and poor survival in several tumour types, including ovarian cancer. We sought to test the hypothesis that obesity reduces survival in a large, well-characterised and relatively homogeneous cohort of ovarian cancer patients., Patients and Methods: The relationship between body mass index (BMI) and overall survival (OS) and progression-free survival (PFS) in 1067 patients participating in the Scottish Randomised Trial in Ovarian Cancer I trial was assessed. All patients received first-line carboplatin/taxane chemotherapy. The dose of carboplatin was determined by a measured glomerular filtration rate (GFR), ensuring accurate dosing in all categories of BMI and the dose of taxane was not capped. Patients were assigned to one of four categories: underweight (BMI < 18.5), ideal weight (BMI 18.5-24.9), overweight (BMI 25-29.9) or obese (BMI >or= 30)., Results: There were neither statistically significant differences in PFS or OS between these four groups nor were there any differences in taxane or carboplatin dose intensity. Furthermore, there was no association between BMI and tumour stage or grade at presentation, or completeness of debulking surgery., Conclusions: Obese patients with epithelial ovarian cancer do not have a poorer prognosis, provided that they receive optimal doses of chemotherapy based on measured GFR and actual body weight.

Background: Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment., Design: This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design., Results: Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin., Conclusions: The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens.

Aims: Epithelial ovarian cancer is responsible for 4% of all cancer deaths in women, and the five-year overall survival of patients with advanced disease is 30-40%. Treatment currently comprises a combination of surgery and chemotherapy with carboplatin and paclitaxel. The main reason for treatment failure is that the majority of patients present with advanced disease, and current drugs are unable to effect a cure even in chemosensitive patients. This article systematically reviews novel therapeutic strategies that have been evaluated in patients with ovarian cancer in the last 5 years., Methods: Pubmed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed) and American Society of Clinical Oncology Annual conference abstracts were searched using the terms "(phase I OR phase II OR phase III OR phase 1 OR phase 2 OR phase 3) AND (ovary OR ovarian) AND (cancer OR carcinoma)" from January 2000 to May 2005 to identify studies for potential inclusion in this review. Reviews of novel therapies in ovarian cancer were also used to identify additional clinical trials., Findings: A wide range of therapeutic strategies are currently being evaluated in ovarian cancer. These include novel cytotoxics, small molecule inhibitors, monoclonal antibodies, gene therapy and immuno-therapy strategies. The rationale for the development of these agents includes enhancement of efficacy by targeting novel biological pathways, re-sensitisation to existing drugs, simplification of drug administration and/or reduction of drug-toxicity., Conclusions: Current developments have the potential to result in substantial improvements in the outlook for women with ovarian cancer.

The clinical and commercial success of the taxanes and vinca alkaloids resulted in a drive to improve on current formulations and discover new compounds that target the microtubule. These strategies are all aimed at improving on (1) anti-tumour activity, (2) toxicity profile and (3) pharmacology. Drugs undergoing clinical development include the novel semi-synthetic taxane derivatives (DJ-927, XRP6258 and XRP9881), the epothilones, the dolastations, vinflunine and the combretastatin analogues. In several cases, some improvements in tumour response rates have been seen but randomised trials need to be completed before the role of specific novel tubulin-binding agents can be established.

Aim: To ascertain the demographic characteristics, circumstances of death, toxicological results, and major autopsy findings of cocaine-related fatalities., Design: Inspection of the coronial records of all cocaine-related deaths that occurred in New South Wales, Australia between 1 January 1993 and 31 December 2002., Setting: New South Wales, Australia., Findings: 146 cases were identified. Cocaine was implicated in the direct cause of death in 86% of cases, an antecedent cause in 8% and a significant condition contributing to death in 7%. The mean age of decedents was 34.1 years, and 84% were male. Half were employed, and 26% were in professional employment. The predominant route of administration was injection (86%), however nasal (8%), oral (3%), smoking (1%), and anal (1%) administration were all recorded. The most common location of death was a private home (53%). No intervention occurred prior to death in 82% of cases. The median blood benzoylecgonine concentration was 0.40 mg/L (range 0.00-20.00 mg/L). Cases had a mean of 3.5 drugs, with morphine (79%) the most common co-occurring drug. In 5% of cases cocaine was the sole drug detected. Cardiac pathology was noted in 57% of cases, most commonly coronary artery atherosclerosis (39%) and cardiac hypertrophy (14%). In 15% of cases moderate to severe arterial occlusion was noted. Cerebrovascular pathology was noted in 22% of cases, most commonly cerebrovascular atherosclerosis (10%)., Conclusions: Cocaine-related deaths are a significant clinical problem in New South Wales.