Perceived Executive Functioning Deficits After Diagnosis in Women with Non-Metastatic Breast Cancer Prior to Adjuvant Therapies.

BACKGROUND: Perceived deficits in executive functioning are among the many difficulties that women diagnosed with breast cancer experience. This study assessed the presence of perceived deficits in executive functioning among women with breast cancer prior to systemic treatment and radiation and associations between perceived deficits in executive function and comorbid fatigue, sleep, and mood disturbance. METHOD: Participants were recruited following their breast cancer diagnosis and assessed using the Behavior Rating Inventory of Executive Function for Adults (BRIEF-A), subjective and objective measures of sleep duration and efficiency, and self-report measures of insomnia severity, sleep quality, fatigue, and mood disturbance. Hierarchical regression was used to examine associations between symptoms, adjusting for age and education. RESULTS: The final sample included 92 women with a mean age of 60.7 years and 13.5 years of education. Thirteen percent of participants reported global executive dysfunction. After partitioning out variability from other independent variables, fatigue (p = < .001), perceived sleep quality (p = .030), and symptoms of insomnia (p = .008) accounted for 13.3%, 5.7%, and 8.5% of unique variance in perceived executive functioning, respectively. Emotional fatigue was most strongly associated with perceived deficits in executive functioning. Neither subjective or objective sleep duration or efficiency was associated with perceived deficits in executive functioning. CONCLUSION: Fatigue, particularly emotional fatigue, insomnia, and poor sleep quality had the strongest associations with perceived deficits in executive functioning. Sleep interventions and fatigue management strategies may prove useful for women who seek to improve their perceived executive functioning.

Suppression-induced forgetting: a pre-registered replication of the think/no-think paradigm.

Post-traumatic stress disorder is characterised by recurring memories of a traumatic experience despite deliberate attempts to forget (i.e., suppression). The Think/No-Think (TNT) task has been used widely in the laboratory to study suppression-induced forgetting. During the task, participants learn a series of cue-target word pairs. Subsequently, they are presented with a subset of the cue words and are instructed to think (respond items) or not think about the corresponding target (suppression items). Baseline items are not shown during this phase. Successful suppression-induced forgetting is indicated by the reduced recall of suppression compared to baseline items in recall tests using either the same or different cues than originally studied (i.e., same- and independent-probe tests, respectively). The current replication was a pre-registered collaborative effort to evaluate an online experimenter-present version of the paradigm in 150 English-speaking healthy individuals (89 females; MAge = 31.14, SDAge = 7.73). Overall, we did not replicate the suppression-induced forgetting effect (same-probe: BF01 = 7.84; d = 0.03 [95% CI: -0.13; 0.20]; independent-probe: BF01 = 5.71; d = 0.06 [95% CI: -0.12; 0.24]). These null results should be considered in light of our online implementation of the paradigm. Nevertheless, our findings call into question the robustness of suppression-induced forgetting.

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma. METHODS: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791. FINDINGS: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage). INTERPRETATION: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed. FUNDING: Exelixis and Ipsen.

Refining our understanding of depressive states and state transitions in response to cognitive behavioural therapy using latent Markov modelling.

BACKGROUND: It is increasingly recognized that existing diagnostic approaches do not capture the underlying heterogeneity and complexity of psychiatric disorders such as depression. This study uses a data-driven approach to define fluid depressive states and explore how patients transition between these states in response to cognitive behavioural therapy (CBT). METHODS: Item-level Patient Health Questionnaire (PHQ-9) data were collected from 9891 patients with a diagnosis of depression, at each CBT treatment session. Latent Markov modelling was used on these data to define depressive states and explore transition probabilities between states. Clinical outcomes and patient demographics were compared between patients starting at different depressive states. RESULTS: A model with seven depressive states emerged as the best compromise between optimal fit and interpretability. States loading preferentially on cognitive/affective v. somatic symptoms of depression were identified. Analysis of transition probabilities revealed that patients in cognitive/affective states do not typically transition towards somatic states and vice-versa. Post-hoc analyses also showed that patients who start in a somatic depressive state are less likely to engage with or improve with therapy. These patients are also more likely to be female, suffer from a comorbid long-term physical condition and be taking psychotropic medication. CONCLUSIONS: This study presents a novel approach for depression sub-typing, defining fluid depressive states and exploring transitions between states in response to CBT. Understanding how different symptom profiles respond to therapy will inform the development and delivery of stratified treatment protocols, improving clinical outcomes and cost-effectiveness of psychological therapies for patients with depression.

Characterizing production: the production effect is eliminated for unusual voices unless they are frequent at study.

The production effect refers to the finding that items read aloud are better remembered than items read silently. This is often explained with reference to distinctiveness, arguing that aloud items become associated with distinctive sensorimotor features that facilitate retrieval at test. Based on this framework, more distinctive forms of production should result in larger production effects. The present study tested this theory by having participants study items silently or aloud in either their own voice or as a popular character. Participants were then tested for those items using recognition memory. Relative to silent items, aloud items read in the participants' own voice demonstrated a typical production effect; however, contrary to any predictions, no production effect was observed for the character voices. We next manipulated how frequently the character voice was used relative to the participants' own voice. This revealed a production effect for character voices only when those voices were more common than the participant's own voice. This pattern could not be attributed to cognitive demands or performance anxiety but was predicted by a novel computational account based on the Retrieving Effectively from Memory (REM) model. Our results show that the relation between distinctiveness and memory is not necessarily linear.

Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients.

PURPOSE: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients. METHODS: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRsadj) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated. RESULTS: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RRadj 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RRadj 0.40, 95% CI 0.22-0.74). No other significant associations were seen. CONCLUSION: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.

Neural correlates of the production effect: An fMRI study.

Recognition memory is improved for items produced at study (e.g., by reading them aloud) relative to a non-produced control condition (e.g., silent reading). This production effect is typically attributed to the extra elements in the production task (e.g., motor activation, auditory perception) enhancing item distinctiveness. To evaluate this claim, the present study examined the neural mechanisms underlying the production effect. Prior to a recognition memory test, different words within a study list were read either aloud, silently, or while saying "check" (as a sensorimotor control condition). Production improved recognition, and aloud words yielded higher rates of both recollection and familiarity judgments than either silent or control words. During encoding, fMRI revealed stronger activation in regions associated with motor, somatosensory, and auditory processing for aloud items than for either silent or control items. These activations were predictive of recollective success for aloud items at test. Together, our findings are compatible with a distinctiveness-based account of the production effect, while also pointing to the possible role of other processing differences during the aloud trials as compared to silent and control.

Assessment and Transplantation of Orphan Donor Livers: A Back-to-Base Approach to Normothermic Machine Perfusion.

Globally, a large proportion of donor livers are discarded due to concerns over inadequate organ quality. Normothermic machine perfusion (NMP) allows for hepatocellular and biliary viability assessment prior to transplantation and might therefore enable the safe use of these orphan donor livers. We describe here the first Australasian experience of NMP-preserved liver transplants using a 'back-to-base' approach, where NMP was commenced at the recipient hospital following initial static cold storage. In the preclinical phase, 10 human donor livers declined for transplantation (7 from donation after circulatory death [DCD] and 3 from donation after brain death [DBD]) were perfused using a custom-made NMP setup. Subsequently, 10 orphan donor livers (5 from DCD and 5 from DBD) underwent NMP and viability assessment on the OrganOx metra device (OrganOx Limited, Oxford, United Kingdom). Both hepatocellular and biliary viability criteria were used. The median donor risk index was 1.53 (1.16-1.71), and the median recipient Model for End-Stage Liver Disease score was 17 (11-21). In the preclinical phase, 'back-to-base' NMP was deemed suitable and feasible. In the clinical phase, each graft met predefined criteria for implantation during NMP and was subsequently transplanted. Five (50%) recipients developed early allograft dysfunction based on peak aspartate aminotransferase. To date, all grafts function satisfactorily, and none of the 5 recipients who received a DCD liver have developed cholangiopathy. The OrganOx metra using a back-to-base approach has enabled the safe use of 10 high-risk orphan donor livers with 100% 6-month patient and graft survival. NMP improved surgeon confidence to use orphan donor livers and has enabled a safe expansion of the donor pool.

Outcomes for children after second liver transplantations are similar to those after first transplantations: a binational registry analysis.

OBJECTIVE: To assess long term graft and patient survival after donor liver retransplantation in children in Australia and New Zealand during 1986-2017; to determine the factors that influence survival. DESIGN: Retrospective cohort analysis (registry data). SETTING, PARTICIPANTS: Australia and New Zealand Liver Transplant Registry data for all liver retransplantations in children (under 18 years of age), 1986-2017, in all four paediatric and six adult liver transplantation centres in the two countries. MAIN OUTCOME MEASURES: Graft and patient survival at one, 5, 10 and 15 years. RESULTS: 142 liver retransplantations were undertaken in children (59 during 1986-2000, 83 during 2001-2017). Kaplan-Meier survival analysis indicated that survival was significantly greater during 2001-2017 than 1986-2000 (P < 0.001). During 2001-2017, graft survival one year after retransplantation was 84%, at 5 years 75%, at 10 years 70%, and at 15 years 54%; patient survival was 89% at one year, 87% at 5 years, 87% at 10 years, and 71% at 15 years. Median time between transplantations was 0.2 years (IQR, 0.03-1.4 years) during 1986-2000, and 1.8 years (IQR, 0.1-6.8 years) during 2001-2017 (P = 0.002). The proportion of graft failures that involved split grafts was larger during 2001-2017 (35 of 83, 42%) than 1986-2000 (10 of 59, 17%). Graft type, cause of graft failure, and number of transplants did not influence survival following retransplantation. CONCLUSION: Survival for children following retransplantation is excellent. Graft survival is similar for split and whole grafts. Children on the liver waiting list requiring retransplantation should have the same access to donor grafts as children requiring a first transplant.

Distinctive encodings and the production effect: failure to retrieve distinctive encodings decreases recollection of silent items.

Studies have shown that when aloud and silent items are studied together, silent items are remembered more poorly than when they are studied independently. We hypothesise that this cost to silent items emerges because, at test, participants search for memories of having said items aloud and when those memory searches fail, participants become uncertain about whether silent items were studied. This effect should be exaggerated if other unique distinctive encoding conditions are also included at study (e.g., mumbling, writing, typing, etc.). To test this prediction, we examined the impact of introducing mumbled, "important" (i.e., words that participants are told are the most important to remember), and mouthed words to a study list of aloud and silent words. Introducing mumbled and "important" words further impaired the recollection of silent items. Introducing mouthed items did not further impair the memorability of silent items because mouthing and speaking aloud are so similar and hence, are not fully unique from each other. The memorability of aloud items was unaffected in all conditions. These results suggest that participants search for distinctive encoding information at test, and only for items that fail those searches (i.e., silent items) do they lose confidence.

Pancreaticoduodenectomy in a low-resection volume region: a population-level study examining the impact of hospital-volume on surgical quality and longer-term survival.

BACKGROUND: An association between higher hospital-volume and better "quality of surgery" and long-term survival has not been reported following pancreatic cancer surgery in low resection-volume regions such as in Australia. Using a population-level study, we compare "quality of surgery" and two-year survival following pancreaticoduodenectomy between Australian hospitals grouped by resection-volume. METHODS: Data on all patients undergoing pancreaticoduodenectomy for adenocarcinoma in the Australian state of Queensland, between 2001 and 2015, were obtained from the Queensland Oncology Repository. Hospitals were grouped into high (≥6 resections annually) and low (<6) volume centres. Following adjustment for case-mix, "quality-of-treatment" indicators were compared between hospital groups using multivariate logistic regression and Poisson regression analysis; and two-year cancer-specific and overall survival were compared using multivariate Cox proportional hazard models. RESULTS: Compared with high-volume centres, low-volume centres had worse two-year cancer-specific survival (Adjusted HR = 1.31; 95% CI:1.03-1.68), higher 30-day mortality (Adjusted IRR = 3.81; 95% CI: 1.36-10.62) and fewer patients received "high-quality surgery" (Adjusted OR = 0.55; 95% CI: 0.33-0.90). Differences in 30-day mortality, or "quality-of-treatment" indicators did not entirely explain the observed survival difference between hospital-volume groups. CONCLUSION: In an Australian environment, a "high" hospital-volume was significantly associated with better quality surgery and two-year survival following pancreaticoduodenectomy.

Increasing Incidence of Nonalcoholic Steatohepatitis as an Indication for Liver Transplantation in Australia and New Zealand.

The worldwide increase in obesity and diabetes has led to predictions that nonalcoholic steatohepatitis (NASH) will become the leading indication for orthotopic liver transplantation (OLT). Data supporting this prediction from outside the United States are limited. Thus, we aimed to determine trends in the frequency of NASH among adults listed and undergoing OLT in Australia and New Zealand (ANZ) from 1994 to 2017. Data from the ANZ Liver Transplant Registry were analyzed with patients listed for fulminant liver failure, retransplantation, or multivisceral transplants excluded. Nonparametric trend, Spearman rank correlation, and regression analysis were used to assess trends in etiologies of liver disease over time. Of 5016 patient wait-list registrants, a total of 3470 received an OLT. The percentage of patients with NASH activated for OLT increased significantly from 2.0% in 2003 to 10.9% in 2017 (trend analyses; P < 0.001). In 2017, NASH was the third leading cause of chronic liver disease (CLD) among wait-list registrants behind chronic hepatitis C virus (HCV; 29.5%) and alcohol (16.1%). Similarly, significant increases over time in the percentage of patients undergoing OLT were observed for HCV and NASH (all trend analyses; P < 0.001) but with significant reductions in primary sclerosing cholangitis and cryptogenic cirrhosis (both P < 0.05). By 2017, NASH was the third leading cause of liver disease among patients undergoing OLT (12.4%) and behind chronic HCV (30.2%) and alcohol (18.2%). NASH also became the third most frequent etiology of CLD in patients transplanted (13.8%) with concomitant hepatocellular carcinoma by 2017. In conclusion, NASH is increasing as a primary etiology of liver disease requiring listing and liver transplantation in ANZ.

Weight-based tacrolimus trough concentrations post liver transplant.

BACKGROUND: Tacrolimus is one of the most widely used liver transplant medications. With the increasing number of obese patients requiring liver transplants, knowledge of the effect of body size affecting post-transplant outcomes, for example drug exposure is increasingly required. AIMS: (i) To investigate whether patient body size (i.e. total bodyweight) affects trough plasma concentrations of tacrolimus when a standard mg/kg dosing regimen is used; and (ii) to investigate whether obese patients have different numbers of plasma concentrations outside the therapeutic range compared to non-obese patients in the first months after liver transplant. METHODS: Using a transplant database, data tacrolimus concentrations were available for 69 patients. Tacrolimus was initially dosed at a standard 0.1 mg/kg/day after liver transplant, and adjusted to maintain a target trough concentration. Trough blood samples, phenotypic and outcome variables were analysed. RESULTS: Trough concentrations were similar between obese and non-obese patients (P > 0.05) at each sampling day. At day 7 post-transplant, 85.7% and 79.5% of the observed plasma concentrations were outside the recommended therapeutic range for obese and non-obese patients respectively, at day 30, 52.9% and 57.4%, and at 6 months, 18.7% and 27.5%. CONCLUSION: In the first week post-transplant, tacrolimus trough concentrations after standard mg/kg dosing post liver transplant appear to be corrected by total bodyweight. Obese patients have a similar number of trough plasma concentrations outside the therapeutic range compared to non-obese patients.

Bone Mineral Density of Very Long-term Survivors After Childhood Liver Transplantation.

OBJECTIVES: Liver transplant patients are at risk of osteopenia and fractures but limited information is available in long-term survivors after childhood transplantation. This study aimed to assess bone mineral density (BMD) of very long-term, >5 years, survivors after liver transplantation in childhood. METHODS: Patients aged <18 years at transplant, having survived >5 years after transplant were potentially eligible but only those with ongoing review in our state were included. Dual-energy x-ray absorptiometry (DXA) was used to measure BMD. Patients aged <20 years had lumbar spine (LS) and total body (TB) measurements whereas those aged 20 years or more had LS and femoral neck but not TB. BMD z-scores for LS and TB, if available, were used in this study. BMD z-score ≤-2.0 was considered reduced. Pre-pubertal children had radiologic bone age assessment. RESULTS: Forty-two patients, 17 boys, participated of whom 64% had biliary atresia. Median age at transplant was 2.22 (range 0.38-14.25) years; time since transplant 10.10 (5.01-25.98) years; and age at DXA 14.64 (6.59-38.07) years. Mean BMD z-scores were LS -0.15 ±â€Š1.07, and TB -0.76 ±â€Š1.14, with no sex difference noted. Four (9.5%) patients had reduced LS BMD, and although ongoing steroid use was more frequent in these patients, other comorbidities were likely important. Age at transplant, time since transplant, height, weight, and body mass index at DXA did not predict LS BMD. Pathologic fractures occurred in 2 of 42 (5%) patients; all within 18 months of transplant. CONCLUSIONS: Very long-term survivors after childhood liver transplant have LS BMD within the normal range.

Low-Dose Lipopolysaccharide Causes Biliary Injury by Blood Biliary Barrier Impairment in a Rat Hepatic Ischemia/Reperfusion Model.

This study explored whether bacterial endotoxins, in the form of lipopolysaccharides (LPS), could have an injurious effect on the biliary tract in conjunction with ischemia. A total of 64 rats were randomly assigned to 4 groups: sham operation (sham group), 1 mg/kg LPS intraperitoneal (LPS group), hepatic ischemia/reperfusion (IR; IR group), and IR combined with LPS (IR+LPS group). Following 1 or 6 hours of reperfusion, serum liver tests, bile duct histology, immunofluorescence microscopy (zonula occludens-1 [ZO-1]), bile composition (bile salts, phospholipids, lactate dehydrogenase), hepatic gene expression (bile salt transporters and inflammatory mediators), as well as serum and biliary cytokine concentrations were quantified and compared between the study groups. In addition, the integrity of the blood biliary barrier (BBB) was assayed in vivo using horseradish peroxidase (HRP). LPS administration induced severe small bile duct injury following 6 hours of reperfusion. Furthermore, total bile salts and bilirubin concentrations in serum were increased in the LPS groups compared with sham controls (LPS, + 3.3-fold and +1.9-fold; IR+LPS, + 3.8-fold and +1.7-fold, respectively). The BBB was impaired in the LPS groups as evidenced by elevated levels of HRP in bile (+4.9-fold), and decreased expression of claudin 1 (-6.7-fold) and claudin 3 (-3.6-fold). LPS was found to be a potent inducer of small bile duct injury following hepatic ischemia and 6 hours of reperfusion. This injury was associated with increased permeability of the BBB and impaired hepatic bile salt clearance. Liver Transplantation 23 194-206 2017 AASLD.

Nonsteroidal anti-inflammatory drugs, statins, and pancreatic cancer risk: a population-based case-control study.

PURPOSE: Studies suggest that aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and statins may reduce risk of some cancers. However, findings have been conflicting as to whether these agents reduce the risk of pancreatic cancer. METHODS: We used data from the Queensland Pancreatic Cancer Study, a population-based case-control study. In total, 704 cases and 711 age- and sex-matched controls were recruited. Participants completed an interview in which they were asked about history of NSAID and statin use. We included 522 cases and 653 controls who had completed the medication section of the interview in this analysis. Unconditional multivariable logistic regression was used to estimate associations between medication use and pancreatic cancer. RESULTS: We found no consistent evidence of an association between use of NSAIDs or statins and risk of pancreatic cancer. There was some suggestion of a protective effect in infrequent users of selective COX-2 inhibitors, but no association in more frequent users. We did not find evidence of protective effects in analyses stratified by sex, smoking status, time between diagnosis and interview, or presence/absence of metastases. CONCLUSIONS: Overall, our results do support the hypothesis that use of NSAIDs or statins may reduce the odds of developing pancreatic cancer.

Association between Helicobacter pylori and pancreatic cancer risk: a meta-analysis.

PURPOSE: Gastric colonization with Helicobacter pylori (H. pylori) has been implicated in the pathogenesis of pancreatic cancer, but results of epidemiological studies have been inconclusive. We analyzed data from the Queensland Pancreatic Cancer Study, an Australian population-based case-control study, and incorporated our findings into an updated meta-analysis. METHODS: Blood samples were obtained from 580 patients and 626 controls, and enzyme-linked immunosorbent assay kits were used to determine seropositivity to H. pylori and its virulence protein, cytotoxin-associated gene A (CagA). Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using logistic regression. Results were incorporated into a meta-analysis along with results of studies identified through systematic literature review. Adjusted ORs and 95 % CIs were calculated using the DerSimonian and Laird random-effects model. RESULTS: No overall association was observed between H. pylori seropositivity and risk of pancreatic cancer (OR 1.00; 95 % CI 0.74-1.35). Nonsignificantly decreased pancreatic cancer risk was observed with CagA seropositivity (OR 0.74; 95 % CI 0.48-1.15) and increased risk with CagA-negative H. pylori seropositivity (OR 1.23; 95 % CI 0.83-1.82). Ten studies were included in the meta-analysis. There was no significant overall association between H. pylori seropositivity and pancreatic cancer risk (OR 1.13; 95 % CI 0.86-1.50), but evidence of CagA strain-specific associations (OR 0.78; 95 % CI 0.67-0.91 and OR 1.30; 95 % CI 1.02-1.65 for CagA-positive and CagA-negative strains, respectively). CONCLUSIONS: Our results provide further evidence for the existence of strain-specific associations between H. pylori and pancreatic cancer.

Remoteness, race and social disadvantage: disparities in hepatocellular carcinoma incidence and survival in Queensland, Australia.

BACKGROUND & AIMS: Incidence and mortality of hepatocellular carcinoma (HCC) is increasing globally, but varies between countries and regions. To target scarce resources to most need, clinical services must be informed by regional epidemiology. Using population-based data, we sought to document the incidence and mortality of HCC in Queensland, Australia, a state occupying a vast land area with diverse at-risk subpopulations. METHODS: Using population-based data from 1996 to 2011, the age-standardised incidence rate (ASR), annual percentage change (APC) and survival of HCC in Queensland were assessed with negative binomial regression, Kaplan-Meier and Cox survival analysis. Spatial patterns of HCC incidence and survival and relevant predictors were mapped. RESULTS: Thousand six hundred and twenty HCCs were diagnosed during this study period, with an overall ASR of 2.00-cases/1000 population. ASR increased by 3.5% per year, (95% CI: 2.1 to 5.0), P < 0.001) among males to 5.6/100,000 in 2011 and a non-significant increase of 2.6% per year, (95% CI = -0.7 to 6.0), P = 0.111) among females to 1.6/100,000 in 2011. Higher incidence was associated with male gender, older age, major city residence and proportionally higher area Indigenous population. Thousand and two hundred and eighty-seven patients died. Median survival was approximately 10 months. Five-year survival improved from 18% in 1996-2000 to 24% in 2006-2011 (P < 0.001). Poorer survival was associated with older age, less recent period of diagnosis, lower hepatitis B prevalence in country of origin and greater area-level social disadvantage. CONCLUSIONS: Over this study period, HCC incidence increased significantly. HCC survival improved but remains poor. Social determinants are critical to HCC epidemiology.

Occupational exposure to N-nitrosamines and pesticides and risk of pancreatic cancer.

OBJECTIVES: Animal evidence shows that N-nitrosamines and similar xenobiotic compounds are pancreatic carcinogens. We aimed to determine whether occupational exposure to N-nitrosamines or to pesticides increases risk of pancreatic cancer development. METHODS: Participants (504 cases, 643 controls) in a population-based case-control study (The Queensland Pancreatic Cancer Study) provided data on demographic, medical and lifestyle factors and lifetime job histories. Specific questions were asked regarding work in rubber and leather industries, metalworking jobs and occupational or direct use of pesticides on animals or crops. An occupational hygienist reviewed this information (blind to case status) to assess likelihood of exposure to N-nitrosamines and pesticides, and estimated level and frequency of such exposures. RESULTS: No associations were found for risk of pancreatic cancer and occupational exposure to N-nitrosamines (OR=0.85, 95% CI 0.51 to 1.42) and no associations were seen with level or frequency of exposure. No associations were observed for ever exposure to pesticides in general (OR=0.90, 95% CI 0.61 to 1.33) or to any of the pesticide subgroups. Stratification by history of cigarette smoking did not change these results. CONCLUSIONS: This comprehensive analysis of a large case-control study does not support an association between occupational exposure to N-nitrosamines or pesticide use and risk of pancreatic cancer.