South West Sydney Clinical Campuses

Paper of the Year

Each year the South West Sydney Clinical Campuses award Paper of the Year prizes in a number of categories: : biomedical; clinical; and epidemiological/health services research.

Criteria for Selection

  • the work must have been published (not in press etc) in the calendar year; the senior author must be a member of staff of the South Western Sydney Sydney Clinical School and must acknowledge their affiliation with UNSW on the publication;
  • the paper must meet the DEEWR criteria for a Category C publication (published in a scholarly journal, peer reviewed original research, ie not a review) from work done in the south west;
  • the submission should include a very short statement of merit such as:
    • the impact factor of the journal;
    • the standing of the journal in its field;
    • involvement of a junior doctor, postgraduate or Honours/ILP student in the work;
    • publication in a new field or involving new collaboration;
    • editorial comment;
    • article featured on the journal cover.


Previous Recipients



Biomedical Research

Br J Cancer. 2020 May;122(10):1486-1495. doi: 10.1038/s41416-020-0782-1.
Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis
Xu Z, Pang TCY, Liu AC, Pothula SP, Mekapogu AR, Perera CJ, Murakami T, Goldstein D, Pirola RC, Wilson JS, Apte MV.

BACKGROUND: Stromal–tumour interactions facilitate pancreatic cancer (PC) progression. The hepatocyte growth factor (HGF)/c-MET pathway is upregulated in PC and mediates the interaction between cancer cells and stromal pancreatic stellate cells (PSCs). This study assessed the effect of HGF/c-MET inhibition plus gemcitabine (G) on the progression of advanced PC.

METHODS: Orthotopic PC was produced by implantation of luciferase-tagged human cancer cells + human PSCs into mouse pancreas. Tumours were allowed to develop without treatment for 4 weeks. Mice were then treated for 6 weeks with one of the following: IgG, G, HGF inhibitor (Hi), c-MET inhibitor (Ci), Hi + Ci, Hi + G, Ci + G, or Hi + Ci + G.

RESULTS: Bioluminescence imaging showed similar tumour sizes in all mice at the initiation of treatments. Triple therapy (Hi + Ci + G): (1) completely eliminated metastasis; (2) significantly reduced tumour size as assessed by bioluminescence and at necropsy; (3) significantly reduced proliferating cancer cell density and stem cell marker DCLK1 expression in tumours. In vitro 3D culture studies supported our in vivo findings.

CONCLUSION: Even at an advanced disease stage, a two-pronged approach, targeting (a) HGF/c-MET with relevant inhibitors and (b) cancer cells with chemotherapy, completely eliminated metastasis and significantly decreased tumour growth, suggesting that this is a promising treatment approach for PC.

Clinical Research

Hypertension. 2020 Apr;75(4):1125-1132. doi: 10.1161/HYPERTENSIONAHA.119.14107.
Clinical Influence of Nonadherence With Prophylactic Aspirin in Preventing Preeclampsia in High-Risk Pregnancies: A Multicenter, Prospective, Observational Cohort Study
Shanmugalingam R, Wang X, Motum P, Fulcher I, Lee G, Kumar R, Hennessy A, Makris A. 

ABSTRACT: Aspirin nonadherence and its associated increase in cardiovascular and cerebrovascular events is well described; however, the prevalence of aspirin nonadherence among high-risk pregnant women at risk of preeclampsia and its influence on clinical outcomes remains unclear. Our study examined the prevalence of aspirin nonadherence and resistance among high-risk pregnant women quantitatively (platelet function analyzer 100 and plasma salicylic acid) and clinical outcomes relative to adherence. High-risk pregnant women were recruited across 3 centers in the South West Sydney Local Health District. Simultaneous clinic data, blood sample, and self-reported adherence assessment were prospectively collected at 4-week intervals from 12 to 36 weeks of gestation. Nonadherence was defined as normal platelet function analyzer 100 and nondetectable plasma salicylic acid in <90% of time points. Value of <90% is based on current data. Two hundred twenty women were recruited over 25 months. No woman was aspirin resistant, and 63 (44%) women demonstrated inadequate adherence. Women with inadequate adherence had higher incidence of early-onset preeclampsia (17% versus 2%; odds ratio [OR], 1.9 [95% CI, 1.1–8.7]; P=0.04), late-onset preeclampsia (41% versus 5%; OR, 4.2 [95% CI, 1.4–19.8]; P=0.04), intrauterine growth restriction (29% versus 5%; OR, 5.8; [95% CI, 1.2–8.3]; P=0.001), preterm delivery (27% versus 10%; OR, 5.2 [95% CI, 1.5–8.7]; P=0.008), and higher likelihood of increase in antihypertensives antenatally (60% versus 10%; OR, 4.6 [95% CI, 1.2–10.5]; P=0.003). Kaplan-Meier analysis demonstrated lower incidence of premature delivery in the ≥90% adherent group (HR, 0.3 [95% CI, 0.2–0.5]; P<0.001).Kappa coefficient agreement between qualitative and quantitative assessment of adherence was moderate (κ=0.48; SE=0.029; P<0.0001). Our data demonstrates that aspirin is an effective prophylactic agent with an absolute risk reduction of 51% (number needed to treat, 2) when adherence is ≥90%, compared with women with inadequate adherence. Women who were <90% adherent had higher rates of preeclampsia, intrauterine growth restriction, preterm delivery, and increase in antenatal antihypertensive requirements. Self-reported adherence does not accurately reflect actual adherence.

Epidemological / Health Services Research

JMIR Public Health Surveill. 2020 Sep 18;6(3):e18965. doi: 10.2196/18965.
Freely Available Stochastic Individual Contact Model for Exploring COVID-19 Intervention and Control Strategies: Development and Simulation
Churches T, Jorm L.

BACKGROUND: Throughout March 2020, leaders in countries across the world were making crucial decisions about how and when to implement public health interventions to combat the coronavirus disease (COVID-19). They urgently needed tools to help them to explore what will work best in their specific circumstances of epidemic size and spread, and feasible intervention scenarios.

OBJECTIVE: We sought to rapidly develop a flexible, freely available simulation model for use by modelers and researchers to allow investigation of how various public health interventions implemented at various time points might change the shape of the COVID-19 epidemic curve.

METHODS: “COVOID” (COVID-19 Open-Source Infection Dynamics) is a stochastic individual contact model (ICM), which extends the ICMs provided by the open-source EpiModel package for the R statistical computing environment. To demonstrate its use and inform urgent decisions on March 30, 2020, we modeled similar intervention scenarios to those reported by other investigators using various model types, as well as novel scenarios. The scenarios involved isolation of cases, moderate social distancing, and stricter population “lockdowns” enacted over varying time periods in a hypothetical population of 100,000 people. On April 30, 2020, we simulated the epidemic curve for the three contiguous local areas (population 287,344) in eastern Sydney, Australia that recorded 5.3% of Australian cases of COVID-19 through to April 30, 2020, under five different intervention scenarios and compared the modeled predictions with the observed epidemic curve for these areas.

RESULTS: COVOID allocates each member of a population to one of seven compartments. The number of times individuals in the various compartments interact with each other and their probability of transmitting infection at each interaction can be varied to simulate the effects of interventions. Using COVOID on March 30, 2020, we were able to replicate the epidemic response patterns to specific social distancing intervention scenarios reported by others. The simulated curve for three local areas of Sydney from March 1 to April 30, 2020, was similar to the observed epidemic curve in terms of peak numbers of cases, total numbers of cases, and duration under a scenario representing the public health measures that were actually enacted, including case isolation and ramp-up of testing and social distancing measures.

CONCLUSIONS: COVOID allows rapid modeling of many potential intervention scenarios, can be tailored to diverse settings, and requires only standard computing infrastructure. It replicates the epidemic curves produced by other models that require highly detailed population-level data, and its predicted epidemic curve, using parameters simulating the public health measures that were enacted, was similar in form to that actually observed in Sydney, Australia. Our team and collaborators are currently developing an extended open-source COVOID package comprising of a suite of tools to explore intervention scenarios using several categories of models.



Clinical Research

Br J Anaesth. 2019 Sep;123(3):360-367.
Adductor canal versus femoral triangle anatomical locations for continuous catheter analgesia after total knee arthroplasty: a multicentre randomised controlled study. 
Chuan A, Lansdown A, Brick KL, Bourgeois AJG, Pencheva LB, Hue B, Goddard S, Lennon MJ, Walters A, Auyong D. The CAFE study investigators.

BACKGROUND: Adductor canal (AC) catheters are being used to provide continuous postoperative analgesia after total knee arthroplasty (TKA) surgery. There are anatomical arguments that most AC catheters are being inserted into the femoral triangle (FT) compartment of the thigh rather than the AC compartment. The clinical relevance of this is unknown with respect to motor weakness, quality of analgesia, and opioid consumption. We hypothesised that AC catheters provide superior functional mobilisation on postoperative Day 1 after TKA as measured using the Timed Up and Go (TUG) test.

METHODS: In this multinational, multicentre, double-blinded RCT, catheters were inserted under ultrasound guidance into the anatomical AC and FT compartments. The standardised protocol included spinal anaesthesia without intrathecal morphine, fixed catheter infusion rates, and oral analgesia.

RESULTS: Of 151 subjects recruited, 75 were in the AC group and 76 in the FT group. There was no statistically significant difference in TUG on postoperative Day 1 between AC (38 [29-55] s) and FT subjects (44 [32-64] s) (median [inter-quartile range]); P=0.11). There was no difference in TUG Day 2, AC (38 [27-53] s) vs FT (42 [31-59] s); P=0.66. There were no statistically significant differences for secondary endpoints of pain level, effectiveness of pain relief, interference of functional activities and interpersonal relationships by pain, and opioid consumption between groups.

CONCLUSIONS: There were no differences in immediate postoperative functional mobility, analgesia, and opioid consumption provided by catheters inserted into the AC vs FT locations for TKA surgery.

Epidemological / Health Services Research

Radiother Oncol. 2019 Jul;136:154-160.
Estimating the cost of radiotherapy for 5-year local control and overall survival benefit
Batumalai V, Wong K, Shafiq J, Hanna TP, Gabriel G, Heberle J, Koprivic I, Kaadan N, King O, Tran T, Cassapi L, Forstner D, Delaney GP, Barton M. 

BACKGROUND AND PURPOSE: Escalating health care costs have led to greater efforts directed at measuring the cost and benefits of medical treatments. The aim of this study was to estimate the costs of 5-year local control and overall survival benefits of radiotherapy for the cancer population in Australia.

MATERIALS AND METHODS: The local control and overall survival benefits of radiotherapy at 5-years and optimal number of fractions per course have been estimated for 26 tumour sites for which radiotherapy is indicated. For this study, a hybrid approach that merges features from activity based costing (ABC) and relative value units costing (RVU) were used to provide cost estimates. ABC methodology was used to allocate costs to all radiotherapy activities associated with each patient's treatment course, while the RVUs represent the cost of each radiotherapy activity relative to the average cost of all activities and were used to achieve a weighted cost allocation. A patient's journey for the financial year was constructed by consolidating all the radiotherapy activities and their associated costs, and the average cost per activity (fraction) was determined. The cost of radiotherapy per 5-year overall survival and local control was then estimated.

RESULTS: The estimated population 5-year local control and overall survival benefits of radiotherapy for all cancer were 23% and 6%, respectively. The optimal number of fractions per treatment course if guidelines were followed was 19.4 fractions. The average cost per fraction for all cancer was AU$276. The estimated cost of radiotherapy was AU$23,585 per 5-year local control and AU$86,480 per 5-year overall survival (equivalent to 5 life years) for all cancer.

CONCLUSION: The cost of AU$86,480 per 5-year overall survival would translate to AU$17,296 1-year overall survival. Therefore, the cost of radiotherapy is inexpensive if delivered optimally. Policy implications from this study include knowledge about cost to deliver radiotherapy to allow one to quantify the expected benefit at a population level.



Clinical Research

Aliment Pharmacol Ther. 2018 Oct;48(7):704-712
Randomised clinical trial: oral taurine supplementation versus placebo reduces muscle cramps in patients with chronic liver disease
Vidot H, Cvejic E, Carey S, Strasser S, McCaughan GW, Allman-Farinelli M, Shackel NA.

BACKGROUND: Painful muscle cramps occur in the majority of patients with cirrhosis impacting significantly on quality of life and sleep patterns. They are frequently unrecognised or overlooked. Current management is based on anecdotal evidence or case study reports.

AIM: To investigate the effect of oral taurine supplementation on frequency, duration, and intensity of muscle cramps in patients with chronic liver disease.

METHODS: Patients with chronic liver disease who experienced three or more muscle cramps/week were enrolled in a double-blinded, randomised control, crossover, taurine dose-variable study. Each participant received either taurine supplementation or placebo for 4 weeks then crossed to the alternative arm. Primary outcome data for frequency, duration, and intensity of muscle cramps was recorded by participants. Participants recorded frequency, duration, and location of muscle cramps. Biochemical parameters, including serum taurine and methionine levels, were measured at each time point. Linear mixed models were used to analyse outcomes.

RESULTS: Forty-nine patients were enrolled in the study and 30 patients completed the protocol. Participants who were unable to complete the protocol were not included in the final analysis due to the absence of outcome data. The mean age of participants was 54.7 years and 70% were males. Oral taurine supplementation increased serum taurine levels (P < 0.001). There were no adverse side effects associated with taurine supplementation. Participants receiving 2 g taurine/d experienced a reduction in cramp frequency (seven cramps fewer/fortnight, P = 0.03), duration (89 minutes less/fortnight P = 0.03), and severity (1.4 units less on a Likert scale P < 0.004) compared to placebo.

CONCLUSIONS: Oral supplementation with 2 g taurine/d results in a clinically significant reduction in the frequency, duration, and intensity of muscle cramps in patients with chronic liver disease. Taurine should be considered as a safe and effective intervention in the management of muscle cramps in individuals with chronic liver disease.

Epidemological / Health Services Research

J Hosp Med. 2018 May 30;13(5)
Use of short peripheral intravenous catheters: characteristics, management and outcomes worldwide
Alexandrou E, Ray-Barruel G, Carr PJ, Frost SA, Inwood S, Higgins N, Lin F, Alberto L, Mermel L, Rickard CM; OMG Study Group.

BACKGROUND: Peripheral intravenous catheter (PIVC) use in health care is common worldwide. Failure of PIVCs is also common, resulting in premature removal and replacement.

OBJECTIVE: To investigate the characteristics, management practices, and outcomes of PIVCs internationally.

SETTING/PATIENTS: Cross-sectional study. Hospitalized patients from rural, regional, and metropolitan areas internationally.

MEASUREMENTS: Hospital, device, and inserter characteristics were collected along with assessment of the catheter insertion site. PIVC use in different geographic regions was compared.

RESULTS: We reviewed 40,620 PIVCs in 51 countries. PIVCs were used primarily for intravenous medication (n = 28,571, 70%) and predominantly inserted in general wards (n = 22,167, 55%). Two-thirds of all devices were placed in non-recommended sites such as the hand, wrist, or antecubital veins. Nurses inserted most PIVCs (n = 28,575, 71%); although there was wide regional variation (26% to 97%). The prevalence of iIn this study, we found that many PIVCs were placed in areas of flexion, were symptomatic or idle, had suboptimal dressings, or lacked adequate documentation. This suggests inconsistency between recommended management guidelines for PIVCs and current practice.dle PIVCs was 14% (n = 5,796). Overall, 10% (n = 4,204) of PIVCs were painful to the patient or otherwise symptomatic of phlebitis; a further 10% (n = 3,879) had signs of PIVC malfunction; and 21% of PIVC dressings were suboptimal (n = 8,507). Over one-third of PIVCs (n = 14,787, 36%) had no documented daily site assessment and half (n = 19,768, 49%) had no documented date and time of insertion.

CONCLUSIONS: In this study, we found that many PIVCs were placed in areas of flexion, were symptomatic or idle, had suboptimal dressings, or lacked adequate documentation. This suggests inconsistency between recommended management guidelines for PIVCs and current practice.



Biomedical Research

Oncotarget. 2017 Sep 11;8(44):76722-76739
Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer
Pothula SP, Xu Z, Goldstein D, Merrett N, Pirola RC, Wilson JS, Apte MV.

ABSTRACT: Stromal-tumor interactions in pancreatic cancer (PC) impact on treatment outcomes. Pancreatic stellate cells (PSCs) produce the collagenous stroma of PC and interact with cancer cells to facilitate disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells. We studied the effects on PC progression of inhibiting the HGF/c-MET pathway in the presence and absence of a representative chemotherapeutic agent, gemcitabine. Using an orthotopic model of PC we have shown that "triple therapy" (inhibition of both HGF and c-MET combined with gemcitabine) resulted in the greatest reduction in tumor volume compared to each of the treatments alone or in dual combinations. Importantly, metastasis was virtually eliminated in mice receiving triple therapy. Our in vivo findings were supported by in vitro studies showing that the increase in cancer cell proliferation and migration in response to PSC secretions was significantly inhibited by the triple regimen. Our studies suggest that a combined approach, that targets tumor cells by chemotherapy while inhibiting specific pathways that mediate stromal-tumor interactions, may represent a novel therapeutic strategy to improve outcomes in PC.

Clinical Research

JAMA. 2017 Mar 14;317(10):1037-1046
Effect of Inpatient Rehabilitation vs a Monitored Home-Based Program on Mobility in Patients With Total Knee Arthroplasty: The HIHO Randomized Clinical Trial
Buhagiar MA, Naylor JM, Harris IA, Xuan W, Kohler F, Wright R, Fortunato R.

IMPORTANCE: Formal rehabilitation programs, including inpatient programs, are often assumed to optimize recovery among patients after undergoing total knee arthroplasty. However, these programs have not been compared with any outpatient or home-based programs.

OBJECTIVE: To determine whether 10 days of inpatient rehabilitation followed by a monitored home-based program after total knee arthroplasty provided greater improvements than a monitored home-based program alone in mobility, function, and quality of life.

Design, setting, and participants: DESIGN, SETTING AND PARTICIPANTS:  In this 2-group, parallel, randomized clinical trial, including a nonrandomized observational group, conducted at 2 public, high-volume arthroplasty hospitals in Sydney, Australia (July 2012-December 2015), 940 patients with osteoarthritis undergoing primary total knee arthroplasty were screened for eligibility. Of the 525 eligible patients consecutively invited to participate, 165 were randomized either to receive inpatient hospital rehabilitation and home-based rehabilitation or to receive home-based rehabilitation alone, and 87 patients enrolled in the observation group.

INTERVENTIONS: Eighty-one patients were randomized to receive 10 days of hospital inpatient rehabilitation followed by an 8-week clinician-monitored home-based program, 84 were randomized to receive the home-based program alone, and 87 agreed to be in the observational group, which included only the home-based program.

MAIN OUTCOMES AND MEASURES: Mobility at 26 weeks after surgery, measured with the 6-minute walk test. Secondary outcomes included the Oxford Knee Score, which ranges from 0 (worst) to 48 (best) and has a minimal clinically important difference of 5 points; and EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual analog scale, which ranges from 0 (worst) to 100 (best), and has a minimal clinically important difference of 23 points.

RESULTS: Among the 165 randomized participants, 68% were women, and the cohort had a mean age, 66.9 years (SD, 8.4 years). There was no significant difference in the 6-minute walk test between the inpatient rehabilitation and either of the 2 home program groups (mean difference, -1.01; 95% CI, -25.56 to 23.55), nor in patient-reported pain and function (knee score mean difference, 2.06; 95% CI, -0.59 to 4.71), or quality of life (EQ-5D visual analog scale mean difference, 1.41; 95% CI, -6.42 to 3.60). The number of postdischarge complications for the inpatient group was 12 vs 9 among the home group, and there were no adverse events reported that were a result of trial participation.

CONCLUSIONS AND RELEVANCE: Among adults undergoing uncomplicated total knee arthroplasty, the use of inpatient rehabilitation compared with a monitored home-based program did not improve mobility at 26 weeks after surgery. These findings do not support inpatient rehabilitation for this group of patients.

Epidemological / Health Services Research (Joint Recipient)

Lancet Infect Dis 2017; 17(7): 770-9
Post-migration follow-up of migrants identified to be at increased risk of developing tuberculosis at pre-migration screening: a systematic review and meta-analysis
Chan IHY, Kaushik N, Dobler CC.

BACKGROUND: Post-migration follow-up of migrants considered at increased risk of developing tuberculosis based on pre-migration screening abnormalities (high-risk migrants) is implemented in several low-incidence countries. We aimed to determine the rate of tuberculosis in this population to inform cross-border tuberculosis control policies.

METHODS: We searched MEDLINE and Embase (since inception to Jan 12, 2017) for studies evaluating post-migration follow-up of high-risk migrants. Outcomes evaluated were the number of tuberculosis cases occurring post-migration, expressed as the tuberculosis incidence per 100 000 person-years of follow-up, as cumulative incidence of tuberculosis per 100 000 persons, and the cumulative incidence of tuberculosis at the first post-migration follow-up visit. Random-effects models were used to summarise outcomes across studies.

FINDINGS: We identified 20 publications (describing 23 study cohorts) reporting the pre-migration screening outcomes of 8 355 030 migrants processed between Jan 1, 1981, and May 1, 2014, with 222 375 high-risk migrants identified. The pooled cumulative incidence of tuberculosis post-migration in our study population from 22 cohorts was 2794 per 100 000 persons (95% CI 2179-3409; I2=99%). The pooled cumulative incidence of tuberculosis at the first follow-up visit from ten cohorts was 3284 per 100 000 persons (95% CI 2173-4395; I2=99%). The pooled tuberculosis incidence from 15 cohorts was 1249 per 100 000 person-years of follow-up (95% CI 924-1574; I2=98%).

INTERPRETATION: The high rate of tuberculosis in high-risk migrants suggests that tuberculosis control measures in this population, including more sensitive pre-migration screening, preventive treatment of latent tuberculosis infection, or post-migration follow-up, are potentially effective cross-border tuberculosis control strategies in low-incidence countries.

Epidemological / Health Services Research (Joint Recipient)

Clin Oncol (R Coll Radiol). 2017 Feb;29(2):72-83
The Benefits of Providing External Beam Radiotherapy in Low- and Middle-income Countries
Yap ML, Hanna TP, Shafiq J, Ferlay J, Bray F, Delaney GP, Barton M.

ABSTRACT: More than half of all cancer diagnoses worldwide occur in low- and middle-income countries (LMICs) and the incidence is projected to rise substantially within the next 20 years. Radiotherapy is a vital, cost-effective treatment for cancer; yet there is currently a huge deficit in radiotherapy services within these countries. The aim of this study was to estimate the potential outcome benefits if external beam radiotherapy was provided to all patients requiring such treatment in LMICs, according to the current evidence-based guidelines. Projected estimates of these benefits were calculated to 2035, obtained by applying the previously published Collaboration for Cancer Outcomes, Research and Evaluation (CCORE) demand and outcome benefit estimates to cancer incidence and projection data from the GLOBOCAN 2012 data. The estimated optimal radiotherapy utilisation rate for all LMICs was 50%. There were about 4.0 million cancer patients in LMICs who required radiotherapy in 2012. This number is projected to increase by 78% by 2035, a far steeper increase than the 38% increase expected in high-income countries. National radiotherapy benefits varied widely, and were influenced by case mix. The 5 year population local control and survival benefits for all LMICs, if radiotherapy was delivered according to guidelines, were estimated to be 9.6% and 4.4%, respectively, compared with no radiotherapy use. This equates to about 1.3 million patients who would derive a local control benefit in 2035, whereas over 615 000 patients would derive a survival benefit if the demand for radiotherapy in LMICs was met. The potential outcome benefits were found to be higher in LMICs. These results further highlight the urgent need to reduce the gap between the supply of, and demand for, radiotherapy in LMICs. We must attempt to address this 'silent crisis' as a matter of priority and the approach must consider the complex societal challenges unique to LMICs.



Biomedical Research

Br J Cancer. 2016 Feb 2;114(3):269-80
Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer
Pothula SP, Xu Z, Goldstein D, Biankin AV, Pirola RC, Wilson JS, Apte MV.

BACKGROUND: Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c-MET pathway.

METHODS: Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs.

RESULTS: We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions.

CONCLUSIONS: Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.

Clinical Research

Lancet Infect Dis. 2016Sep;16(9):1045-51
Reassessment of the positive predictive value and specificity ofXpert MTB/RIF: a diagnostic accuracy study in the context of community-wide screening for tuberculosis
Ho J, Nguyen PT, Nguyen TA, Tran KH, Van Nguyen S, Nguyen NV, Nguyen HB, Luu KB, Fox GJ, Marks GB

BACKGROUND: Community-wide screening for tuberculosis with Xpert MTB/RIF as a primary screening tool overcomes some of the limitations of conventional screening. However, concerns exist about the low positive predictive value of this test in screening settings. We did a cross-sectional assessment of this diagnostic test to directly estimate the actual positive predictive value of Xpert MTB/RIF when used in the setting of community-wide screening for tuberculosis, and to draw an inference about the specificity of the test for tuberculosis detection.

METHODS: Field staff visited households in 60 randomly selected villages in Ca Mau province, Vietnam. We included people aged 15 years or older who provided written informed consent and were able to produce 0·5 mL or more of sputum, irrespective of reported symptoms. Participants were tested with Xpert MTB/RIF, then those with positive results had two further sputum samples tested for smear microscopy and culture, and underwent chest radiography at the provincial TB Health Center. The positive predictive value of Xpert MTB/RIF was compared against two reference standards for tuberculosis diagnosis-a positive sputum culture for Mycobacterium tuberculosis, and a positive sputum culture or a chest radiograph consistent with active pulmonary tuberculosis. We then calculated the specificity of Xpert MTB/RIF for tuberculosis detection on the basis of these positive predictive values and disease prevalence in this setting.

FINDINGS: 43 435 adults consented to screening with Xpert MTB/RIF. Sputum samples of 0·5 mL or greater were collected from 23 202 participants, producing 22 673 valid results. 169 participants had positive Xpert MTB/RIF results (0·39% of those screened and 0·75% of those with valid sputum results). The positive predictive value of Xpert MTB/RIF was 61·0% (95% CI 52·8-68·7) when compared against a positive sputum culture and 83·9% (76·8-89·2) when compared against a positive sputum culture or chest radiograph consistent with active tuberculosis. On the basis of these positive predictive values, the specificity of Xpert MTB/RIF was determined to be between 99·78% (95% CI 99·71-99·84) and 99·93% (99·88-99·96).

INTERPRETATION: The positive predictive value and specificity of Xpert MTB/RIF in the context of community-wide screening for tuberculosis is substantially higher than that predicted in previous studies. Our findings support the potential role of Xpert MTB/RIF as a primary screening tool to detect prevalent cases of tuberculosis in the community.

Epidemological / Health Services Research (Joint Recipient)

Eur Respir J. 2016 Feb;47(2):499-509 
Change in the manifestations of asthma and asthma-related traits in childhood: a latent transition analysis
Garden FL, Simpson JM, Mellis CM, Marks GB; CAPS Investigators.

ABSTRACT: It is known that asthma is a heterogeneous entity whose manifestations vary with age. Our objective was to examine changes in the manifestation of asthma and asthma-related traits in childhood by defining empirically derived childhood asthma phenotypes and examining their transitions over time.To define the phenotypes we used data on respiratory symptoms, healthcare utilisation, medications, spirometry, airway hyperresponsiveness (AHR), exhaled nitric oxide concentration and atopy from a birth cohort recruited on the basis of having a first-degree relative with asthma. Data were acquired at ages 1.5-11.5 years and analysed using latent transition analysis.In a study population of 370 participants, we classified subjects into four phenotypes: 1) nonatopic, few symptoms (prevalence range from 1.5 to 5 years: 52-60%), 2) atopic, few symptoms (3-21%), 3) nonatopic, asthma and rhinitis symptoms (13-35%), and 4) atopic, asthma and rhinitis symptoms (2-14%) in early childhood; and 1) nonatopic, no respiratory disease (prevalence range from 8 to 11.5 years: 41-46%), 2) atopic, no respiratory disease (23-33%), 3) nonatopic, asthma symptoms, no AHR or airway inflammation (8-12%) and 4) atopic asthma (19%) in mid-childhood. Transitioning between phenotypes was common in early childhood, but less common in later childhood.This analysis represents the first attempt to incorporate longitudinal patterns of several manifestations of asthma into a single model to simultaneously define phenotypes and examine their transitions over time. It provides quantitative support for the view that asthma is a heterogeneous entity, and that some children with wheeze and other respiratory symptoms in early life progress to asthma in mid-childhood, while others become asymptomatic.

Epidemological / Health Services Research (Joint Recipient)

Resuscitation.2016 Oct;107:47-56
Impact of a standardized rapid response system on outcomes in a large healthcare jurisdiction
Chen J, Ou L, Flabouris A, Hillman K, Bellomo R, Parr M.

AIM: To assess the impact of a standardized rapid response system (RRS) implemented across a large health care jurisdiction on reducing serious adverse events, hospital mortality and unexpected deaths.

METHOD: We conducted an interrupted time series (2007-2013) population-based study in the state of New South Wales (NSW), Australia to evaluate the impact of introducing a statewide standardized RRS (the between-the-flags [BTF] system) which employed a five-component intervention strategy. We studied 9,799,081 admissions in all 232 public hospitals in NSW. We studied changes in trends for annual rates of multiple key patient-centered outcomes before and after its introduction.

RESULTS: Before the BTF system (2007-2009), there was a progressive decrease in mortality, cardiac arrest rates, cardiac arrests related mortality, and failure to rescue rates, but no changes in mortality rate among low mortality diagnostic related group (LMDRGs) patients. After the BTF program (2010-2013), the same trends continued for all outcomes with an overall (2013 vs 2007) 46% reduction in cardiac arrest rates; a 54% reduction in cardiac arrest related mortality rates; a 19% reduction in hospital mortality; a 35% decrease in failure to rescue rates (all Ps<0.001) over seven-years. In addition, there was a new 20% (p<0.001) mortality reduction among LMDRG patients (2013 vs 2007).

CONCLUSIONS: The BTF program was associated with continued decrease in the overall cardiac arrests rates, deaths after cardiac arrest, hospital mortality and failure to rescue. In addition, among patients in the LMDRC group, it induced a new and significant post-intervention reduction in mortality which was never reported before.



Biomedical Research

Alcohol Clin Exp Res. 2015 Nov;39(11):2123-33
Alcohol and cigarette smoke components activate human pancreatic stellate cells: implications for the progression of chronic pancreatitis
Lee AT, Xu Z, Pothula SP, Patel MB, Pirola RC, Wilson JS, Apte MV.

BACKGROUND: Chronic pancreatitis, a known complication of alcohol abuse, is characterized histopathologically by prominent fibrosis. Pancreatic stellate cells (PSCs) are responsible for producing this fibrous tissue in chronic pancreatitis and are activated by alcohol. Progression of alcoholic chronic pancreatitis (as assessed by calcification and fibrosis) is thought to be facilitated by concurrent smoking, but the mechanisms are unknown. This study aimed to (a) determine whether human PSCs (hPSCs) and rat PSCs express nicotinic acetylcholine receptors (nAChRs), which are known to bind 2 important components of cigarette smoke, namely nicotine and nicotine-derived nitrosamine ketone (NNK), and (b) examine the effects of cigarette smoke components in the presence and absence of alcohol on PSC activation in vitro.

METHODS: Western blotting was used to detect the presence of nAChRs in primary cultures of PSCs. Clinically relevant concentrations of cigarette smoke components (either cigarette smoke extract [CSE], NNK, or nicotine) ± ethanol (EtOH) were used to treat primary cultures of PSCs, and stellate cell activation was assessed by cell migration, proliferation, collagen production, and apoptosis.

RESULTS: We demonstrate, for the first time, that PSCs express nAChRs (isoforms α3, α7, β, ε) and that the expression of the α7 isoform in hPSCs is induced by CSE + EtOH. We also provide novel findings that PSCs are activated by CSE and NNK (both alone and in combination with EtOH) as evidenced by an increase in cell migration and/or proliferation. Further, we demonstrate that activation of PSCs by CSE + EtOH and NNK + EtOH may be mediated via nAChRs on the cells.

CONCLUSIONS: PSCs are activated by clinically relevant concentrations of cigarette smoke components (CSE and NNK), alone and in combination with EtOH. Thus, in alcoholics who smoke, progression of pancreatic fibrosis may be facilitated by the combined effects of alcohol and cigarette smoke components on hPSC behavior.

Clinical Research

Int J Radiat Oncol Biol Phys. 2015 Jun 1;92(2):268-76
Subclinical cardiac dysfunction detected by strain imaging during breast irradiation with persistent changes 6 weeks after treatment
Lo Q, Hee L, Batumalai V, Allman C, MacDonald P, Delaney GP, Lonergan D, Thomas L.

PURPOSE: To evaluate 2-dimensional strain imaging (SI) for the detection of subclinical myocardial dysfunction during and after radiation therapy (RT).

METHODS AND MATERIALS: Forty women with left-sided breast cancer, undergoing only adjuvant RT to the left chest, were prospectively recruited. Standard echocardiography and SI were performed at baseline, during RT, and 6 weeks after RT. Strain (S) and strain rate (Sr) parameters were measured in the longitudinal, circumferential, and radial planes. Correlation of change in global longitudinal strain (GLS % and Δ change) and the volume of heart receiving 30 Gy (V30) and mean heart dose (MHD) were examined.

RESULTS: Left ventricular ejection fraction was unchanged; however, longitudinal systolic S and Sr and radial S were significantly reduced during RT and remained reduced at 6 weeks after treatment [longitudinal S (%) -20.44 ± 2.66 baseline vs -18.60 ± 2.70* during RT vs -18.34 ± 2.86* at 6 weeks after RT; longitudinal Sr (s(-1)) -1.19 ± 0.21 vs -1.06 ± 0.18* vs -1.06 ± 0.16*; radial S (%) 56.66 ± 18.57 vs 46.93 ± 14.56* vs 49.22 ± 15.81*; *P<.05 vs baseline]. Diastolic Sr were only reduced 6 weeks after RT [longitudinal E Sr (s(-1)) 1.47 ± 0.32 vs 1.29 ± 0.27*; longitudinal A Sr (s(-1)) 1.19 ± 0.31 vs 1.03 ± 0.24*; *P<.05 vs baseline], whereas circumferential strain was preserved throughout. A modest correlation between S and Sr and V30 and MHD was observed (GLS Δ change and V30 ρ = 0.314, P=.05; GLS % change and V30 ρ = 0.288, P=.076; GLS Δ change and MHD ρ = 0.348, P=.03; GLS % change and MHD ρ = 0.346, P=.031).

CONCLUSIONS: Subclinical myocardial dysfunction was detected by 2-dimensional SI during RT, with changes persisting 6 weeks after treatment, though long-term effects remain unknown. Additionally, a modest correlation between strain reduction and radiation dose was observed.

Epidemological / Health Services Research

Lancet Oncol. 2015Sep;16(10):1153-86
Expanding global access to radiotherapy
Atun R, Jaffray DA, Barton MB, Bray F, Baumann M, Vikram B, Hanna TP, Knaul FM, Lievens Y, Lui TY, Milosevic M, O'Sullivan B, Rodin DL, Rosenblatt E, Van Dyk J, Yap ML, Zubizarreta E, Gospodarowicz M.

ABSTRACT: Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015-35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015-35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries-a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015-35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015-35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015-35 (-$14·9 billion in low-income countries; -$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (-$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.



Biomedical Research

Carcinogenesis. 2014Aug;35(8):1891-900
The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: antiangiogenic implications in pancreatic cancer
Patel MB, Pothula SP, Xu Z, Lee AK, Goldstein D, Pirola RC, Apte MV, Wilson JS.

ABSTRACT: Activated cancer-associated human pancreatic stellate cells (CAhPSCs, which produce the collagenous stroma of pancreatic cancer [PC]) are known to play a major role in PC progression. Apart from inducing cancer cell proliferation and migration, CAhPSCs have also been implicated in neoangiogenesis in PC. However, the mechanisms mediating the observed angiogenic effects of CAhPSCs are unknown. A candidate pathway that may be involved in this process is the hepatocyte growth factor (HGF)/c-MET pathway and its helper molecule, urokinase-type plasminogen activator (uPA). This study investigated the effects of CAhPSC secretions on endothelial cell function in the presence and absence of HGF, c-MET and uPA inhibitors. HGF levels in CAhPSC secretions were quantified using ELISA. CAhPSC secretions were then incubated with human microvascular endothelial cells (HMEC-1) and angiogenesis assessed by quantifying HMEC-1 tube formation and proliferation. CAhPSC-secreted HGF significantly increased HMEC-1 tube formation and proliferation; notably, these effects were downregulated by inhibition of HGF, its receptor c-MET and uPA. Phosphorylation of p38 mitogen-activated protein kinase was downregulated during inhibition of the HGF/c-MET pathway, whereas phosphatidylinositol-3 kinase and ERK1/2 remained unaffected. Our studies have shown for the first time that CAhPSCs induce proliferation and tube formation of HMEC-1 and that the HGF/c-MET pathway plays a major role in this induction. Given that standard antiangiogenic treatment targeting vascular endothelial growth factor has had limited success in the clinical setting, the findings of the current study provide strong support for a novel, alternative antiangiogenic approach targeting the HGF/c-MET and uPA pathways in PC.

Clinical Research

J Crohns Colitis. 2014 Oct 1;8(10):1237-45
Prospective validation study of the International Classification of Functioning, Disability and Health score in Crohn's disease and ulcerative colitis
Leong RW, Huang T, Ko Y, Jeon A, Chang J, Kohler F, Kariyawasam V.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) may result in disability. We aim to validate a novel scoring system for the IBD disability index (IBD-DI), and identify predictors of disability and its correlation with work absenteeism.

METHODS: This prospective IBD ambulatory clinic cohort study measured IBD-DI, Crohn's Disease Activity Index (CDAI) for Crohn's disease (CD) or partial Mayo score (pMayo) for ulcerative colitis (UC), IBDQ quality-of-life, and Work Productivity and Activity Impairment. Negative IBD-DI represented greater disability. Validation tests were performed and predictors and extent of work absenteeism were determined.

RESULTS: 166 consecutive subjects were recruited (75 CD, 41 UC, 50 controls). IBD-DI correlated with CDAI (r=-0.77, P<0.001), pMayo (r=-0.82, P<0.001) and IBDQ (r=0.86, P<0.001). IBD-DI differentiated CD, and UC from controls (medians -7, -4, +10; P<0.001) with a score of >3.5 identifying controls with 94% sensitivity and 83% specificity (area-under-curve 0.92). Stable patients had unchanged IBD-DI (P=ns) but not in those who relapsed (P<0.001). Intraclass correlation was 0.89 and Cronbach's alpha of internal consistency was 0.94. Diagnosis age, sex, phenotype, perianal disease, prior surgery, steroid-use and disease duration did not influence the IBD-DI but active use of biological agents significantly reduced disability (P=0.03). 21.6% of IBD patients had moderate-severe disability equating to missing >25% of work hours in the previous week. Multivariate analysis identified that only IBD-DI to be predictive of unemployment status (OR: 0.94; 95% CI: 0.89-0.99).

CONCLUSIONS: The IBD-DI is a valid tool measuring disability in both CD and UC and correlates with workforce participation. It is a potential useful tool in the assessment of participation restriction and activity limitation.

Epidemological / Health Services Research

Radiother Oncol. 2014 Jul;112(1):140-4
Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012
Barton MB, Jacob S, Shafiq J, Wong K, Thompson SR, Hanna TP, Delaney GP. 

BACKGROUND AND PURPOSE: In 2003 we estimated that 52.3% of new cases of cancer in Australia had an indication for external beam radiotherapy at least once at some time during the course of their illness. This update reviews the contemporary evidence to define the optimal proportion of new cancers that would benefit from radiotherapy as part of their treatment and estimates the changes to the optimal radiotherapy utilisation rate from 2003 to 2012.

MATERIALS AND METHOD: National and international guidelines were reviewed for external beam radiotherapy indications in the management of cancers. Epidemiological data on the proportion of new cases of cancer with each indication for radiotherapy were identified. Indications and epidemiological data were merged to develop an optimal radiotherapy utilisation tree. Univariate and Monte Carlo simulations were used in sensitivity analysis.

RESULTS: The overall optimal radiotherapy utilisation rate (external beam radiotherapy) for all registered cancers in Australia changed from 52.3% in 2003 to 48.3% in 2012. Overall 8.9% of all cancer patients in Australia have at least one indication for concurrent chemo-radiotherapy during the course of their illness.

CONCLUSIONS: The reduction in the radiotherapy utilisation rate was due to changes in epidemiological data, changes to radiotherapy indications and refinements of the model structure.



Biomedical Research

J Immunol. 2013 Aug 1;191(3):1404-12. doi: 10.4049/jimmunol.1300856. Epub 2013 Jun 24.
Mast cell-restricted, tetramer-forming tryptases induce aggrecanolysis in articular cartilage by activating matrix metalloproteinase-3 and -13 zymogens.
Magarinos NJ, Bryant KJ, Fosang AJ, Adachi R, Stevens RL, McNeil HP.

ABSTRACT: Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-β mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-β, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-β was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN↓FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP-6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-β was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13, which are constitutively present in articular cartilage.

Clinical Research

Int J Cardiol. 2013 Aug 20;167(4):1276-81. doi: 10.1016/j.ijcard.2012.03.162. Epub 2012 May 4.
Risk factor modification in diabetic patients following angiographic identification of multi-vessel disease.
Hee L, Thomas L, Ang X, Yang L, Lo S, Juergens CP, Mussap CJ, Dignan R, French JK.

ABSTRACT: There is little information on whether identification of multi-vessel disease (MVD) in patients with diabetic mellitus (DM) affects risk factor management. From 1125 consecutively screened patients between June 2006 and March 2010, we examined 227 diabetic patients with MVD on coronary angiography. Diabetic control and cholesterol levels were assessed by glycated haemoglobin (HbA1c) and total cholesterol (TC) respectively which were evaluated at baseline and at 1-year follow-up. Patients were grouped by age into <55(n=33), 55-65(n=75), 66-75(n=75) and >75(n=44). Target levels were defined as HbA1c<7% and TC<4.0 mmol/L. Patients <55 years had the highest HbA1c at 9.1[7.6-11.2]% with the lowest proportion of patients (n=3; 11.1%) within target at baseline, while 66-75 years had the best HbA1c at 7.1[6.4-7.8]% with the highest proportion (n=28, 45.2%) reaching target (p<0.0001). At 1-year, the poorest HbA1c control was again observed in the age <55 with fewer patients achieving target compared to the 66-75 age group (HbA1c: 8.5% vs 6.9%; % of patients at target: 20.7% vs 54.5%; p<0.0001). Furthermore, the group <55 years demonstrated the worst TC control at 1-year with a significant increase compared to the baseline TC (p=0.01). Patients with a lower body mass index (BMI) were likely to have an improvement in HbA1c and reach target (p=0.01). Paradoxically, patients who were current smokers demonstrated a beneficial effect on optimal TC control (29.2% vs 15.4%, p=0.027). In younger diabetic patients, risk factor modification at 1-year was poor despite identification of MVD. Developing an effective education and monitoring programme to improve glycaemic control in this high risk group should be a priority.

Epidemological / Health Services Research

Psycho-Oncology. 2013 Jul;22(7):1557-64. doi: 10.1002/pon.3166. Epub 2012 Sep 3.
Some things change, some things stay the same: a longitudinal analysis of cancer caregivers' unmet supportive care needs.
Girgis A, Lambert SD, McElduff P, Bonevski B, Lecathelinais C, Boyes A, Stacey F.

OBJECTIVE: The objective of this study was to identify caregivers' unmet needs and the psychosocial variables associated with unmet need count within the first 24 months post-survivor diagnosis.

METHODS: Caregivers completed a comprehensive survey measuring the primary outcome, psychosocial variables, and demographics of interest at 6 (n=547), 12 (n=519), and 24 (n=443) months post-survivor diagnosis.

RESULTS: Although prevalence of unmet needs significantly decreased over time, almost a third of caregivers still reported unmet needs at 24 months. Unmet needs were more prevalent among caregivers of lung cancer survivors, at 6 and 24 months. Top ranking unmet needs across time included 'managing concerns about cancer coming back', 'reducing stress in the person with cancer's life', 'understanding the experience of the person with cancer', and 'accessible hospital parking'. At 24 months, some of the top ranking unmet needs were related to caregivers' well-being and relationships. Increased interference in activities due to caregiving, anxiety, depression, avoidant and active coping, and out-of-pocket expenses was associated with reporting more unmet needs. Less involvement in caregiving roles and increased physical well-being and social support were associated with reporting less unmet needs. For some variables (e.g. anxiety and depression), association with unmet needs strengthened over time.

CONCLUSIONS: This is the first longitudinal analysis of caregivers' unmet needs as they enter early and extended survivorship. Findings provide valuable insights into caregiver's unmet needs over time and identified a sub-group of caregivers at risk of experiencing unmet needs, extending previous research and informing the timing and content of psychosocial services.



Biomedical / Clinical Research (Joint Recipient)

Am Heart J. 2012 Apr;163(4):649-56.e1. doi: 10.1016/j.ahj.2012.01.014.
Safety and efficacy of rescue angioplasty for ST-elevation myocardial infarction with high utilization rates of glycoprotein IIb/IIIa inhibitors.
Shugman IM, Hsieh V, Cheng S, Parikh D, Tobing D, Wouters N, van der Vijver R, Lo Q, Rajaratnam R, Hopkins AP, Lo S, Leung D, Juergens CP, French JK.

BACKGROUND: Fibrinolytic therapies remain widely used for ST-elevation myocardial infarction, and for "failed reperfusion," rescue percutaneous coronary intervention (PCI) is guideline recommended to improve outcomes. However, these recommendations are based on data from an earlier era of pharmacotherapy and procedural techniques.

METHODS AND RESULTS: To determine factors affecting prognosis after rescue PCI, we studied 241 consecutive patients (median age 55 years, interquartile range [IQR] 48-65) undergoing procedures between 2001 and 2009 (53% anterior ST-elevation myocardial infarction and 78% transferred). The median treatment-related times were 1.2 hours (IQR 0.8-2.2) from symptom onset to door, 2 hours (IQR 1.3-3.2) from symptom onset to fibrinolysis (93% tenecteplase), and 3.9 hours (IQR 3.1-5.2) from fibrinolysis to balloon. Procedural characteristics were stent deployment in 95% (11.6% drug eluting) and 78% glycoprotein IIb/IIIa inhibitor use, and Thrombolysis In Myocardial Infarction (TIMI) 3 flow rates pre-PCI and post-PCI were 41% and 91%, respectively (P < .001). At 30 days, TIMI major bleeding occurred in 16 (6.6%) patients, and 23 (9.5%) patients received transfusions; nonfatal stroke occurred in 4 (1.7%) patients (2 hemorrhagic). Predictors of TIMI major bleeding were female gender (odds ratio 3.194, 95% CI 1.063-9.597; P = .039) and pre-PCI shock (odds ratio 3.619, 95% CI,1.073-12.207; P = .038). Mortality at 30 days was 6.2%, and 3.2% in patients without pre-PCI shock. One-year mortality was 8.2% (5.3% in patients without pre-PCI cardiogenic shock), 5.2% had reinfarction, and the target vessel revascularization rate was 6.4% (2.6% in arteries ≥ 3.5 mm in diameter). Pre-PCI shock, female gender, and post-PCI TIMI flow grades ≤ 2 were significant predictors of 1-year mortality on multivariable regression modeling, but TIMI major bleeding was not.

CONCLUSIONS: Rescue PCI with contemporary treatments can achieve mortality rates similar to rates for contemporary primary PCI in patients without pre-PCI shock. Whether rates of bleeding can be reduced by different pharmacotherapies and interventional techniques needs clarification in future studies.

Biomedical / Clinical Research (Joint Recipient)

Stroke. 2012 Aug;43(8):2097-101. doi: 10.1161/STROKEAHA.112.659888. Epub 2012 May 22.
Clinical significance of impaired cerebrovascular autoregulation after severe aneurysmal subarachnoid hemorrhage.
Jaeger M, Soehle M, Schuhmann MU, Meixensberger J.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the relationship between cerebrovascular autoregulation and outcome after aneurysmal subarachnoid hemorrhage.

METHODS: In a prospective observational study, 80 patients after severe subarachnoid hemorrhage were continuously monitored for cerebral perfusion pressure and partial pressure of brain tissue oxygen for an average of 7.9 days (range, 1.9-14.9 days). Autoregulation was assessed using the index of brain tissue oxygen pressure reactivity (ORx), a moving correlation coefficient between cerebral perfusion pressure and partial pressure of brain tissue oxygen. High ORx indicates impaired autoregulation; low ORx signifies intact autoregulation. Outcome was determined at 6 months and dichotomized into favorable (Glasgow Outcome Scale 4-5) and unfavorable outcome (Glasgow Outcome Scale 1-3).

RESULTS: Twenty-four patients had a favorable and 56 an unfavorable outcome. In a univariate analysis, there were significant differences in autoregulation (ORx 0.19±0.10 versus 0.37±0.11, P<0.001, for favorable versus unfavorable outcome, respectively), age (44.1±11.0 years versus 54.2±12.1 years, P=0.001), occurrence of delayed cerebral infarction (8% versus 46%, P<0.001), use of coiling (25% versus 54%, P=0.02), partial pressure of brain tissue oxygen (24.9±6.6 mm Hg versus 21.8±6.3 mm Hg, P=0.048), and Fisher grade (P=0.03). In a multivariate analysis, ORx (P<0.001) and age (P=0.003) retained an independent predictive value for outcome. ORx correlated with Glasgow Outcome Scale (r=-0.70, P<0.001).

CONCLUSIONS: The status of cerebrovascular autoregulation might be an important pathophysiological factor in the disease process after subarachnoid hemorrhage, because impaired autoregulation was independently associated with an unfavorable outcome.

Epidemiological / Health Services Research

Ann Behav Med. 2012 Oct;44(2):225-35. doi: 10.1007/s12160-012-9385-2.
Distressed partners and caregivers do not recover easily: adjustment trajectories among partners and caregivers of cancer survivors.
Lambert SD, Jones BL, Girgis A, Lecathelinais C.

BACKGROUND: Although a number of cross-sectional studies document the distress experienced by partners and caregivers of cancer survivors, few have considered their potential differential patterns of adjustment over time.

PURPOSE: Identify distinct trajectories of anxiety and depression among partners and caregivers of cancer survivors and predictors of these trajectories.

METHODS: Participants completed a survey to examine the impact of caring for, or living with, a cancer survivor at 6, 12, and 24 months post-survivor diagnosis. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (N(anxiety) = 510; N(depression) = 511).

RESULTS: Anxiety trajectories included: no anxiety (15.1% scored <3; 37.8% scored 3-5); chronic, borderline anxiety (33.2%); and chronic, clinical anxiety (13.9%). The depression trajectories were: no depression (38.9% scored <2; 31.5% scored around 3); a sustained score of 7 (25.5%); and chronic, clinical depression (4.1%). Variables associated with the trajectories included most of the psychosocial variables.

CONCLUSIONS: Findings highlight that most caregivers maintained their baseline level of distress, which is particularly concerning for participants reporting chronic anxiety or depression.



Biomedical / Clinical Research

JACC: Cardiovascular Imaging. 2011 Mar; 4:234-242.
Atrial dilation and altered function are mediated by age and diastolic function but do not occur before the eighth decade.
Boyd AC, Schiller NB, Leung DY, Ross DL, Thomas L.

OBJECTIVES: This study investigated changes in left atrial (LA) volumes and phasic atrial function, by deciles, with normal aging.

BACKGROUND: LA volume increase is a sensitive independent marker for cardiovascular disease and adverse outcomes. To use this variable more effectively as a marker of pathology and a gauge of outcome, physiological changes due to aging alone need to be quantitated.

METHODS: A detailed transthoracic echocardiogram was performed in 220 normal subjects; 89 (41%) were male and their age ranged from 20 to 80 years (mean 45 ± 17 years). Maximum (end-ventricular systole), minimum (end-ventricular diastole), and pre-a-wave volumes were measured using the biplane method of disks. LA filling, passive emptying, conduit and active emptying volumes, and fractions were calculated. Transmitral inflow, pulmonary vein flow, and pulsed-wave Doppler tissue imaging parameters were measured as expressions of left ventricular diastolic function. For purposes of analysis, subjects were divided by age deciles.

RESULTS: LA indexed maximum (0.05 ml/m(2) per year) and minimum (0.06 ml/m(2) per year) volume increased with age but only became significant in the eighth decade (26.0 ± 6.3 ml/m(2), p = 0.02, and 13.5 ± 3.9 ml/m(2), respectively; p < 0.001). Impaired left ventricular diastolic relaxation was apparent in decade 6 and was associated with a shift in phasic LA volumes so that LA expansion index and passive emptying decreased with increasing age, whereas active emptying volume increased.

CONCLUSIONS: In normal healthy subjects, LA indexed volumes remain nearly stable until the eighth decade when they increase significantly. Therefore, an increase in LA size that occurs before the eighth decade is likely to represent a pathological change. Changes in phasic atrial volumes develop earlier consequent to age-related alteration in LV diastolic relaxation.

Epidemiological / Health Services Research

Cancer 2011:117:5112-‐5120.
Do multidisciplinary teams make a difference in the management of lung cancer?
Boxer MM, Vinod SK, Shafiq J and Duggan KJ.

BACKGROUND: There is limited evidence regarding the effectiveness of multidisciplinary team (MDT) meetings in lung cancer. The objective of this study was to compare the patterns of care for patients with newly diagnosed lung cancer who were presented at a lung cancer MDT meeting with the patterns of care for patients who were not presented.

METHODS: All patients who had lung cancer newly diagnosed in South West Sydney (SWS) between December 1, 2005, and December 31, 2008, were identified from the local Clinical Cancer Registry. Patient and tumor characteristics and treatment receipt were compared between patients who were and were not presented at MDT meetings. A logistic regression model was constructed to determine predictors for receiving treatment and survival.

RESULTS: In total, there were 988 patients, including 504 patients who were presented at MDT meetings and 484 who were not presented at MDT meetings. The median patient age was 69 years and 73 years in the MDT group and the non-MDT group, respectively (P < .01). There was no pathologic diagnosis for 13% of non-MDT patients compared with 4% of MDT patients (P < .01). Treatment receipt for MDT patients versus non-MDT patients was 12% versus 13%, respectively, for surgery (P value nonsignificant); 66% versus 33%, respectively, for radiotherapy (P < .001); 46% versus 29%, respectively, for chemotherapy (P < .001); and 66% versus 53%, respectively, for palliative care (P < .001). In patients with good performance status, the MDT group had significantly better receipt of radiotherapy among patients with stage I through IV nonsmall cell lung cancer (NSCLC) and had significantly better receipt of chemotherapy among patients with stage IV NSCLC. MDT discussion was an independent predictor of receiving radiotherapy, chemotherapy, and referral to palliative care but did not influence survival.

CONCLUSIONS: MDT discussion was associated with better treatment receipt, which potentially may improve quality of life for patients with lung cancer. However, it did not improve survival.

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